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Tsou PS, Ali RA, Lu C, Sule G, Carmona-Rivera C, Lucotti S, Ikari Y, Wu Q, Campbell PL, Gurrea-Rubio M, Maeda K, Fox SE, Brodie WD, Mattichak MN, Foster C, Tambralli A, Yalavarthi S, Amin MA, Kmetova K, Fonseca BM, Chong E, Zuo Y, Maile MD, Imberti L, Caruso A, Caccuri F, Quaresima V, Sottini A, Kuhns DB, Fink D, Castagnoli R, Delmonte OM, Kenney H, Zhang Y, Magliocco M, Su H, Notarangelo L, Zemans RL, Mao-Draayer Y, Matei IR, Salvatore M, Lyden D, Kanthi Y, Kaplan MJ, Knight JS, Fox DA. Soluble CD13 is a potential mediator of neutrophil-induced thrombogenic inflammation in SARS-CoV-2 infection. JCI Insight 2025; 10:e184975. [PMID: 40168094 DOI: 10.1172/jci.insight.184975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Accepted: 03/27/2025] [Indexed: 04/03/2025] Open
Abstract
The soluble variant of the ectopeptidase CD13 (sCD13), released from the cell surface by matrix metalloproteinase 14 (MMP14), is a potent pro-inflammatory mediator, displaying chemotactic, angiogenic, and arthritogenic properties through bradykinin receptor B1 (B1R). We revealed a link between sCD13 and amplified neutrophil-mediated inflammatory responses in SARS-CoV-2 infection. sCD13 was markedly elevated in patients with COVID-19 and correlated with disease severity and variants, ethnicity, inflammation markers, and neutrophil extracellular trap formation (NETosis). Neutrophils treated with sCD13 showed heightened NETosis and chemotaxis, which were inhibited by sCD13 receptor blockade. Meanwhile sCD13 did not induce platelet aggregation. Single-cell analysis of COVID-19 lungs revealed coexpression of CD13 and MMP14 by various cell types, and higher CD13 expression compared with controls. Neutrophils with high CD13 mRNA were enriched for genes associated with immaturity, though CD13 protein expression was lower. Histological examination of COVID-19 lungs revealed CD13-positive leukocytes trapped in vessels with fibrin thrombi. Flow cytometry verified the presence of B1R and a second sCD13 receptor, protease-activated receptor 4, on monocytes and neutrophils. These findings identify sCD13 as a potential instigator of COVID-19-associated NETosis, potentiating vascular stress and thromboembolic complications. The potent pro-inflammatory effects of sCD13 may contribute to severe COVID-19, suggesting that sCD13 and its receptors might be therapeutic targets.
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Affiliation(s)
- Pei-Suen Tsou
- Division of Rheumatology, Department of Internal Medicine, and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, Michigan, USA
| | - Ramadan A Ali
- Division of Rheumatology, Department of Internal Medicine, and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, Michigan, USA
| | - Chenyang Lu
- Division of Rheumatology, Department of Internal Medicine, the Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Gautam Sule
- Division of Rheumatology, Department of Internal Medicine, and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, Michigan, USA
| | - Carmelo Carmona-Rivera
- Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland, USA
| | - Serena Lucotti
- Department of Pediatrics, Weill Cornell Medical College, New York, New York, USA
| | - Yuzo Ikari
- Division of Rheumatology, Department of Internal Medicine, and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, Michigan, USA
| | - Qi Wu
- Division of Rheumatology, Department of Internal Medicine, and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, Michigan, USA
| | - Phillip L Campbell
- Division of Rheumatology, Department of Internal Medicine, and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, Michigan, USA
| | - Mikel Gurrea-Rubio
- Division of Rheumatology, Department of Internal Medicine, and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, Michigan, USA
| | - Kohei Maeda
- Division of Rheumatology, Department of Internal Medicine, and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, Michigan, USA
| | - Sharon E Fox
- Department of Pathology, Louisiana State University, Health Sciences Center, New Orleans, Louisiana, USA
| | - William D Brodie
- Division of Rheumatology, Department of Internal Medicine, and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, Michigan, USA
| | - Megan N Mattichak
- Division of Rheumatology, Department of Internal Medicine, and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, Michigan, USA
| | - Caroline Foster
- Division of Rheumatology, Department of Internal Medicine, and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, Michigan, USA
| | - Ajay Tambralli
- Division of Rheumatology, Department of Internal Medicine, and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, Michigan, USA
| | - Srilakshmi Yalavarthi
- Division of Rheumatology, Department of Internal Medicine, and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, Michigan, USA
| | - M Asif Amin
- Division of Rheumatology, Department of Internal Medicine, and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, Michigan, USA
| | - Katarina Kmetova
- Division of Rheumatology, Department of Internal Medicine, and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, Michigan, USA
| | - Bruna Mazetto Fonseca
- Division of Rheumatology, Department of Internal Medicine, and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, Michigan, USA
- School of Medical Science, University of Campinas (UNICAMP), Campinas, Brazil
| | - Emily Chong
- Division of Rheumatology, Department of Internal Medicine, and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, Michigan, USA
| | - Yu Zuo
- Division of Rheumatology, Department of Internal Medicine, and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, Michigan, USA
| | - Michael D Maile
- Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan, USA
| | - Luisa Imberti
- Section of Microbiology, University of Brescia, Brescia, Italy
| | - Arnaldo Caruso
- Section of Microbiology, University of Brescia, Brescia, Italy
| | | | - Virginia Quaresima
- Clinical Chemistry Laboratory, ASST Spedali Civili of Brescia, Brescia, Italy
| | - Alessandra Sottini
- Clinical Chemistry Laboratory, ASST Spedali Civili of Brescia, Brescia, Italy
| | - Douglas B Kuhns
- Leidos Biomedical Research, Inc.; Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA
| | - Danielle Fink
- Leidos Biomedical Research, Inc.; Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA
| | - Riccardo Castagnoli
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA
| | - Ottavia M Delmonte
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA
| | - Heather Kenney
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA
| | - Yu Zhang
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA
| | - Mary Magliocco
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA
| | - Helen Su
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA
| | - Luigi Notarangelo
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA
| | - Rachel L Zemans
- Division of Pulmonary & Critical Care Medicine, Department of Internal Medicine; and Program in Cellular and Molecular Biology, School of Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Yang Mao-Draayer
- Multiple Sclerosis Center of Excellence, Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation (OMRF), Oklahoma City, Oklahoma, USA
| | - Irina R Matei
- Department of Pediatrics, Weill Cornell Medical College, New York, New York, USA
| | - Mirella Salvatore
- Joan and Sanford I. Weill Department of Medicine and Department of Population Health Sciences, Weill Cornell Medical College, New York, New York, USA
| | - David Lyden
- Department of Pediatrics, Weill Cornell Medical College, New York, New York, USA
| | - Yogendra Kanthi
- Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA
| | - Mariana J Kaplan
- Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland, USA
| | - Jason S Knight
- Division of Rheumatology, Department of Internal Medicine, and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, Michigan, USA
| | - David A Fox
- Division of Rheumatology, Department of Internal Medicine, and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, Michigan, USA
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Chaichan W, Chuamanochan M, Mahanupab P, Chiewchanvit S, Tovanabutra N. Chilblain-like lesion associated with coronavirus disease 2019 vaccine in tropical country: a case report. J Med Case Rep 2025; 19:213. [PMID: 40336095 PMCID: PMC12057029 DOI: 10.1186/s13256-025-05254-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 03/28/2025] [Indexed: 05/09/2025] Open
Abstract
BACKGROUND Chilblains have emerged as a cutaneous manifestation following coronavirus disease 2019 vaccination. While there are many case reports on chilblain-like lesions, documentation from tropical countries remains limited. In this context, we report a case detailing chilblain-like lesions associated with coronavirus disease 2019 vaccination in Thailand. CASE PRESENTATION A 35-year-old Thai female patient presented with several painful, red papules on the fingers and toes 9 days after receiving the mRNA-1273 vaccination. Skin biopsy was performed, and the results were consistent with chilblains. Laboratory workup revealed positive result for lupus anticoagulant. The rash completely resolved without any treatment but reappeared following the second vaccine dose. CONCLUSION Chilblain-like lesion following coronavirus disease 2019 vaccination is frequently observed in temperate countries, with few reports from tropical areas. The presence of lupus anticoagulant may contribute to the development of chilblains after coronavirus disease 2019 vaccination.
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Affiliation(s)
- Wasuchon Chaichan
- Division of Dermatology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, 110 Intavarorot Road, Sriphum District, Maung, Chiang Mai, 50200, Thailand
| | - Mati Chuamanochan
- Division of Dermatology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, 110 Intavarorot Road, Sriphum District, Maung, Chiang Mai, 50200, Thailand
| | - Pongsak Mahanupab
- Department of Pathology, Faculty of Medicine, Chiang Mai University, 110 Inravarorot Road, Sriphum District, Maung, Chiang Mai, 50200, Thailand
| | - Siri Chiewchanvit
- Division of Dermatology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, 110 Intavarorot Road, Sriphum District, Maung, Chiang Mai, 50200, Thailand
| | - Napatra Tovanabutra
- Division of Dermatology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, 110 Intavarorot Road, Sriphum District, Maung, Chiang Mai, 50200, Thailand.
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Adiguzel Y, Bogdanos DP, Shoenfeld Y. Molecular/antigenic mimicry and immunological cross-reactivity explains SARS-CoV-2-induced autoimmunity. Autoimmun Rev 2025; 24:103811. [PMID: 40209971 DOI: 10.1016/j.autrev.2025.103811] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2025] [Revised: 03/07/2025] [Accepted: 03/11/2025] [Indexed: 04/12/2025]
Abstract
COVID-19 pandemic is over, but its effects on chronic illnesses remain a challenging issue. Understanding the influence of SARS-COV-2-mediated autoimmunity and overt autoimmune disease is of paramount importance, as it can provide a critical mass of information regarding both infection-mediated (and vaccination-induced) autoimmune phenomena in susceptible individuals during the disease course, and short or long-term post-disease sequelae. The high prevalence of organ and non-organ specific autoantibody positivity in patients with COVID-19 led to studies attempting to delineate the origin and the underlying mechanism responsible for their induction nature, identifying novel autoantigens, and the self-epitope sequences which could be the impetus for the initiating autoreactive responses. Herein, we provide a meticulous review of the studies reporting those mimicking sequences that have been experimentally validated, based on the assumption that molecular mimicry and immunological crossreactivity may account for autoantibody development. Most reports are based on bioinformatics approaches, and only a disproportionally small number of studies currently demonstrate immunological crossreactivity. We took the opportunity to further review and searched for the linear human epitope sequences of human, through the epitopes deposited at the Immune Epitope Database. This included an analysis of autoimmune disease as the disease data to comprehensively understand the subject matter. The critical overview of the findings underscore the urgent and immense need for further research to gain a comprehensive understanding of the mechanisms involved and the anticipated appraisal that molecular mimicry and immunological crossreactivity is indeed central to the loss of immunological tolerance during SARS-COV-2 infection.
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Affiliation(s)
- Yekbun Adiguzel
- Department of Medical Biology, School of Medicine, Atilim University, Ankara, Turkey.
| | - Dimitros P Bogdanos
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece.
| | - Yehuda Shoenfeld
- Dina Recanati School of Medicine, Reichman University, Herzliya, Israel; Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Israel.
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Dhawan M, Thakur N, Sharma M, Rabaan AA. The comprehensive insights into the B-cells-mediated immune response against COVID-19 infection amid the ongoing evolution of SARS-CoV-2. Biomed Pharmacother 2025; 185:117936. [PMID: 40056829 DOI: 10.1016/j.biopha.2025.117936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Revised: 02/08/2025] [Accepted: 02/20/2025] [Indexed: 03/10/2025] Open
Abstract
The antibody-mediated immune response is crucial for the development of protective immunity against SARS-CoV-2, the virus responsible for the COVID-19 pandemic. Understanding the interaction between SARS-CoV-2 and the immune system is critical because new variants emerge as a result of the virus's ongoing evolution. Understanding the function of B cells in the SARS-CoV-2 infection process is critical for developing effective and long-lasting vaccines against this virus. Triggered by the innate immune response, B cells transform into memory B cells (MBCs). It is fascinating to observe how MBCs provide enduring immune defence, not only eradicating the infection but also safeguarding against future reinfection. If there is a lack of B cell activation or if the B cells are not functioning properly, it can lead to a serious manifestation of the disease and make immunisation less effective. Individuals with disruptions in the B cells have shown increased production of cytokines and chemokines, resulting in a poor prognosis for the disease. Therefore, we have developed an updated review article to gain insight into the involvement of B cells in SARS-CoV-2 infection. The discussion has covered the generation, functioning, and dynamics of neutralising antibodies (nAbs). Furthermore, we have emphasised immunotherapeutics that rely on nAbs.
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Affiliation(s)
- Manish Dhawan
- Department of Microbiology, Punjab Agricultural University, Ludhiana, Punjab 141004, India; Trafford College, Altrincham, Altrincham, Manchester WA14 5PQ, UK.
| | - Nanamika Thakur
- University Institute of Biotechnology, Department of Biotechnology, Chandigarh University, Mohali 140413, India
| | - Manish Sharma
- University Institute of Biotechnology, Department of Biotechnology, Chandigarh University, Mohali 140413, India
| | - Ali A Rabaan
- Research Center, Dr. Sulaiman Alhabib Medical Group, Riyadh 13328, Saudi Arabia; Molecular Diagnostic Laboratory, Johns Hopkins Aramco Healthcare, Dhahran 31311, Saudi Arabia; Department of Public Health and Nutrition, The University of Haripur, Haripur 22610, Pakistan.
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5
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Talwar S, Harker JA, Openshaw PJM, Thwaites RS. Autoimmunity in long COVID. J Allergy Clin Immunol 2025; 155:1082-1094. [PMID: 39956285 DOI: 10.1016/j.jaci.2025.02.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 01/24/2025] [Accepted: 02/07/2025] [Indexed: 02/18/2025]
Abstract
Long COVID (also termed postacute sequelae of SARS-CoV-2, or PASC) affects up to 10% of people recovering from infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Diagnosis is hampered by diffuse symptomatology, lack of biomarkers, incomplete understanding of pathogenesis, and lack of validated treatments. In terms of pathogenesis, hypothesized causes include virus persistence, the legacy of endotheliitis and thrombosis, low-grade tissue-based inflammation and/or scarring, perturbation of the host virome/microbiome, or triggering of autoimmunity. Several studies show preexisting and/or de novo production of autoantibodies after infection with SARS-CoV-2, but the persistence of these antibodies and their role in causing long COVID is debated. Here, we review the mechanisms through which autoimmune responses can arise during and after viral infection, focusing on the evidence for B-cell dysregulation and autoantibody production in acute and long COVID.
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Affiliation(s)
- Shubha Talwar
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - James A Harker
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Peter J M Openshaw
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Ryan S Thwaites
- National Heart and Lung Institute, Imperial College London, London, United Kingdom.
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Chambers JP, Daum LT, Arulanandam BP, Valdes JJ. Polyunsaturated Fatty Acid Imbalance-A Contributor to SARS CoV-2 Disease Severity. J Nutr Metab 2025; 2025:7075883. [PMID: 40166706 PMCID: PMC11957867 DOI: 10.1155/jnme/7075883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Accepted: 01/18/2025] [Indexed: 04/02/2025] Open
Abstract
Overview: SARS CoV-2 infection is accompanied by the development of acute inflammation, resolution of which determines the course of infection and its outcome. If not resolved (brought back to preinjury status), the inflamed state progresses to a severe clinical presentation characterized by uncontrolled cytokine release, systemic inflammation, and in some death. In severe CoV-2 disease, the required balance between protective inflammation and its resolution appears missing, suggesting that the ω-3-derived specialized proresolving mediators (SPMs) needed for resolution are either not present or present at ineffective levels compared to competing ω-6 polyunsaturated fatty acid (PUFA) metabolic derivatives. Aim: To determine whether ω-6 PUFA linoleic acid (LA) metabolites increased in those infected with severe disease compared to uninfected controls. Findings: Increased levels of ω-6 LA metabolites, e.g., arachidonic acid (AA), epoxyeicosatrienoic (EET) acid derivatives of AA (8,9-, 11,12-, and 14,15-EETs), AA-derived hydroxyeicosatetraenoic (HETE) acid, dihydroxylated diols (leukotoxin and isoleukotoxin), and prostaglandin E2 with decreased levels of ω-3-derived inflammation resolving SPMs. Therapeutic treatment of SARS CoV-2 patients with ω-3 PUFA significantly increased 18-HEPE (SPM precursor) and EPA-derived diols (11,12- and 14,15-diHETE), while toxic 9,10- and 12,13-diHOMEs (leukotoxin and iosleukotoxin, respectively) decreased. Conclusion: Unbalanced dietary intake of ω-6/ω-3 PUFAs contributed to SARS CoV-2 disease severity by decreasing ω-3-dependent SPM resolution of inflammation and increasing membrane-associated ferroptotic AA peroxidation.
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Affiliation(s)
- James P. Chambers
- Department of Molecular Microbiology and Immunology, The University of Texas at San Antonio, San Antonio, Texas 78249, USA
| | - Luke T. Daum
- Lujo BioScience Laboratory, San Antonio, Texas 78209, USA
| | - Bernard P. Arulanandam
- Department of Immunology, Tufts University School of Medicine, Boston, Massachusetts 02111, USA
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Leitzke M, Roach DT, Hesse S, Schönknecht P, Becker GA, Rullmann M, Sattler B, Sabri O. Long COVID - a critical disruption of cholinergic neurotransmission? Bioelectron Med 2025; 11:5. [PMID: 40011942 DOI: 10.1186/s42234-025-00167-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Accepted: 01/30/2025] [Indexed: 02/28/2025] Open
Abstract
BACKGROUND Following the COVID-19 pandemic, there are many chronically ill Long COVID (LC) patients with different symptoms of varying degrees of severity. The pathological pathways of LC remain unclear until recently and make identification of path mechanisms and exploration of therapeutic options an urgent challenge. There is an apparent relationship between LC symptoms and impaired cholinergic neurotransmission. METHODS This paper reviews the current literature on the effects of blocked nicotinic acetylcholine receptors (nAChRs) on the main affected organ and cell systems and contrasts this with the unblocking effects of the alkaloid nicotine. In addition, mechanisms are presented that could explain the previously unexplained phenomenon of post-vaccination syndrome (PVS). The fact that not only SARS-CoV-2 but numerous other viruses can bind to nAChRs is discussed under the assumption that numerous other post-viral diseases and autoimmune diseases (ADs) may also be due to impaired cholinergic transmission. We also present a case report that demonstrates changes in cholinergic transmission, specifically, the availability of α4β2 nAChRs by using (-)-[18F]Flubatine whole-body positron emission tomography (PET) imaging of cholinergic dysfunction in a LC patient along with a significant neurological improvement before and after low-dose transcutaneous nicotine (LDTN) administration. Lastly, a descriptive analysis and evaluation were conducted on the results of a survey involving 231 users of LDTN. RESULTS A substantial body of research has emerged that offers a compelling explanation for the phenomenon of LC, suggesting that it can be plausibly explained because of impaired nAChR function in the human body. Following a ten-day course of transcutaneous nicotine administration, no enduring neuropathological manifestations were observed in the patient. This observation was accompanied by a significant increase in the number of free ligand binding sites (LBS) of nAChRs, as determined by (-)-[18F]Flubatine PET imaging. The analysis of the survey shows that the majority of patients (73.5%) report a significant improvement in the symptoms of their LC/MEF/CFS disease as a result of LDTN. CONCLUSIONS In conclusion, based on current knowledge, LDTN appears to be a promising and safe procedure to relieve LC symptoms with no expected long-term harm.
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Affiliation(s)
- Marco Leitzke
- Department of Nuclear Medicine, University of Leipzig Medical Centre, Leipzig, 04103, Germany.
- Department of Anesthesiology, Intensive Care Medicine, Pain- and Palliative Therapy Helios Clinics, Colditzer Straße 48, Leisnig, 04703, Germany.
| | - Donald Troy Roach
- School of Comillas University, Renegade Research, Madrid, 28015, Spain
| | - Swen Hesse
- Department of Nuclear Medicine, University of Leipzig Medical Centre, Leipzig, 04103, Germany
| | - Peter Schönknecht
- Department of Psychiatry and Neurology Altscherbitz, Schkeuditz, 04435, Germany
- Outpatient Department for Forensic-Psychiatric Research, University of Leipzig, Leipzig, 04103, Germany
| | - Georg-Alexander Becker
- Department of Nuclear Medicine, University of Leipzig Medical Centre, Leipzig, 04103, Germany
| | - Michael Rullmann
- Department of Nuclear Medicine, University of Leipzig Medical Centre, Leipzig, 04103, Germany
| | - Bernhardt Sattler
- Department of Nuclear Medicine, University of Leipzig Medical Centre, Leipzig, 04103, Germany
| | - Osama Sabri
- Department of Nuclear Medicine, University of Leipzig Medical Centre, Leipzig, 04103, Germany
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Sennett C, Pula G. Trapped in the NETs: Multiple Roles of Platelets in the Vascular Complications Associated with Neutrophil Extracellular Traps. Cells 2025; 14:335. [PMID: 40072064 PMCID: PMC11898727 DOI: 10.3390/cells14050335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 02/18/2025] [Accepted: 02/20/2025] [Indexed: 03/15/2025] Open
Abstract
Neutrophil extracellular traps (NETs) have received significant attention in recent years for their role in both the immune response and the vascular damage associated with inflammation. Platelets have been described as critical components of NETs since the initial description of this physio-pathological response of neutrophils. Platelets have been shown to play a dual role as responders and also as stimulators of NETs. The direct interaction with DNA leads to the entrapment of platelets into NETs, a phenomenon that significantly contributes to the thrombotic complications of inflammation and neutrophil activation, while the direct and paracrine stimulation of neutrophils by platelets has been shown to initiate the process of NET formation. In this review, we provide a comprehensive description of our current understanding of the molecular mechanisms underlying the entrapping of platelets into NETs and, in parallel, the platelet-driven cellular responses promoting NET formation. We then illustrate established examples of the contribution of NETs to vascular pathologies, describe the important questions that remain to be answered regarding the contribution of platelets to NET formation and NET-dependent cardiovascular complication, and highlight the fundamental steps taken towards the application of our understanding of platelets' contribution to NETs for the development of novel cardiovascular therapies.
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Affiliation(s)
| | - Giordano Pula
- Biomedical Institute for Multimorbidity (BIM), Hull York Medical School (HYMS), University of Hull, Hull HU6 7RX, UK
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Hatayama Y, Miyakawa K, Kimura Y, Horikawa K, Hirahata K, Kimura H, Kato H, Goto A, Ryo A. Identification of Putative Serum Autoantibodies Associated with Post-Acute Sequelae of COVID-19 via Comprehensive Protein Array Analysis. Int J Mol Sci 2025; 26:1751. [PMID: 40004214 PMCID: PMC11855120 DOI: 10.3390/ijms26041751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 02/13/2025] [Accepted: 02/16/2025] [Indexed: 02/27/2025] Open
Abstract
Post-acute sequelae of SARS-CoV-2 infection (PASC), commonly known as "Long COVID", represents a significant clinical challenge characterized by persistent symptoms following acute COVID-19 infection. We conducted a comprehensive retrospective cohort study to identify serum autoantibody biomarkers associated with PASC. Initial screening using a protein bead array comprising approximately 20,000 human proteins identified several candidate PASC-associated autoantibodies. Subsequent validation by enzyme-linked immunosorbent assay (ELISA) in an expanded cohort-consisting of PASC patients, non-PASC COVID-19 convalescents, and pre-pandemic healthy controls-revealed two promising biomarkers: autoantibodies targeting PITX2 and FBXO2. PITX2 autoantibodies demonstrated high accuracy in distinguishing PASC patients from both non-PASC convalescents (area under the curve [AUC] = 0.891) and healthy controls (AUC = 0.866), while FBXO2 autoantibodies showed moderate accuracy (AUC = 0.762 and 0.786, respectively). Notably, the levels of these autoantibodies were associated with several PASC symptoms, including fever, dyspnea, palpitations, loss of appetite, and brain fog. The identification of PITX2 and FBXO2 autoantibodies as biomarkers not only enhances our understanding of PASC pathophysiology but also provides promising candidates for further investigation.
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Affiliation(s)
- Yasuyoshi Hatayama
- Department of Virology III, National Institute of Infectious Diseases, Musashimurayama 208-0011, Japan;
- Department of Microbiology, Yokohama City University School of Medicine, Yokohama 236-0004, Japan;
| | - Kei Miyakawa
- Department of Microbiology, Yokohama City University School of Medicine, Yokohama 236-0004, Japan;
- Research Center for Influenza and Respiratory Viruses, National Institute of Infectious Diseases, Musashimurayama 208-0011, Japan
| | - Yayoi Kimura
- Advanced Medical Research Center, Yokohama City University, Yokohama 236-0004, Japan; (Y.K.); (K.H.)
| | - Kazuo Horikawa
- Advanced Medical Research Center, Yokohama City University, Yokohama 236-0004, Japan; (Y.K.); (K.H.)
| | | | - Hirokazu Kimura
- Department of Health Science, Gunma Paz University Graduate School of Health Sciences, Takasaki 370-0006, Japan;
| | - Hideaki Kato
- Infection Prevention and Control Department, Yokohama City University Hospital, Yokohama 236-0004, Japan;
| | - Atsushi Goto
- Department of Public Health, Yokohama City University School of Medicine, Yokohama 236-0004, Japan;
| | - Akihide Ryo
- Department of Virology III, National Institute of Infectious Diseases, Musashimurayama 208-0011, Japan;
- Department of Microbiology, Yokohama City University School of Medicine, Yokohama 236-0004, Japan;
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10
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Talkington GM, Kolluru P, Gressett TE, Ismael S, Meenakshi U, Acquarone M, Solch-Ottaiano RJ, White A, Ouvrier B, Paré K, Parker N, Watters A, Siddeeque N, Sullivan B, Ganguli N, Calero-Hernandez V, Hall G, Longo M, Bix GJ. Neurological sequelae of long COVID: a comprehensive review of diagnostic imaging, underlying mechanisms, and potential therapeutics. Front Neurol 2025; 15:1465787. [PMID: 40046430 PMCID: PMC11881597 DOI: 10.3389/fneur.2024.1465787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 11/18/2024] [Indexed: 03/09/2025] Open
Abstract
One lingering effect of the COVID-19 pandemic created by SARS-CoV-2 is the emergence of Long COVID (LC), characterized by enduring neurological sequelae affecting a significant portion of survivors. This review provides a thorough analysis of these neurological disruptions with respect to cognitive dysfunction, which broadly manifest as chronic insomnia, fatigue, mood dysregulation, and cognitive impairments with respect to cognitive dysfunction. Furthermore, we characterize how diagnostic tools such as PET, MRI, EEG, and ultrasonography provide critical insight into subtle neurological anomalies that may mechanistically explain the Long COVID disease phenotype. In this review, we explore the mechanistic hypotheses of these neurological changes, which describe CNS invasion, neuroinflammation, blood-brain barrier disruption, and gut-brain axis dysregulation, along with the novel vascular disruption hypothesis that highlights endothelial dysfunction and hypoperfusion as a core underlying mechanism. We lastly evaluate the clinical treatment landscape, scrutinizing the efficacy of various therapeutic strategies ranging from antivirals to anti-inflammatory agents in mitigating the multifaceted symptoms of LC.
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Affiliation(s)
- Grant McGee Talkington
- Department of Neurosurgery, Clinical Neuroscience Research Center, Tulane University School of Medicine, New Orleans, LA, United States
- Tulane Brain Institute, Tulane University, New Orleans, LA, United States
| | - Paresh Kolluru
- Tulane Brain Institute, Tulane University, New Orleans, LA, United States
| | - Timothy E. Gressett
- Department of Neurosurgery, Clinical Neuroscience Research Center, Tulane University School of Medicine, New Orleans, LA, United States
- Tulane Brain Institute, Tulane University, New Orleans, LA, United States
| | - Saifudeen Ismael
- Department of Neurosurgery, Clinical Neuroscience Research Center, Tulane University School of Medicine, New Orleans, LA, United States
| | - Umar Meenakshi
- Department of Neurosurgery, Clinical Neuroscience Research Center, Tulane University School of Medicine, New Orleans, LA, United States
| | - Mariana Acquarone
- Department of Neurology, Tulane University School of Medicine, New Orleans, LA, United States
| | | | - Amanda White
- Department of Neurosurgery, Clinical Neuroscience Research Center, Tulane University School of Medicine, New Orleans, LA, United States
| | - Blake Ouvrier
- Department of Neurosurgery, Clinical Neuroscience Research Center, Tulane University School of Medicine, New Orleans, LA, United States
- Tulane Brain Institute, Tulane University, New Orleans, LA, United States
| | - Kristina Paré
- Department of Neurosurgery, Clinical Neuroscience Research Center, Tulane University School of Medicine, New Orleans, LA, United States
| | - Nicholas Parker
- Tulane Brain Institute, Tulane University, New Orleans, LA, United States
| | - Amanda Watters
- Tulane Brain Institute, Tulane University, New Orleans, LA, United States
| | - Nabeela Siddeeque
- Tulane Brain Institute, Tulane University, New Orleans, LA, United States
| | - Brooke Sullivan
- Tulane Brain Institute, Tulane University, New Orleans, LA, United States
| | - Nilesh Ganguli
- Tulane Brain Institute, Tulane University, New Orleans, LA, United States
| | | | - Gregory Hall
- Department of Neurosurgery, Clinical Neuroscience Research Center, Tulane University School of Medicine, New Orleans, LA, United States
| | - Michele Longo
- Department of Neurology, Tulane University School of Medicine, New Orleans, LA, United States
| | - Gregory J. Bix
- Department of Neurosurgery, Clinical Neuroscience Research Center, Tulane University School of Medicine, New Orleans, LA, United States
- Tulane Brain Institute, Tulane University, New Orleans, LA, United States
- Department of Neurology, Tulane University School of Medicine, New Orleans, LA, United States
- Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA, United States
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11
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Zhu W, Zheng Y, Yu M, Witman N, Zhou L, Wei J, Zhang Y, Topchyan P, Nguyen C, Wang D, Janecke R, Padmanabhan A, Baumann Kreuziger L, White GC, Hari P, Gu T, Fields AT, Kornblith LZ, Aster R, Zhu J, Cui W, Jobe S, Graham MB, Wang D, Wen R. Prothrombotic antibodies targeting the spike protein's receptor-binding domain in severe COVID-19. Blood 2025; 145:635-647. [PMID: 39576992 PMCID: PMC11811936 DOI: 10.1182/blood.2024025010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 10/21/2024] [Accepted: 11/06/2024] [Indexed: 11/24/2024] Open
Abstract
ABSTRACT Thromboembolic complication is common in severe coronavirus disease 2019 (COVID-19), leading to an investigation into the presence of prothrombotic antibodies akin to those found in heparin-induced thrombocytopenia (HIT). In a study of samples from 130 hospitalized patients, collected 3.6 days after COVID-19 diagnosis, 80% had immunoglobulin G (IgG) antibodies recognizing complexes of heparin and platelet factor 4 (PF4; PF4/H), and 41% had antibodies inducing PF4-dependent P-selectin expression in CpG oligodeoxynucleotide-treated normal platelets. Unlike HIT, both PF4/H-reactive and platelet-activating antibodies were found in patients with COVID-19 regardless of recent heparin exposure. Notably, PF4/H-reactive IgG antibodies correlated with those targeting the receptor-binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 spike protein. Moreover, introducing exogenous RBD to or removing RBD-reactive IgG from COVID-19 plasma or IgG purified from COVID-19 plasma significantly reduced their ability to activate platelets. RBD-specific antibodies capable of platelet activation were cloned from peripheral blood B cells of patients with COVID-19. These antibodies possessed sequence motifs in the heavy-chain complementarity-determining region 3 (HCDR3), resembling those identified in pathogenic HIT antibodies. Furthermore, IgG+ B cells having these HCDR3 signatures were markedly expanded in patients with severe COVID-19. Importantly, platelet-activating antibodies present in patients with COVID-19 were associated with a specific elevation of platelet α-granule proteins in the plasma and showed a positive correlation with markers for inflammation and tissue damage, suggesting a functionality of these antibodies in patients. The demonstration of functional and structural similarities between certain RBD-specific antibodies in patients with COVID-19 and pathogenic antibodies typical of HIT suggests a novel mechanism by which RBD-specific antibodies might contribute to thrombosis in COVID-19.
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Affiliation(s)
- Wen Zhu
- Versiti Blood Research Institute, Milwaukee, WI
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI
| | | | - Mei Yu
- Versiti Blood Research Institute, Milwaukee, WI
| | - Nathan Witman
- Versiti Blood Research Institute, Milwaukee, WI
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI
| | - Lu Zhou
- Versiti Blood Research Institute, Milwaukee, WI
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI
| | - Jianhui Wei
- Versiti Blood Research Institute, Milwaukee, WI
- Biomedical Research Center of South China, College of Life Sciences, Fujian Normal University, Fuzhou, China
| | - Yongguang Zhang
- Versiti Blood Research Institute, Milwaukee, WI
- Biomedical Research Center of South China, College of Life Sciences, Fujian Normal University, Fuzhou, China
| | - Paytsar Topchyan
- Versiti Blood Research Institute, Milwaukee, WI
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI
| | - Christine Nguyen
- Versiti Blood Research Institute, Milwaukee, WI
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI
| | - David Wang
- School of Art and Science Undergraduate Program, Washington University in St. Louis, St. Louis, MO
| | - Rae Janecke
- Versiti Blood Research Institute, Milwaukee, WI
| | - Anand Padmanabhan
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Lisa Baumann Kreuziger
- Versiti Blood Research Institute, Milwaukee, WI
- Division of Hematology Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI
| | | | - Parameswaran Hari
- Division of Hematology Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI
| | - Tongjun Gu
- Versiti Blood Research Institute, Milwaukee, WI
| | - Alexander T. Fields
- Department of Surgery, University of California San Francisco, San Francisco, CA
| | - Lucy Z. Kornblith
- Department of Surgery, University of California San Francisco, San Francisco, CA
- Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA
| | - Richard Aster
- Versiti Blood Research Institute, Milwaukee, WI
- Division of Hematology Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI
| | - Jieqing Zhu
- Versiti Blood Research Institute, Milwaukee, WI
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI
| | - Weiguo Cui
- Versiti Blood Research Institute, Milwaukee, WI
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Shawn Jobe
- Versiti Blood Research Institute, Milwaukee, WI
- Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, East Lansing, MI
| | - Mary Beth Graham
- Division of Infectious Disease, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI
| | - Demin Wang
- Versiti Blood Research Institute, Milwaukee, WI
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI
| | - Renren Wen
- Versiti Blood Research Institute, Milwaukee, WI
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI
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12
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Galipeau Y, Cooper C, Langlois MA. Autoantibodies in COVID-19: implications for disease severity and clinical outcomes. Front Immunol 2025; 15:1509289. [PMID: 39835117 PMCID: PMC11743527 DOI: 10.3389/fimmu.2024.1509289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 12/13/2024] [Indexed: 01/22/2025] Open
Abstract
Few pathogens have historically been subjected to as intense scientific and clinical scrutiny as SARS-CoV-2. The genetic, immunological, and environmental factors influencing disease severity and post-infection clinical outcomes, known as correlates of immunity, remain largely undefined. Clinical outcomes of SARS-CoV-2 infection vary widely, ranging from asymptomatic cases to those with life-threatening COVID-19 symptoms. While most infected individuals return to their former health and fitness within a few weeks, some develop debilitating chronic symptoms, referred to as long-COVID. Autoimmune responses have been proposed as one of the factors influencing long-COVID and the severity of SARS-CoV-2 infection. The association between viral infections and autoimmune pathologies is not new. Viruses such as Epstein-Barr virus and cytomegalovirus, among others, have been shown to induce the production of autoantibodies and the onset of autoimmune conditions. Given the extensive literature on SARS-CoV-2, here we review current evidence on SARS-CoV-2-induced autoimmune pathologies, with a focus on autoantibodies. We closely examine mechanisms driving autoantibody production, particularly their connection with disease severity and long-COVID.
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Affiliation(s)
- Yannick Galipeau
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Curtis Cooper
- The Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Marc-André Langlois
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Centre for Infection, Immunity and Inflammation (CI3), University of Ottawa, Ottawa, ON, Canada
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13
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Moriishi M, Takazono T, Hashizume J, Aibara N, Kutsuna YJ, Okamoto M, Sawai T, Hoshino T, Mori Y, Fukuda Y, Awaya Y, Yamanashi H, Furusato Y, Yanagihara T, Miyamoto H, Sato K, Kodama Y, Mizukami S, Sakamoto N, Yamamoto K, Sakamoto K, Yanagihara K, Izumikawa K, Maeda T, Nakashima M, Fukushima K, Mukae H, Ohyama K. Immune complexome analysis reveals an autoimmune signature predictive of COVID-19 severity. Clin Biochem 2025; 135:110865. [PMID: 39689808 DOI: 10.1016/j.clinbiochem.2024.110865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 11/24/2024] [Accepted: 12/11/2024] [Indexed: 12/19/2024]
Abstract
BACKGROUND The factors contributing to the development of severe coronavirus disease 2019 (COVID-19) following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain unclear. Although the presence of immune complexes (ICs), formed between antibodies and their antigens, has been linked to COVID-19 severity, their role requires further investigation, and the antigens within these ICs are yet to be characterized. METHOD Here, a C1q enzyme-liked immunosorbent assay and immune complexome analysis were used to determine IC concentrations and characterize IC antigens, respectively, in the sera of 64 unvaccinated COVID-19 patients with PCR-confirmed SARS-CoV-2 infection, enrolled at seven participating centers in 2020. For the analysis, the patients were split into the severe (n = 35) and non-severe (n = 28) groups on the basis of their COVID-19 symptoms. RESULTS We found that neither serum IC concentration nor IC antigen number was associated with COVID-19 severity. However, we identified six IC antigens, which were significantly enriched in the severe versus non-severe group. These IC antigens were all derived from human proteins, namely haptoglobin, the serum amyloid A-2 protein, the serum amyloid A-1 protein, clusterin, and lipopolysaccharide-binding protein, and complement-factor-H-related protein 3. Meanwhile, we found no association between COVID-19 severity and IC antigens derived from SARS-CoV-2 proteins. Collectively, the six IC antigens predicted COVID-19 severity with a moderate degree of accuracy (area under the receiver operating characteristic curve = 0.90, sensitivity = 94 %, specificity = 79 %). CONCLUSIONS The IC antigen signature identified in this study may have important implications for the diagnosis and treatment of severe COVID-19.
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Affiliation(s)
- Marino Moriishi
- Department of Pharmacy Practice, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Takahiro Takazono
- Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Department of Infectious Diseases, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Junya Hashizume
- Department of Hospital Pharmacy, Nagasaki University Hospital, Nagasaki, Japan
| | - Nozomi Aibara
- Department of Pharmacy Practice, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Yuki Jimbayashi Kutsuna
- Department of Molecular Pathochemistry, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Masaki Okamoto
- Department of Respirology, NHO Kyushu Medical Center, Fukuoka, Japan; Division of Respiratory, Neurology and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Toyomitsu Sawai
- Department of Respiratory Medicine, Nagasaki Harbor Medical Center, Nagasaki, Japan
| | - Teppei Hoshino
- Department of Internal Medicine, Kitakyushu Municipal Yahata Hospital, Kitakyushu, Fukuoka, Japan
| | - Yusuke Mori
- Department of Internal Medicine, Kitakyushu Municipal Yahata Hospital, Kitakyushu, Fukuoka, Japan
| | - Yuichi Fukuda
- Department of Respiratory Medicine, Sasebo City General Hospital, Sasebo, Japan
| | - Yukikazu Awaya
- Division of Respiratory Medicine, Itabashi Chuo Medical Center, Itabashi-ku, Tokyo, Japan
| | - Hirotomo Yamanashi
- Department of General Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan
| | | | - Toyoshi Yanagihara
- Department of Respiratory Medicine, NHO Fukuoka National Hospital, Fukuoka, Japan
| | - Hirotaka Miyamoto
- Department of Pharmaceutics, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Kayoko Sato
- Department of Hospital Pharmacy, Nagasaki University Hospital, Nagasaki, Japan
| | - Yukinobu Kodama
- Department of Hospital Pharmacy, Nagasaki University Hospital, Nagasaki, Japan; Department of Molecular Pathochemistry, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Shusaku Mizukami
- Department of Immune Regulation, Shionogi Global Infectious Diseases Division, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan
| | - Noriho Sakamoto
- Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Kazuko Yamamoto
- First Department of Internal Medicine, Division of Infectious, Respiratory, and Digestive Medicine, University of the Ryukyus Graduate School of Medicine, Okinawa, Japan
| | - Kei Sakamoto
- Department of Microbiology and Immunology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
| | - Katsunori Yanagihara
- Division of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Koichi Izumikawa
- Department of Infectious Diseases, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Infection Control and Education Center, Nagasaki University Hospital, Nagasaki, Japan
| | - Takahiro Maeda
- Department of General Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Mikiro Nakashima
- Department of Pharmacy Practice, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Kiyoyasu Fukushima
- Department of Respiratory Medicine, Japanese Red Cross Nagasaki Genbaku Isahaya Hospital, Isahaya, Japan
| | - Hiroshi Mukae
- Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Kaname Ohyama
- Department of Hospital Pharmacy, Nagasaki University Hospital, Nagasaki, Japan; Department of Molecular Pathochemistry, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
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14
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Tiniakou E, Casciola‐Rosen L, Thomas MA, Manabe Y, Antar AAR, Damarla M, Hassoun PM, Gao L, Wang Z, Zeger S, Rosen A. Autoantibodies in hospitalised patients with COVID-19. Clin Transl Immunology 2024; 13:e70019. [PMID: 39734590 PMCID: PMC11671454 DOI: 10.1002/cti2.70019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 10/07/2024] [Accepted: 11/13/2024] [Indexed: 12/31/2024] Open
Abstract
Objectives CD209L and its homologous protein CD209 act as alternative entry receptors for the SARS-CoV-2 virus and are highly expressed in the virally targeted tissues. We tested for the presence and clinical features of autoantibodies targeting these receptors and compared these with autoantibodies known to be associated with COVID-19. Methods Using banked samples (n = 118) from Johns Hopkins patients hospitalised with COVID-19, we defined autoantibodies against CD209 and CD209L by enzyme-linked immunosorbent assay (ELISA). Clinical associations of these antibodies were compared with those of patients with anti-interferon (IFN) and anti-angiotensin-converting enzyme-2 (ACE2) autoantibodies. Results Amongst patients hospitalised with COVID-19, 19.5% (23/118) had IgM autoantibodies against CD209L and were more likely to have coronary artery disease (44% vs 19%, P = 0.03). Antibodies against CD209 were present in 5.9% (7/118); interestingly, all 7 were male (P = 0.02). In our study, the presence of either antibody was positively associated with disease severity [OR 95% confidence interval (95% CI): 1.80 (0.69-5.03)], but the association did not reach statistical significance. In contrast, 10/118 (8.5%) had IgG autoantibodies against IFNα, and 21 (17.8%) had IgM antibodies against ACE2. These patients had significantly worse prognosis (intubation or death) and prolonged hospital stays. However, when adjusting for patient characteristics on admission, only the presence of anti-ACE2 IgM remained significant [pooled common OR (95% CI), 4.14 (1.37, 12.54)]. Conclusion We describe IgM autoantibodies against CD209 and CD209L amongst patients hospitalised with COVID-19. These were not associated with disease severity. Conversely, patients with either anti-ACE2 IgM or anti-IFNα IgG antibodies had worse outcomes. Due to the small size of the study cohort, conclusions drawn should be considered cautiously.
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Affiliation(s)
- Eleni Tiniakou
- Division of Rheumatology, Department of MedicineJohns Hopkins University School of MedicineBaltimoreMDUSA
| | - Livia Casciola‐Rosen
- Division of Rheumatology, Department of MedicineJohns Hopkins University School of MedicineBaltimoreMDUSA
| | - Mekha A Thomas
- Division of Rheumatology, Department of MedicineJohns Hopkins University School of MedicineBaltimoreMDUSA
| | - Yuka Manabe
- Division of Infectious Diseases, Department of MedicineJohns Hopkins University School of MedicineBaltimoreMDUSA
| | - Annukka AR Antar
- Division of Infectious Diseases, Department of MedicineJohns Hopkins University School of MedicineBaltimoreMDUSA
| | - Mahendra Damarla
- Division of Pulmonary and Critical Care, Department of MedicineJohns Hopkins University School of MedicineBaltimoreMDUSA
| | - Paul M Hassoun
- Division of Pulmonary and Critical Care, Department of MedicineJohns Hopkins University School of MedicineBaltimoreMDUSA
| | - Li Gao
- Division of Allergy and Immunology, Department of MedicineJohns Hopkins University, School of MedicineBaltimoreMDUSA
| | - Zitong Wang
- Department of BiostatisticsBloomberg School of Public HealthBaltimoreMDUSA
| | - Scott Zeger
- Department of BiostatisticsBloomberg School of Public HealthBaltimoreMDUSA
| | - Antony Rosen
- Division of Rheumatology, Department of MedicineJohns Hopkins University School of MedicineBaltimoreMDUSA
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15
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Li X, Zhu H, Xu P, Zhang J, Wang Z, He H, Shen F, Jiang Y, Shen L, Xiang J, Yang L, Yang C, Jiang H, Gao G, Jin J, Shen H, Wang Y, Wu L, Qian C, Liu D, Qiu W, Li Q, Chen Y, Lin F, Liu Y. A comprehensive immune repertoire signature distinguishes pulmonary infiltration in SARS-CoV-2 Omicron variant infection. Front Immunol 2024; 15:1486352. [PMID: 39742285 PMCID: PMC11685115 DOI: 10.3389/fimmu.2024.1486352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Accepted: 11/27/2024] [Indexed: 01/03/2025] Open
Abstract
Introduction The coronavirus disease 2019 (COVID-19) global pandemic has been the most severe public health emergency since 2019. Currently, the Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been the most dominant. The most prominent symptom of SARS-CoV-2 infection is respiratory. Meanwhile, the fatality of COVID-19 was mainly from pneumonia. However ,in patients with SARS-CoV-2 infection who have pneumonia and those who do not, the differences in the immune repertoire still require further investigation. Methods We conducted seven-chain adaptome immune repertoire analyses on patients with SARS-CoV-2 Omicron infection, both with and without pulmonary infiltration. Results Patients with pulmonary infiltration exhibit lymphopenia, a decreased proportion of the overall TCR repertoire alongside an increased BCR repertoire, reduced IGHD and IGHM isotype expression, a shorter mean CDR3 length for TRG, and a longer mean length for TRD, as well as diminished clonality and diversity in the TCR/BCR repertoire. Meanwhile, patients with pulmonary infiltration have distinct V-J gene usage and unique CDR3 signature, as well as BCR class switch recombination pattern. Finally, prior vaccination triggered less BCR IGHM/IGHD somatic hypermutation response, preserved the diversity of the entire adaptive immune repertoire, and provided clinical protection against severe or critical conditions following Omicron infection. Discussion We report a unique, comprehensive adaptive immune system signature in patients with pulmonary infiltration, which may serve as potential immunological biomarkers and therapeutic targets.
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Affiliation(s)
- Xuechuan Li
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Hongyi Zhu
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Peipei Xu
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Jie Zhang
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Zhe Wang
- Tilcure Biotherapeutics, Shanghai, China
| | - Hui He
- Department of Training Department, China Medical University Benxi Central Hospital Postgraduate Training Workstation, Shanghai, China
| | - Fang Shen
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Yi Jiang
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Lijuan Shen
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Jing Xiang
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Linhua Yang
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Chao Yang
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Hao Jiang
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Ganglong Gao
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Junshuo Jin
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Huojian Shen
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Yinping Wang
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Linshi Wu
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Changlin Qian
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Dejun Liu
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Weiqing Qiu
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Qiwei Li
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Yuanwen Chen
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Fujun Lin
- Renal Division, Department of Internal Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yun Liu
- Shanghai Cancer Institute, Shanghai, China
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16
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Sakakibara S, Liu YC, Ishikawa M, Edahiro R, Shirai Y, Haruna S, El Hussien MA, Xu Z, Li S, Yamaguchi Y, Murakami T, Morita T, Kato Y, Hirata H, Takeda Y, Sugihara F, Naito Y, Motooka D, Tsai CY, Ono C, Matsuura Y, Wing JB, Matsumoto H, Ogura H, Okada M, Kumanogoh A, Okada Y, Standley DM, Kikutani H, Okuzaki D. Clonal landscape of autoantibody-secreting plasmablasts in COVID-19 patients. Life Sci Alliance 2024; 7:e202402774. [PMID: 39288992 PMCID: PMC11408605 DOI: 10.26508/lsa.202402774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 09/05/2024] [Accepted: 09/06/2024] [Indexed: 09/19/2024] Open
Abstract
Whereas severe COVID-19 is often associated with elevated autoantibody titers, the underlying mechanism behind their generation has remained unclear. Here we report clonal composition and diversity of autoantibodies in humoral response to SARS-CoV-2. Immunoglobulin repertoire analysis and characterization of plasmablast-derived monoclonal antibodies uncovered clonal expansion of plasmablasts producing cardiolipin (CL)-reactive autoantibodies. Half of the expanded CL-reactive clones exhibited strong binding to SARS-CoV-2 antigens. One such clone, CoV1804, was reactive to both CL and viral nucleocapsid (N), and further showed anti-nucleolar activity in human cells. Notably, antibodies sharing genetic features with CoV1804 were identified in COVID-19 patient-derived immunoglobulins, thereby constituting a novel public antibody. These public autoantibodies had numerous mutations that unambiguously enhanced anti-N reactivity, when causing fluctuations in anti-CL reactivity along with the acquisition of additional self-reactivities, such as anti-nucleolar activity, in the progeny. Thus, potentially CL-reactive precursors may have developed multiple self-reactivities through clonal selection, expansion, and somatic hypermutation driven by viral antigens. Our results revealed the nature of autoantibody production during COVID-19 and provided novel insights into the origin of virus-induced autoantibodies.
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Affiliation(s)
- Shuhei Sakakibara
- Laboratory of Immune Regulation, Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Yu-Chen Liu
- Laboratory of Human Immunology (Single Cell Genomics), Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Masakazu Ishikawa
- Laboratory of Human Immunology (Single Cell Genomics), Immunology Frontier Research Center, Osaka University, Osaka, Japan
- Center for Infectious Disease Education and Research, Osaka University, Osaka, Japan
| | - Ryuya Edahiro
- Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Osaka, Japan
- Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan
- Laboratory of Statistical Immunology, Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Yuya Shirai
- Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Osaka, Japan
- Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan
- Laboratory of Statistical Immunology, Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Soichiro Haruna
- Laboratory of Immune Regulation, Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Marwa Ali El Hussien
- Laboratory of Immune Regulation, Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Zichang Xu
- Laboratory of Systems Immunology, Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Songling Li
- Laboratory of Systems Immunology, Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Yuta Yamaguchi
- Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Osaka, Japan
- Department of Immunopathology, Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Teruaki Murakami
- Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Osaka, Japan
- Department of Immunopathology, Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Takayoshi Morita
- Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Osaka, Japan
- Department of Immunopathology, Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Yasuhiro Kato
- Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Osaka, Japan
- Department of Immunopathology, Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Haruhiko Hirata
- Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Yoshito Takeda
- Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Fuminori Sugihara
- Core Instrumentation Facility, Immunology Frontier Research Center and Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Yoko Naito
- Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Daisuke Motooka
- Laboratory of Human Immunology (Single Cell Genomics), Immunology Frontier Research Center, Osaka University, Osaka, Japan
- Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
- Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka, Japan
| | - Chao-Yuan Tsai
- Laboratory of Immune Regulation, Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Chikako Ono
- Center for Infectious Disease Education and Research, Osaka University, Osaka, Japan
- Laboratory of Virus Control, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
- Center for Advanced Modalities and DDS, Osaka University, Osaka, Japan
| | - Yoshiharu Matsuura
- Center for Infectious Disease Education and Research, Osaka University, Osaka, Japan
- Laboratory of Virus Control, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
- Center for Advanced Modalities and DDS, Osaka University, Osaka, Japan
| | - James B Wing
- Center for Infectious Disease Education and Research, Osaka University, Osaka, Japan
- Laboratory of Human Single Cell Immunology, Immunology Frontier Research Center, Osaka University, Osaka, Japan
- Center for Advanced Modalities and DDS, Osaka University, Osaka, Japan
| | - Hisatake Matsumoto
- Center for Infectious Disease Education and Research, Osaka University, Osaka, Japan
- Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Hiroshi Ogura
- Center for Infectious Disease Education and Research, Osaka University, Osaka, Japan
- Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Masato Okada
- Center for Advanced Modalities and DDS, Osaka University, Osaka, Japan
| | - Atsushi Kumanogoh
- Center for Infectious Disease Education and Research, Osaka University, Osaka, Japan
- Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Osaka, Japan
- Department of Immunopathology, Immunology Frontier Research Center, Osaka University, Osaka, Japan
- Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka, Japan
- Center for Advanced Modalities and DDS, Osaka University, Osaka, Japan
- Japan Agency for Medical Research and Development - Core Research for Evolutional Science and Technology (AMED-CREST), Osaka University, Osaka, Japan
| | - Yukinari Okada
- Center for Infectious Disease Education and Research, Osaka University, Osaka, Japan
- Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan
- Laboratory of Statistical Immunology, Immunology Frontier Research Center, Osaka University, Osaka, Japan
- Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka, Japan
- Center for Advanced Modalities and DDS, Osaka University, Osaka, Japan
- Department of Genome Informatics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan
- Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Wakō, japan
| | - Daron M Standley
- Center for Infectious Disease Education and Research, Osaka University, Osaka, Japan
- Laboratory of Systems Immunology, Immunology Frontier Research Center, Osaka University, Osaka, Japan
- Center for Advanced Modalities and DDS, Osaka University, Osaka, Japan
| | - Hitoshi Kikutani
- Laboratory of Immune Regulation, Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Daisuke Okuzaki
- Laboratory of Human Immunology (Single Cell Genomics), Immunology Frontier Research Center, Osaka University, Osaka, Japan
- Center for Infectious Disease Education and Research, Osaka University, Osaka, Japan
- Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
- Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka, Japan
- Japan Agency for Medical Research and Development - Core Research for Evolutional Science and Technology (AMED-CREST), Osaka University, Osaka, Japan
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17
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Aghajani Mir M. Brain Fog: a Narrative Review of the Most Common Mysterious Cognitive Disorder in COVID-19. Mol Neurobiol 2024; 61:9915-9926. [PMID: 37874482 DOI: 10.1007/s12035-023-03715-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Accepted: 10/14/2023] [Indexed: 10/25/2023]
Abstract
It has been more than three years since COVID-19 impacted the lives of millions of people, many of whom suffer from long-term effects known as long-haulers. Notwithstanding multiorgan complaints in long-haulers, signs and symptoms associated with cognitive characteristics commonly known as "brain fog" occur in COVID patients over 50, women, obesity, and asthma at excessive. Brain fog is a set of symptoms that include cognitive impairment, inability to concentrate and multitask, and short-term and long-term memory loss. Of course, brain fog contributes to high levels of anxiety and stress, necessitating an empathetic response to this group of COVID patients. Although the etiology of brain fog in COVID-19 is currently unknown, regarding the mechanisms of pathogenesis, the following hypotheses exist: activation of astrocytes and microglia to release pro-inflammatory cytokines, aggregation of tau protein, and COVID-19 entry in the brain can trigger an autoimmune reaction. There are currently no specific tests to detect brain fog or any specific cognitive rehabilitation methods. However, a healthy lifestyle can help reduce symptoms to some extent, and symptom-based clinical management is also well suited to minimize brain fog side effects in COVID-19 patients. Therefore, this review discusses mechanisms of SARS-CoV-2 pathogenesis that may contribute to brain fog, as well as some approaches to providing therapies that may help COVID-19 patients avoid annoying brain fog symptoms.
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Affiliation(s)
- Mahsa Aghajani Mir
- Deputy of Research and Technology, Babol University of Medical Sciences, Babol, Iran.
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18
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Dieudonné Y, Lorenzetti R, Rottura J, Janowska I, Frenger Q, Jacquel L, Vollmer O, Carbone F, Chengsong Z, Luka M, Depauw S, Wadier N, Giorgiutti S, Nespola B, Herb A, Voll RE, Guffroy A, Poindron V, Ménager M, Martin T, Soulas-Sprauel P, Rizzi M, Korganow AS, Gies V. Defective germinal center selection results in persistence of self-reactive B cells from the primary to the secondary repertoire in Primary Antiphospholipid Syndrome. Nat Commun 2024; 15:9921. [PMID: 39548093 PMCID: PMC11568317 DOI: 10.1038/s41467-024-54228-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 11/04/2024] [Indexed: 11/17/2024] Open
Abstract
Primary antiphospholipid syndrome (PAPS) is a life-threatening clotting disorder mediated by pathogenic autoantibodies. Here we dissect the origin of self-reactive B cells in human PAPS using peripheral blood and bone marrow of patients with triple-positive PAPS via combined single-cell RNA sequencing, B cell receptors (BCR) repertoire profiling, CITEseq analysis and single cell immortalization. We find that antiphospholipid (aPL)-specific B cells are present in the naive compartment, polyreactive, and derived from the natural repertoire. Furthermore, B cells with aPL specificities are not eliminated in patients with PAPS, persist until the memory and long-lived plasma cell stages, likely after defective germinal center selection, while becoming less polyreactive. Lastly, compared with the non-PAPS cells, PAPS B cells exhibit distinct IFN and APRIL signature as well as dysregulated mTORC1 and MYC pathways. Our findings may thus elucidate the survival mechanisms of these autoreactive B cells and suggest potential therapeutic targets for the treatment of PAPS.
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Affiliation(s)
- Yannick Dieudonné
- Department of Clinical Immunology and Internal Medicine, National Reference Center for Systemic Autoimmune Diseases (CNR RESO), Tertiary Center for Primary Immunodeficiency, Strasbourg University Hospital, Strasbourg, France.
- INSERM UMR - S1109, Institut thématique interdisciplinaire (ITI) de Médecine de Précision de Strasbourg, Transplantex NG, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France.
- Université de Strasbourg, Faculty of Medicine, Strasbourg, France.
| | - Raquel Lorenzetti
- Center for Chronic Immunodeficiency, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Department of Rheumatology and Clinical Immunology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Division of Rheumatology and Clinical Immunology, Medical University of Graz, Graz, Austria
| | - Julien Rottura
- INSERM UMR - S1109, Institut thématique interdisciplinaire (ITI) de Médecine de Précision de Strasbourg, Transplantex NG, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
- Université de Strasbourg, Faculty of Life Sciences, Strasbourg, France
| | - Iga Janowska
- Center for Chronic Immunodeficiency, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Department of Rheumatology and Clinical Immunology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Quentin Frenger
- INSERM UMR - S1109, Institut thématique interdisciplinaire (ITI) de Médecine de Précision de Strasbourg, Transplantex NG, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
- Université de Strasbourg, Faculty of Life Sciences, Strasbourg, France
| | - Léa Jacquel
- Department of Clinical Immunology and Internal Medicine, National Reference Center for Systemic Autoimmune Diseases (CNR RESO), Tertiary Center for Primary Immunodeficiency, Strasbourg University Hospital, Strasbourg, France
- INSERM UMR - S1109, Institut thématique interdisciplinaire (ITI) de Médecine de Précision de Strasbourg, Transplantex NG, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
- Université de Strasbourg, Faculty of Medicine, Strasbourg, France
| | - Olivier Vollmer
- Department of Clinical Immunology and Internal Medicine, National Reference Center for Systemic Autoimmune Diseases (CNR RESO), Tertiary Center for Primary Immunodeficiency, Strasbourg University Hospital, Strasbourg, France
- INSERM UMR - S1109, Institut thématique interdisciplinaire (ITI) de Médecine de Précision de Strasbourg, Transplantex NG, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
- Université de Strasbourg, Faculty of Medicine, Strasbourg, France
| | - Francesco Carbone
- Université Paris Cité, Institut Imagine, Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, INSERM UMR 1163, Paris, France
| | - Zhu Chengsong
- Department of Immunology, Microarray and Immune Phenotyping Core Facility, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Marine Luka
- Université Paris Cité, Institut Imagine, Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, INSERM UMR 1163, Paris, France
| | - Sabine Depauw
- INSERM UMR - S1109, Institut thématique interdisciplinaire (ITI) de Médecine de Précision de Strasbourg, Transplantex NG, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
| | - Nadège Wadier
- INSERM UMR - S1109, Institut thématique interdisciplinaire (ITI) de Médecine de Précision de Strasbourg, Transplantex NG, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
| | - Stéphane Giorgiutti
- Department of Clinical Immunology and Internal Medicine, National Reference Center for Systemic Autoimmune Diseases (CNR RESO), Tertiary Center for Primary Immunodeficiency, Strasbourg University Hospital, Strasbourg, France
- INSERM UMR - S1109, Institut thématique interdisciplinaire (ITI) de Médecine de Précision de Strasbourg, Transplantex NG, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
- Université de Strasbourg, Faculty of Medicine, Strasbourg, France
| | - Benoît Nespola
- Laboratoire d'Immunologie, Plateau technique de Biologie, Strasbourg University Hospital, Strasbourg, France
| | - Agathe Herb
- Hematology laboratory, Strasbourg University Hospital, Strasbourg, France
| | - Reinhard Edmund Voll
- Center for Chronic Immunodeficiency, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Department of Rheumatology and Clinical Immunology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Aurélien Guffroy
- Department of Clinical Immunology and Internal Medicine, National Reference Center for Systemic Autoimmune Diseases (CNR RESO), Tertiary Center for Primary Immunodeficiency, Strasbourg University Hospital, Strasbourg, France
- INSERM UMR - S1109, Institut thématique interdisciplinaire (ITI) de Médecine de Précision de Strasbourg, Transplantex NG, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
- Université de Strasbourg, Faculty of Medicine, Strasbourg, France
| | - Vincent Poindron
- Department of Clinical Immunology and Internal Medicine, National Reference Center for Systemic Autoimmune Diseases (CNR RESO), Tertiary Center for Primary Immunodeficiency, Strasbourg University Hospital, Strasbourg, France
| | - Mickaël Ménager
- Université Paris Cité, Institut Imagine, Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, INSERM UMR 1163, Paris, France
| | - Thierry Martin
- Department of Clinical Immunology and Internal Medicine, National Reference Center for Systemic Autoimmune Diseases (CNR RESO), Tertiary Center for Primary Immunodeficiency, Strasbourg University Hospital, Strasbourg, France
- INSERM UMR - S1109, Institut thématique interdisciplinaire (ITI) de Médecine de Précision de Strasbourg, Transplantex NG, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
- Université de Strasbourg, Faculty of Medicine, Strasbourg, France
| | - Pauline Soulas-Sprauel
- Department of Clinical Immunology and Internal Medicine, National Reference Center for Systemic Autoimmune Diseases (CNR RESO), Tertiary Center for Primary Immunodeficiency, Strasbourg University Hospital, Strasbourg, France
- INSERM UMR - S1109, Institut thématique interdisciplinaire (ITI) de Médecine de Précision de Strasbourg, Transplantex NG, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
- Université de Strasbourg, Faculty of Pharmacy, Illkirch, France
| | - Marta Rizzi
- Center for Chronic Immunodeficiency, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Department of Rheumatology and Clinical Immunology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Division of Clinical and Experimental Immunology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
- CIBSS - Centre for Integrative Biological Signaling Studies, University of Freiburg, Freiburg, Germany
| | - Anne-Sophie Korganow
- Department of Clinical Immunology and Internal Medicine, National Reference Center for Systemic Autoimmune Diseases (CNR RESO), Tertiary Center for Primary Immunodeficiency, Strasbourg University Hospital, Strasbourg, France
- INSERM UMR - S1109, Institut thématique interdisciplinaire (ITI) de Médecine de Précision de Strasbourg, Transplantex NG, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
- Université de Strasbourg, Faculty of Medicine, Strasbourg, France
| | - Vincent Gies
- Department of Clinical Immunology and Internal Medicine, National Reference Center for Systemic Autoimmune Diseases (CNR RESO), Tertiary Center for Primary Immunodeficiency, Strasbourg University Hospital, Strasbourg, France.
- INSERM UMR - S1109, Institut thématique interdisciplinaire (ITI) de Médecine de Précision de Strasbourg, Transplantex NG, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France.
- Université de Strasbourg, Faculty of Pharmacy, Illkirch, France.
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19
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Murre C, Patta I, Mishra S, Hu M. Constructing polymorphonuclear cells: chromatin folding shapes nuclear morphology. Trends Immunol 2024; 45:851-860. [PMID: 39438171 DOI: 10.1016/j.it.2024.09.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 09/23/2024] [Accepted: 09/25/2024] [Indexed: 10/25/2024]
Abstract
Immune cell fate decisions are regulated, at least in part, by nuclear architecture. Here, we outline how nuclear architecture instructs mammalian polymorphonuclear cell differentiation. We discuss how in neutrophils loop extrusion mechanisms regulate the expression of genes involved in phagocytosis and shape nuclear morphology. We propose that diminished loop extrusion programs also orchestrate eosinophil and basophil differentiation. We portray a new model in which competitive physical forces, loop extrusion, and phase separation, instruct mononuclear versus polymorphonuclear cell fate decisions. We posit that loop extrusion programs instruct the spatial organization of cytoplasmic organelles, including neutrophil granules, mitochondria, and endoplasmic reticulum. Finally, we suggest that changing loop extrusion programs might allow the engineering of new nuclear shapes and artificial cytoplasmic architectures.
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Affiliation(s)
- Cornelis Murre
- Department of Molecular Biology, University of California, San Diego, La Jolla, CA, USA.
| | - Indumathi Patta
- Department of Molecular Biology, University of California, San Diego, La Jolla, CA, USA
| | - Shreya Mishra
- Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Ming Hu
- Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
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20
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Yalcinkaya A, Cavalli M, Aranda-Guillén M, Cederholm A, Güner A, Rietrae I, Mildner H, Behere A, Eriksson O, Gonzalez L, Mugabo CH, Johnsson A, Lakshmikanth T, Brodin P, Wadelius M, Hallberg P, Landegren N. Autoantibodies to protein S may explain rare cases of coagulopathy following COVID-19 vaccination. Sci Rep 2024; 14:24512. [PMID: 39424883 PMCID: PMC11489816 DOI: 10.1038/s41598-024-75514-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Accepted: 10/07/2024] [Indexed: 10/21/2024] Open
Abstract
While Coronavirus disease 2019 (COVID-19) vaccines have proven to be both effective and generally safe, rare but severe adverse events following immunization (AEFIs) are described. Autoantibodies to platelet factor-4 are associated with catastrophic thrombotic AEFIs, but comprehensive investigations of other autoantibodies are lacking. We aimed to detect and describe autoantibodies targeting coagulation-related proteins in a population-wide cohort (SWEDEGENE) including AEFIs attributed to COVID-19 vaccines in Sweden. Subjects were recruited from December 2020 to October 2022 and were stratified based on diagnosis and COVID-19 exposure. Screening was carried out in two phases, with a multiplex bead-based assay in the first subset (until September 2021) and with targeted assays for the second (until October 2022). Positivity was defined based on absolute, relative, and biological/technical thresholds. Patients with coagulation-related AEFIs were older and the Vaxzevria vaccine was overrepresented in this group. Two cases had antiphospholipid antibodies but none had PF4 antibodies. We identified six positives for protein S autoantibodies. Protein S concentrations were negatively correlated with autoantibody response in patients with immunoreactivity and functional analysis revealed low protein S activity in three subjects. Our population-wide analysis reveals cases with autoantibodies against protein S which possibly underlie coagulopathic AEFIs.
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Affiliation(s)
- Ahmet Yalcinkaya
- Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
- Department of Medical Biochemistry, Faculty of Medicine, Hacettepe University, Ankara, Turkey.
| | - Marco Cavalli
- Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
- Department of Medical Sciences, Clinical Pharmacogenomics, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Maribel Aranda-Guillén
- Department of Medicine (Solna), Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Axel Cederholm
- Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
| | - Almira Güner
- Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
| | - Isabel Rietrae
- Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
| | - Hedvig Mildner
- Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
| | - Anish Behere
- Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
| | - Oskar Eriksson
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Laura Gonzalez
- Unit for Clinical Pediatrics, Department of Women's and Children's Health (Solna), Karolinska Institutet, Stockholm, Sweden
| | - Constantin Habimana Mugabo
- Unit for Clinical Pediatrics, Department of Women's and Children's Health (Solna), Karolinska Institutet, Stockholm, Sweden
| | - Anette Johnsson
- Unit for Clinical Pediatrics, Department of Women's and Children's Health (Solna), Karolinska Institutet, Stockholm, Sweden
| | - Tadepally Lakshmikanth
- Unit for Clinical Pediatrics, Department of Women's and Children's Health (Solna), Karolinska Institutet, Stockholm, Sweden
| | - Petter Brodin
- Unit for Clinical Pediatrics, Department of Women's and Children's Health (Solna), Karolinska Institutet, Stockholm, Sweden
- Department of Immunology and Inflammation, Imperial College London, London, UK
| | - Mia Wadelius
- Department of Medical Sciences, Clinical Pharmacogenomics, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Pär Hallberg
- Department of Medical Sciences, Clinical Pharmacogenomics, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Nils Landegren
- Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
- Department of Medicine (Solna), Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
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21
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Matula Z, Király V, Bekő G, Gönczi M, Zóka A, Steinhauser R, Uher F, Vályi-Nagy I. High prevalence of long COVID in anti-TPO positive euthyroid individuals with strongly elevated SARS-CoV-2-specific T cell responses and moderately raised anti-spike IgG levels 23 months post-infection. Front Immunol 2024; 15:1448659. [PMID: 39450181 PMCID: PMC11499158 DOI: 10.3389/fimmu.2024.1448659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Accepted: 09/24/2024] [Indexed: 10/26/2024] Open
Abstract
Introduction Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection, the causative agent of coronavirus disease 2019 (COVID-19), causes post-acute infection syndrome in a surprisingly large number of cases worldwide. This condition, also known as long COVID or post-acute sequelae of COVID-19, is characterized by extremely complex symptoms and pathology. There is a growing consensus that this condition is a consequence of virus-induced immune activation and the inflammatory cascade, with its prolonged duration caused by a persistent virus reservoir. Methods In this cross-sectional study, we analyzed the SARS-CoV-2-specific T cell response against the spike, nucleocapsid, and membrane proteins, as well as the levels of spike-specific IgG antibodies in 51 healthcare workers, categorized into long COVID or convalescent control groups based on the presence or absence of post-acute symptoms. Additionally, we compared the levels of autoantibodies previously identified during acute or critical COVID-19, including anti-dsDNA, anti-cardiolipin, anti-β2-glycoprotein I, anti-neutrophil cytoplasmic antibodies, and anti-thyroid peroxidase (anti-TPO). Furthermore, we analyzed the antibody levels targeting six nuclear antigens within the ENA-6 S panel, as positivity for certain anti-nuclear antibodies has recently been shown to associate not only with acute COVID-19 but also with long COVID. Finally, we examined the frequency of diabetes in both groups. Our investigations were conducted at an average of 18.2 months (convalescent control group) and 23.1 months (long COVID group) after confirmed acute COVID-19 infection, and an average of 21 months after booster vaccination. Results Our results showed significant differences between the two groups regarding the occurrence of acute infection relative to administering the individual vaccine doses, the frequency of acute symptoms, and the T cell response against all structural SARS-CoV-2 proteins. A statistical association was observed between the incidence of long COVID symptoms and highly elevated anti-TPO antibodies based on Pearson's chi-squared test. Although patients with long COVID showed moderately elevated anti-SARS-CoV-2 spike IgG serum antibody levels compared to control participants, and further differences were found regarding the positivity for anti-nuclear antibodies, anti-dsDNA, and HbA1c levels between the two groups, these differences were not statistically significant. Disscussion This study highlights the need for close monitoring of long COVID development in patients with elevated anti-TPO titers, which can be indicated by strongly elevated SARS-CoV-2-specific T cell response and moderately raised anti-spike IgG levels even long after the acute infection. However, our results do not exclude the possibility of new-onset thyroid autoimmunity after COVID-19, and further investigations are required to clarify the etiological link between highly elevated anti-TPO titers and long COVID.
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Affiliation(s)
- Zsolt Matula
- Laboratory for Experimental Cell Therapy, Central Hospital of Southern Pest, National Institute of Hematology and Infectious Diseases, Budapest, Hungary
| | - Viktória Király
- Central Laboratory of Central Hospital of Southern Pest, National Institute of Hematology and Infectious Diseases, Budapest, Hungary
| | - Gabriella Bekő
- Central Laboratory of Central Hospital of Southern Pest, National Institute of Hematology and Infectious Diseases, Budapest, Hungary
| | - Márton Gönczi
- Central Laboratory of Central Hospital of Southern Pest, National Institute of Hematology and Infectious Diseases, Budapest, Hungary
| | - András Zóka
- Central Laboratory of Central Hospital of Southern Pest, National Institute of Hematology and Infectious Diseases, Budapest, Hungary
| | - Róbert Steinhauser
- Central Laboratory of Central Hospital of Southern Pest, National Institute of Hematology and Infectious Diseases, Budapest, Hungary
| | - Ferenc Uher
- Laboratory for Experimental Cell Therapy, Central Hospital of Southern Pest, National Institute of Hematology and Infectious Diseases, Budapest, Hungary
| | - István Vályi-Nagy
- Department of Hematology and Stem Cell Transplantation, Central Hospital of Southern Pest, National Institute of Hematology and Infectious Diseases, Budapest, Hungary
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22
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Mahroum N, Habra M, Alrifaai MA, Shoenfeld Y. Antiphospholipid syndrome in the era of COVID-19 - Two sides of a coin. Autoimmun Rev 2024; 23:103543. [PMID: 38604461 DOI: 10.1016/j.autrev.2024.103543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 04/08/2024] [Accepted: 04/08/2024] [Indexed: 04/13/2024]
Abstract
In addition to the respiratory symptoms associated with COVID-19, the disease has consistently been linked to many autoimmune diseases such as systemic lupus erythematous and antiphospholipid syndrome (APS). APS in particular was of paramount significance due to its devastating clinical sequela. In fact, the hypercoagulable state seen in patients with acute COVID-19 and the critical role of anticoagulant treatment in affected individuals shed light on the possible relatedness between APS and COVID-19. Moreover, the role of autoimmunity in the assumed association is not less important especially with the accumulated data available regarding the autoimmunity-triggering effect of SARS-CoV-2 infection. This is furtherly strengthened at the time patients with COVID-19 manifested antiphospholipid antibodies of different types following infection. Additionally, the severe form of the APS spectrum, catastrophic APS (CAPS), was shown to have overlapping characteristics with severe COVID-19 such as cytokine storm and multi-organ failure. Interestingly, COVID vaccine-induced autoimmune phenomena described in the medical literature have pointed to an association with APS. Whether the antiphospholipid antibodies were present or de novo, COVID vaccine-induced vascular thrombosis in certain individuals necessitates further investigations regarding the possible mechanisms involved. In our current paper, we aimed to focus on the associations mentioned, their implications, importance, and consequences.
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Affiliation(s)
- Naim Mahroum
- International School of Medicine, Istanbul Medipol University, Istanbul, Turkey.
| | - Mona Habra
- International School of Medicine, Istanbul Medipol University, Istanbul, Turkey
| | | | - Yehuda Shoenfeld
- Zabludowicz Center for autoimmune diseases, Sheba Medical Center, Ramat-Gan, Israel; Reichman University, Herzliya, Israel
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23
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Eustes AS, Ahmed A, Swamy J, Patil G, Jensen M, Wilson KM, Kudchadkar S, Wahab A, Perepu U, Miller FJ, Lentz SR, Dayal S. Extracellular histones: a unifying mechanism driving platelet-dependent extracellular vesicle release and thrombus formation in COVID-19. J Thromb Haemost 2024; 22:2514-2530. [PMID: 38815756 PMCID: PMC11343660 DOI: 10.1016/j.jtha.2024.05.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 05/12/2024] [Accepted: 05/18/2024] [Indexed: 06/01/2024]
Abstract
BACKGROUND COVID-19 can cause profound inflammation and coagulopathy, and while many mechanisms have been proposed, there is no known common pathway leading to a prothrombotic state. OBJECTIVES From the beginning of the COVID-19 pandemic, elevated levels of extracellular histones have been found in plasma of patients infected with SARS-CoV-2. We hypothesized that platelet activation triggered by extracellular histones might represent a unifying mechanism leading to increased thrombin generation and thrombosis. METHODS We utilized blood samples collected from an early clinical trial of hospitalized COVID-19 patients (NCT04360824) and recruited healthy subjects as controls. Using plasma samples, we measured the procoagulant and prothrombotic potential of circulating extracellular histones and extracellular vesicles (EVs). Platelet prothrombotic activity was assessed via thrombin generation potential and platelet thrombus growth. Circulating EVs were assessed for thrombin generation potential in vitro in plasma and enhancement of thrombotic susceptibility in vivo in mice. RESULTS Compared with controls, COVID-19 patients had elevated plasma levels of citrullinated histone H3, cell-free DNA, nucleosomes, and EVs. Plasma from COVID-19 patients promoted platelet activation, platelet-dependent thrombin generation, thrombus growth under venous shear stress, and release of platelet-derived EVs. These prothrombotic effects of COVID-19 plasma were inhibited by an RNA aptamer that neutralizes both free and DNA-bound histones. EVs isolated from COVID-19 plasma enhanced thrombin generation in vitro and potentiated venous thrombosis in mice in vivo. CONCLUSION We conclude that extracellular histones and procoagulant EVs drive the prothrombotic state in COVID-19 and that histone-targeted therapy may prove beneficial.
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Affiliation(s)
- Alicia S Eustes
- Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
| | - Azaj Ahmed
- Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
| | - Jagadish Swamy
- Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
| | - Gokul Patil
- Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
| | - Melissa Jensen
- Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
| | - Katina M Wilson
- Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
| | - Shibani Kudchadkar
- Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
| | - Abdul Wahab
- Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
| | - Usha Perepu
- Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
| | - Francis J Miller
- Department of Internal Medicine, Vanderbilt University Medical Center and VA Medical Center, Nashville, Tennessee, USA
| | - Steven R Lentz
- Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
| | - Sanjana Dayal
- Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA; Iowa City VA Healthcare System, Iowa City, Iowa, USA.
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24
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Chatterjee S, Bhattacharya M, Saxena S, Lee SS, Chakraborty C. Autoantibodies in COVID-19 and Other Viral Diseases: Molecular, Cellular, and Clinical Perspectives. Rev Med Virol 2024; 34:e2583. [PMID: 39289528 DOI: 10.1002/rmv.2583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 08/29/2024] [Accepted: 08/30/2024] [Indexed: 09/19/2024]
Abstract
Autoantibodies are immune system-produced antibodies that wrongly target the body's cells and tissues for attack. The COVID-19 pandemic has made it possible to link autoantibodies to both the severity of pathogenic infection and the emergence of several autoimmune diseases after recovery from the infection. An overview of autoimmune disorders and the function of autoantibodies in COVID-19 and other infectious diseases are discussed in this review article. We also investigated the different categories of autoantibodies found in COVID-19 and other infectious diseases including the potential pathways by which they contribute to the severity of the illness. Additionally, it also highlights the probable connection between vaccine-induced autoantibodies and their adverse outcomes. The review also discusses the therapeutic perspectives of autoantibodies. This paper advances our knowledge about the intricate interaction between autoantibodies and COVID-19 by thoroughly assessing the most recent findings.
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Affiliation(s)
- Srijan Chatterjee
- Institute for Skeletal Aging & Orthopedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital, Chuncheon, South Korea
| | | | - Sanskriti Saxena
- Division of Biology, Indian Institute of Science Education and Research-Tirupati, Tirupati, India
| | - Sang-Soo Lee
- Institute for Skeletal Aging & Orthopedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital, Chuncheon, South Korea
| | - Chiranjib Chakraborty
- Department of Biotechnology, School of Life Science and Biotechnology, Adamas University, Kolkata, India
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25
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Arévalo-Cortés A, Rodriguez-Pinto D, Aguilar-Ayala L. Evidence for Molecular Mimicry between SARS-CoV-2 and Human Antigens: Implications for Autoimmunity in COVID-19. Autoimmune Dis 2024; 2024:8359683. [PMID: 39247752 PMCID: PMC11380714 DOI: 10.1155/2024/8359683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Accepted: 08/26/2024] [Indexed: 09/10/2024] Open
Abstract
As for other viral diseases, the mechanisms behind the apparent relationship between COVID-19 and autoimmunity are yet to be clearly defined. Molecular mimicry, the existence of sequence and/or conformational homology between viral and human antigens, could be an important contributing factor. Here, we review the accumulated evidence supporting the occurrence of mimicry between SARS-CoV-2 and human proteins. Both bioinformatic approaches and antibody cross-reactions have yielded a significant magnitude of mimicry events, far more common than expected to happen by chance. The clinical implication of this phenomenon is ample since many of the identified antigens may participate in COVID-19 pathophysiology or are targets of autoimmune diseases. Thus, autoimmunity related to COVID-19 may be partially explained by molecular mimicry and further research designed specifically to address this possibility is needed.
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Affiliation(s)
| | - Daniel Rodriguez-Pinto
- Department of Health Sciences Faculty of Health Sciences Universidad Técnica Particular de Loja, Loja 110108, Ecuador
| | - Leonardo Aguilar-Ayala
- Department of Health Sciences Faculty of Health Sciences Universidad Técnica Particular de Loja, Loja 110108, Ecuador
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26
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Sales LP, Souza LVB, Fernandes AL, Murai IH, Santos MD, Vendramini MBG, Oliveira RM, Figueiredo CP, Caparbo VF, Gualano B, Pereira RMR. Effect of vitamin D 3 on antiphospholipid antibodies in hospitalized patients with moderate to severe COVID-19. Clinics (Sao Paulo) 2024; 79:100474. [PMID: 39208655 PMCID: PMC11399608 DOI: 10.1016/j.clinsp.2024.100474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 06/05/2024] [Accepted: 07/21/2024] [Indexed: 09/04/2024] Open
Abstract
OBJECTIVE To investigate the effect of a single oral dose of 200,000 IU of vitamin D3 on antiphospholipid antibodies in hospitalized patients with moderate to severe COVID-19. METHODS This is a post-hoc, exploratory analysis from a double-blind, placebo-controlled, randomized clinical trial performed in two centers in Sao Paulo, Brazil. Hospitalized patients with COVID-19 were randomly assigned to receive either vitamin D3 (n = 97) or placebo (n = 97). In this post-hoc analysis, the endpoints were titers and frequency of anti-β2-Glycoprotein-I (aβ2-GP) and Anticardiolipin (aCL) antibodies [Immunoglobulin G, M and A (IgG, IgM and IgA)]. RESULTS Overall mean (SD) age was 55.3 (13.9) years, Body Mass Index (BMI) was 32.2 (7.1 kg/m2), and 106 participants (54.6 %) were male. There was a significant group by time interaction (p = 0.046) for frequency of aCL IgG, with increased values from baseline to discharge in the placebo group [n (%), from 13 (13.4) to 25 (25.8)] compared to the vitamin D3 [from 25 (25.8) to 29 (29.9)]. However, the frequency of aCL IgG did not change between the groups on discharge. No significant differences between vitamin D3 and placebo groups were found for any other autoantibodies. CONCLUSION These findings do not support the use of a single oral dose of 200,000 IU of vitamin D3 to modulate autoantibodies in hospitalized patients with moderate to severe COVID-19.
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Affiliation(s)
- Lucas P Sales
- Rheumatology Division, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brazil
| | - Lucas V B Souza
- Rheumatology Division, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brazil
| | - Alan L Fernandes
- Rheumatology Division, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brazil
| | - Igor H Murai
- Rheumatology Division, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brazil
| | - Mayara D Santos
- Rheumatology Division, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brazil
| | - Margarete B G Vendramini
- Rheumatology Division, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brazil
| | | | - Camille P Figueiredo
- Rheumatology Division, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brazil
| | - Valéria F Caparbo
- Rheumatology Division, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brazil
| | - Bruno Gualano
- Rheumatology Division, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brazil.
| | - Rosa M R Pereira
- Rheumatology Division, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brazil
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27
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Khodanovich M, Svetlik M, Kamaeva D, Usova A, Kudabaeva M, Anan’ina T, Vasserlauf I, Pashkevich V, Moshkina M, Obukhovskaya V, Kataeva N, Levina A, Tumentceva Y, Vasilieva S, Schastnyy E, Naumova A. Demyelination in Patients with POST-COVID Depression. J Clin Med 2024; 13:4692. [PMID: 39200834 PMCID: PMC11355865 DOI: 10.3390/jcm13164692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 07/31/2024] [Accepted: 08/06/2024] [Indexed: 09/02/2024] Open
Abstract
Background: Depression is one of the most severe sequelae of COVID-19, with major depressive disorder often characterized by disruption in white matter (WM) connectivity stemming from changes in brain myelination. This study aimed to quantitatively assess brain myelination in clinically diagnosed post-COVID depression (PCD) using the recently proposed MRI method, macromolecular proton fraction (MPF) mapping. Methods: The study involved 63 recovered COVID-19 patients (52 mild, 11 moderate, and 2 severe) at 13.5 ± 10.0 months post-recovery, with matched controls without prior COVID-19 history (n = 19). A post-COVID depression group (PCD, n = 25) was identified based on psychiatric diagnosis, while a comparison group (noPCD, n = 38) included participants with neurological COVID-19 complications, excluding clinical depression. Results: Fast MPF mapping revealed extensive demyelination in PCD patients, particularly in juxtacortical WM (predominantly occipital lobe and medial surface), WM tracts (inferior fronto-occipital fasciculus (IFOF), posterior thalamic radiation, external capsule, sagittal stratum, tapetum), and grey matter (GM) structures (hippocampus, putamen, globus pallidus, and amygdala). The noPCD group also displayed notable demyelination, but with less magnitude and propagation. Multiple regression analysis highlighted IFOF demyelination as the primary predictor of Hamilton scores, PCD presence, and severity. The number of post-COVID symptoms was a significant predictor of PCD presence, while the number of acute symptoms was a significant predictor of PCD severity. Conclusions: This study, for the first time, reveals extensive demyelination in numerous WM and GM structures in PCD, outlining IFOF demyelination as a key biomarker.
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Affiliation(s)
- Marina Khodanovich
- Laboratory of Neurobiology, Research Institute of Biology and Biophysics, Tomsk State University, 36 Lenina Ave., Tomsk 634050, Russia
| | - Mikhail Svetlik
- Laboratory of Neurobiology, Research Institute of Biology and Biophysics, Tomsk State University, 36 Lenina Ave., Tomsk 634050, Russia
| | - Daria Kamaeva
- Laboratory of Neurobiology, Research Institute of Biology and Biophysics, Tomsk State University, 36 Lenina Ave., Tomsk 634050, Russia
- Mental Health Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk 634014, Russia
| | - Anna Usova
- Laboratory of Neurobiology, Research Institute of Biology and Biophysics, Tomsk State University, 36 Lenina Ave., Tomsk 634050, Russia
- Cancer Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, 12/1 Savinykh Street, Tomsk 634028, Russia
| | - Marina Kudabaeva
- Laboratory of Neurobiology, Research Institute of Biology and Biophysics, Tomsk State University, 36 Lenina Ave., Tomsk 634050, Russia
| | - Tatyana Anan’ina
- Laboratory of Neurobiology, Research Institute of Biology and Biophysics, Tomsk State University, 36 Lenina Ave., Tomsk 634050, Russia
| | - Irina Vasserlauf
- Laboratory of Neurobiology, Research Institute of Biology and Biophysics, Tomsk State University, 36 Lenina Ave., Tomsk 634050, Russia
| | - Valentina Pashkevich
- Laboratory of Neurobiology, Research Institute of Biology and Biophysics, Tomsk State University, 36 Lenina Ave., Tomsk 634050, Russia
| | - Marina Moshkina
- Laboratory of Neurobiology, Research Institute of Biology and Biophysics, Tomsk State University, 36 Lenina Ave., Tomsk 634050, Russia
| | - Victoria Obukhovskaya
- Laboratory of Neurobiology, Research Institute of Biology and Biophysics, Tomsk State University, 36 Lenina Ave., Tomsk 634050, Russia
- Department of Fundamental Psychology and Behavioral Medicine, Siberian State Medical University, 2 Moskovskiy Trakt, Tomsk 634050, Russia
| | - Nadezhda Kataeva
- Laboratory of Neurobiology, Research Institute of Biology and Biophysics, Tomsk State University, 36 Lenina Ave., Tomsk 634050, Russia
- Department of Neurology and Neurosurgery, Siberian State Medical University, 2 Moskovskiy Trakt, Tomsk 634028, Russia
| | - Anastasia Levina
- Laboratory of Neurobiology, Research Institute of Biology and Biophysics, Tomsk State University, 36 Lenina Ave., Tomsk 634050, Russia
- Medica Diagnostic and Treatment Center, 86 Sovetskaya Street, Tomsk 634510, Russia
| | - Yana Tumentceva
- Laboratory of Neurobiology, Research Institute of Biology and Biophysics, Tomsk State University, 36 Lenina Ave., Tomsk 634050, Russia
| | - Svetlana Vasilieva
- Mental Health Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk 634014, Russia
| | - Evgeny Schastnyy
- Mental Health Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk 634014, Russia
| | - Anna Naumova
- Department of Radiology, School of Medicine, South Lake Union Campus, University of Washington, 850 Republican Street, Seattle, WA 98109, USA
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28
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da Silva R, Vallinoto ACR, dos Santos EJM. The Silent Syndrome of Long COVID and Gaps in Scientific Knowledge: A Narrative Review. Viruses 2024; 16:1256. [PMID: 39205230 PMCID: PMC11359800 DOI: 10.3390/v16081256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 07/24/2024] [Accepted: 07/28/2024] [Indexed: 09/04/2024] Open
Abstract
COVID-19 is still a major public health concern, mainly due to the persistence of symptoms or the appearance of new symptoms. To date, more than 200 symptoms of long COVID (LC) have been described. The present review describes and maps its relevant clinical characteristics, pathophysiology, epidemiology, and genetic and nongenetic risk factors. Given the currently available evidence on LC, we demonstrate that there are still gaps and controversies in the diagnosis, pathophysiology, epidemiology, and detection of prognostic and predictive factors, as well as the role of the viral strain and vaccination.
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Affiliation(s)
- Rosilene da Silva
- Laboratory of Genetics of Complex Diseases, Institute of Biological Sciences, Federal University of Pará, Belém 66075-110, Brazil;
- Graduate Program in Biology of Infectious and Parasitic Agents, Federal University of Pará, Belém 66075-110, Brazil;
| | - Antonio Carlos Rosário Vallinoto
- Graduate Program in Biology of Infectious and Parasitic Agents, Federal University of Pará, Belém 66075-110, Brazil;
- Laboratory of Virology, Institute of Biological Sciences, Federal University of Pará, Belém 66075-110, Brazil
| | - Eduardo José Melo dos Santos
- Laboratory of Genetics of Complex Diseases, Institute of Biological Sciences, Federal University of Pará, Belém 66075-110, Brazil;
- Graduate Program in Biology of Infectious and Parasitic Agents, Federal University of Pará, Belém 66075-110, Brazil;
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29
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Müller-Calleja N, Ruf W, Lackner KJ. Lipid-binding antiphospholipid antibodies: significance for pathophysiology and diagnosis of the antiphospholipid syndrome. Crit Rev Clin Lab Sci 2024; 61:370-387. [PMID: 38293818 DOI: 10.1080/10408363.2024.2305121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 12/13/2023] [Accepted: 01/10/2024] [Indexed: 02/01/2024]
Abstract
The antiphospholipid syndrome (APS) is an autoimmune disease characterized by the presence of pathogenic antiphospholipid antibodies (aPL). Since approximately 30 years ago, lipid-binding aPL, which do not require a protein cofactor, have been regarded as irrelevant for APS pathogenesis even though anticardiolipin are a diagnostic criterion of APS. In this review, we will summarize the available evidence from in vitro studies, animal models, and epidemiologic studies, which suggest that this concept is no longer tenable. Accordingly, we will only briefly touch on the role of other aPL in APS. This topic has been amply reviewed in detail elsewhere. We will discuss the consequences for laboratory diagnostics and future research required to resolve open questions related to the pathogenic role of different aPL specificities.
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Affiliation(s)
- Nadine Müller-Calleja
- Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
- Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Wolfram Ruf
- Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
- Department of Immunology and Microbiology, Scripps Research, La Jolla, CA, USA
| | - Karl J Lackner
- Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
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30
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Thierry AR, Salmon D. Inflammation-, immunothrombosis,- and autoimmune-feedback loops may lead to persistent neutrophil self-stimulation in long COVID. J Med Virol 2024; 96:e29887. [PMID: 39189651 DOI: 10.1002/jmv.29887] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 07/10/2024] [Accepted: 08/13/2024] [Indexed: 08/28/2024]
Abstract
Understanding the pathophysiology of long COVID is one of the most intriguing challenges confronting contemporary medicine. Despite observations recently made in the relevant molecular, cellular, and physiological domains, it is still difficult to say whether the post-acute sequelae of COVID-19 directly correspond to the consequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This work hypothesizes that neutrophils and neutrophil extracellular traps (NETs) production are at the interconnection of three positive feedback loops which are initiated in the acute phase of SARS-CoV-2 infection, and which involve inflammation, immunothrombosis, and autoimmunity. This phenomenon could be favored by the fact that SARS-CoV-2 may directly bind and penetrate neutrophils. The ensuing strong neutrophil stimulation leads to a progressive amplification of an exacerbated and uncontrolled NETs production, potentially persisting for months beyond the acute phase of infection. This continuous self-stimulation of neutrophils leads, in turn, to systemic inflammation, micro-thromboses, and the production of autoantibodies, whose significant consequences include the persistence of endothelial and multiorgan damage, and vascular complications.
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Affiliation(s)
- Alain R Thierry
- IRCM, Institute of Research on Cancerology of Montpellier, INSERM U1194, University of Montpellier, Montpellier, France
- Montpellier Cancer Institute (ICM), Montpellier, France
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Haga Y, Ohara A, Yakuwa T, Yamashita A, Udo M, Matsuoka M, Ohara H, Yasumoto A, Takahashi H. Persistently High Platelet Factor 4 Levels in an Adolescent with Recurrent Late Thrombotic Complications after SARS-CoV-2 mRNA Vaccination. Hematol Rep 2024; 16:504-511. [PMID: 39189244 PMCID: PMC11348110 DOI: 10.3390/hematolrep16030048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 07/24/2024] [Accepted: 07/25/2024] [Indexed: 08/28/2024] Open
Abstract
Thrombosis after severe acute respiratory syndrome coronavirus 2 vaccination is a serious complication in patients with a thrombophilic predisposition. Herein, we present a 17-year-old female who had underlying antiphospholipid syndrome (APS) and developed deep vein thrombosis (DVT) 6 months after her second BNT162b2 vaccine dose. Although she had no family history of thrombosis, she had previously developed DVT at 6 years of age, with thrombus formation in the right common iliac vein and the inferior vena cava, along with concomitant left pulmonary infarction. The patient had received anticoagulant therapy for 6 years after DVT onset, with subsequent treatment cessation for 5 years without recurrence. She received the BNT162b2 vaccine at 17 years of age, 1 week before a routine outpatient visit. Platelet factor 4 elevation was detected 14 days after the first vaccination, persisting for 5 months without thrombotic symptoms. Six months after the second vaccine dose, the DVT recurred and was treated with a direct oral anticoagulant. The vaccine was hypothesized to exacerbate the patient's APS by activating coagulation. Platelet factor 4 levels may indicate coagulation status. When patients predisposed to thrombosis are vaccinated, coagulation status and platelet activation markers should be monitored to prevent DVT development.
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Affiliation(s)
- Yoichi Haga
- Department of Pediatrics, Toho University Medical Center Omori Hospital, 6-11-1, Omori-Nishi, Ota-ku, Tokyo 143-8541, Japan (M.M.); (H.T.)
| | - Akira Ohara
- Department of Pediatrics, Toho University Medical Center Omori Hospital, 6-11-1, Omori-Nishi, Ota-ku, Tokyo 143-8541, Japan (M.M.); (H.T.)
| | - Tsuneyoshi Yakuwa
- Department of Clinical Laboratory, Toho University Medical Center Omori Hospital, 6-11-1, Omori-Nishi, Ota-ku, Tokyo 143-8541, Japan
| | - Akari Yamashita
- Department of Pediatrics, Toho University Medical Center Omori Hospital, 6-11-1, Omori-Nishi, Ota-ku, Tokyo 143-8541, Japan (M.M.); (H.T.)
| | - Midori Udo
- Department of Pediatrics, Toho University Medical Center Omori Hospital, 6-11-1, Omori-Nishi, Ota-ku, Tokyo 143-8541, Japan (M.M.); (H.T.)
| | - Masaki Matsuoka
- Department of Pediatrics, Toho University Medical Center Omori Hospital, 6-11-1, Omori-Nishi, Ota-ku, Tokyo 143-8541, Japan (M.M.); (H.T.)
| | - Hiroshi Ohara
- Department of Cardiovascular Medicine, Toho University Medical Center Omori Hospital, 6-11-1, Omori-Nishi, Ota-ku, Tokyo 143-8541, Japan;
| | - Atsushi Yasumoto
- Department of Laboratory Medicine and Blood Transfusion, Hokkaido University Hospital, North-14, West-5, Kita-ku, Sapporo-shi 060-8648, Hokkaido, Japan;
| | - Hiroyuki Takahashi
- Department of Pediatrics, Toho University Medical Center Omori Hospital, 6-11-1, Omori-Nishi, Ota-ku, Tokyo 143-8541, Japan (M.M.); (H.T.)
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Mellor-Pita S, Tutor-Ureta P, Velasco P, Plaza A, Diego I, Vázquez-Comendador J, Vionnet AP, Durán-del Campo P, Moreno-Torres V, Vargas JA, Castejon R. IgA Anti-β2-Glycoprotein I Antibodies as Markers of Thrombosis and Severity in COVID-19 Patients. Viruses 2024; 16:1071. [PMID: 39066233 PMCID: PMC11281419 DOI: 10.3390/v16071071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 06/27/2024] [Accepted: 07/01/2024] [Indexed: 07/28/2024] Open
Abstract
Patients with COVID-19 may develop a hypercoagulable state due to tissue and endothelial injury, produced by an unbalanced immune response. Therefore, an increased number of thromboembolic events has been reported in these patients. The aim of this study is to investigate the presence of antiphospholipid antibodies (aPL) in COVID-19 patients, their role in the development of thrombosis and their relationship with the severity of the disease. In this retrospective study, serum samples from 159 COVID-19 patients and 80 healthy donors were analysed for the presence of aPL. A total of 29 patients (18.2%) and 14 healthy donors (17.5%) were positive for aPL. Nineteen COVID-19 patients (12%) but no healthy donor presented a positive percentage of the IgA isotype aPL. IgA anti-β2-glycoprotein I antibodies (anti-β2GPI) were the most frequent type (6.3%) in patients but was not detected in any healthy donor. The positivity of this antibody was found to be significantly elevated in patients with thromboembolic events (25% vs. 5%, p = 0.029); in fact, patients with positive IgA anti-β2GPI had an incidence of thrombosis over six times higher than those who had normal antibody concentrations [OR (CI 95%) of 6.67 (1.5-30.2), p = 0.014]. Additionally, patients with moderate-severe disease presented a higher aPL positivity than patients with mild disease according to the Brescia (p = 0.029) and CURB-65 (p = 0.011) severity scales. A multivariate analysis showed that positivity for IgA anti-β2GPI is significantly associated with disease severity measured by CURB-65 [OR (CI 95%) 17.8 (1.7-187), p = 0.0016]. In conclusion, COVID-19 patients have a significantly higher positive percentage of the IgA isotype aPL than healthy donors. IgA anti-β2GPI antibodies were the most frequently detected aPL in COVID-19 patients and were associated with thrombosis and severe COVID-19 and are thus proposed as a possible marker to identify high-risk patients.
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Affiliation(s)
- Susana Mellor-Pita
- Systemic Autoimmune Diseases Unit, Department of Internal Medicine, IDIPHIM (Puerta de Hierro University Hospital Research Institute), Hospital Universitario Puerta de Hierro Majadahonda, 28222 Madrid, Spain; (S.M.-P.); (P.T.-U.); (P.V.); (I.D.); (J.V.-C.); (P.D.-d.C.); (V.M.-T.); (J.A.V.)
- Department of Medicine, Facultad de Medicina, Universidad Autónoma de Madrid, 28029 Madrid, Spain
| | - Pablo Tutor-Ureta
- Systemic Autoimmune Diseases Unit, Department of Internal Medicine, IDIPHIM (Puerta de Hierro University Hospital Research Institute), Hospital Universitario Puerta de Hierro Majadahonda, 28222 Madrid, Spain; (S.M.-P.); (P.T.-U.); (P.V.); (I.D.); (J.V.-C.); (P.D.-d.C.); (V.M.-T.); (J.A.V.)
- Department of Medicine, Facultad de Medicina, Universidad Autónoma de Madrid, 28029 Madrid, Spain
| | - Paula Velasco
- Systemic Autoimmune Diseases Unit, Department of Internal Medicine, IDIPHIM (Puerta de Hierro University Hospital Research Institute), Hospital Universitario Puerta de Hierro Majadahonda, 28222 Madrid, Spain; (S.M.-P.); (P.T.-U.); (P.V.); (I.D.); (J.V.-C.); (P.D.-d.C.); (V.M.-T.); (J.A.V.)
| | - Aresio Plaza
- Department of Immunology, Hospital Universitario Puerta de Hierro Majadahonda, 28222 Madrid, Spain; (A.P.); (A.P.V.)
| | - Itziar Diego
- Systemic Autoimmune Diseases Unit, Department of Internal Medicine, IDIPHIM (Puerta de Hierro University Hospital Research Institute), Hospital Universitario Puerta de Hierro Majadahonda, 28222 Madrid, Spain; (S.M.-P.); (P.T.-U.); (P.V.); (I.D.); (J.V.-C.); (P.D.-d.C.); (V.M.-T.); (J.A.V.)
| | - José Vázquez-Comendador
- Systemic Autoimmune Diseases Unit, Department of Internal Medicine, IDIPHIM (Puerta de Hierro University Hospital Research Institute), Hospital Universitario Puerta de Hierro Majadahonda, 28222 Madrid, Spain; (S.M.-P.); (P.T.-U.); (P.V.); (I.D.); (J.V.-C.); (P.D.-d.C.); (V.M.-T.); (J.A.V.)
| | - Ana Paula Vionnet
- Department of Immunology, Hospital Universitario Puerta de Hierro Majadahonda, 28222 Madrid, Spain; (A.P.); (A.P.V.)
| | - Pedro Durán-del Campo
- Systemic Autoimmune Diseases Unit, Department of Internal Medicine, IDIPHIM (Puerta de Hierro University Hospital Research Institute), Hospital Universitario Puerta de Hierro Majadahonda, 28222 Madrid, Spain; (S.M.-P.); (P.T.-U.); (P.V.); (I.D.); (J.V.-C.); (P.D.-d.C.); (V.M.-T.); (J.A.V.)
| | - Víctor Moreno-Torres
- Systemic Autoimmune Diseases Unit, Department of Internal Medicine, IDIPHIM (Puerta de Hierro University Hospital Research Institute), Hospital Universitario Puerta de Hierro Majadahonda, 28222 Madrid, Spain; (S.M.-P.); (P.T.-U.); (P.V.); (I.D.); (J.V.-C.); (P.D.-d.C.); (V.M.-T.); (J.A.V.)
| | - Juan Antonio Vargas
- Systemic Autoimmune Diseases Unit, Department of Internal Medicine, IDIPHIM (Puerta de Hierro University Hospital Research Institute), Hospital Universitario Puerta de Hierro Majadahonda, 28222 Madrid, Spain; (S.M.-P.); (P.T.-U.); (P.V.); (I.D.); (J.V.-C.); (P.D.-d.C.); (V.M.-T.); (J.A.V.)
- Department of Medicine, Facultad de Medicina, Universidad Autónoma de Madrid, 28029 Madrid, Spain
| | - Raquel Castejon
- Systemic Autoimmune Diseases Unit, Department of Internal Medicine, IDIPHIM (Puerta de Hierro University Hospital Research Institute), Hospital Universitario Puerta de Hierro Majadahonda, 28222 Madrid, Spain; (S.M.-P.); (P.T.-U.); (P.V.); (I.D.); (J.V.-C.); (P.D.-d.C.); (V.M.-T.); (J.A.V.)
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Tsay GJ, Zouali M. Cellular pathways and molecular events that shape autoantibody production in COVID-19. J Autoimmun 2024; 147:103276. [PMID: 38936147 DOI: 10.1016/j.jaut.2024.103276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 05/26/2024] [Accepted: 06/18/2024] [Indexed: 06/29/2024]
Abstract
A hallmark of COVID-19 is the variety of complications that follow SARS-CoV-2 infection in some patients, and that target multiple organs and tissues. Also remarkable are the associations with several auto-inflammatory disorders and the presence of autoantibodies directed to a vast array of antigens. The processes underlying autoantibody production in COVID-19 have not been completed deciphered. Here, we review mechanisms involved in autoantibody production in COVID-19, multisystem inflammatory syndrome in children, and post-acute sequelae of COVID19. We critically discuss how genomic integrity, loss of B cell tolerance to self, superantigen effects of the virus, and extrafollicular B cell activation could underly autoantibody proaction in COVID-19. We also offer models that may account for the pathogenic roles of autoantibodies in the promotion of inflammatory cascades, thromboembolic phenomena, and endothelial and vascular deregulations.
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Affiliation(s)
- Gregory J Tsay
- Division of Immunology and Rheumatology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan; College of Medicine, China Medical University, Taichung, Taiwan
| | - Moncef Zouali
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
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Rysenga CE, May-Zhang L, Zahavi M, Knight JS, Ali RA. Taxifolin inhibits NETosis through activation of Nrf2 and provides protective effects in models of lupus and antiphospholipid syndrome. Rheumatology (Oxford) 2024; 63:2006-2015. [PMID: 37815837 DOI: 10.1093/rheumatology/kead547] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 09/06/2023] [Accepted: 10/02/2023] [Indexed: 10/11/2023] Open
Abstract
OBJECTIVES Taxifolin (dihydroquercetin) is a bioactive plant flavonoid that exhibits anti-inflammatory and anti-oxidative properties. We hypothesized that taxifolin might be an effective dietary supplement to ameliorate symptoms arising from thrombo-inflammatory diseases such as lupus and APS. METHODS We used in vitro assays and a mouse model to determine mechanisms by which taxifolin inhibits neutrophil extracellular trap (NET) formation (i.e. NETosis) and venous thrombosis in lupus and APS. RESULTS At doses ranging from 0.1 to 1 µg/ml, taxifolin inhibited NETosis from control neutrophils stimulated with autoantibodies isolated from lupus and APS patients, and its suppressive effects were mitigated by blocking the antioxidant transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2). Furthermore, taxifolin at a dose as low as 20 mg/kg/day reduced in vivo NETosis in thrombo-inflammatory mouse models of lupus and APS while also significantly attenuating autoantibody formation, inflammatory cytokine production and large-vein thrombosis. CONCLUSION Our study is the first to demonstrate the protective effects of taxifolin in the context of lupus and APS. Importantly, our study also suggests a therapeutic potential to neutralize neutrophil hyperactivity and NETosis that could have relevance to a variety of thrombo-inflammatory diseases.
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Affiliation(s)
- Christine E Rysenga
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | | | - Miela Zahavi
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Jason S Knight
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Ramadan A Ali
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
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Vélez-Páez JL, Carranza-Jara JM, Almeida-Posso DC, Witkin SS, de Almeida-Neto C. Oligosymptomatic infection by SARS-Cov-2 in catastrophic antiphospholipid syndrome, a singular coincidence: a case report in an Ecuadorian hospital. Hematol Transfus Cell Ther 2024; 46:316-320. [PMID: 37455218 PMCID: PMC11221254 DOI: 10.1016/j.htct.2023.06.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 05/17/2023] [Accepted: 06/07/2023] [Indexed: 07/18/2023] Open
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Drelich AK, Rayavara K, Hsu J, Saenkham-Huntsinger P, Judy BM, Tat V, Ksiazek TG, Peng BH, Tseng CTK. Characterization of Unique Pathological Features of COVID-Associated Coagulopathy: Studies with AC70 hACE2 Transgenic Mice Highly Permissive to SARS-CoV-2 Infection. PLoS Pathog 2024; 20:e1011777. [PMID: 38913740 PMCID: PMC11226087 DOI: 10.1371/journal.ppat.1011777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 07/05/2024] [Accepted: 06/10/2024] [Indexed: 06/26/2024] Open
Abstract
COVID-associated coagulopathy seemly plays a key role in post-acute sequelae of SARS- CoV-2 infection. However, the underlying pathophysiological mechanisms are poorly understood, largely due to the lack of suitable animal models that recapitulate key clinical and pathological symptoms. Here, we fully characterized AC70 line of human ACE2 transgenic (AC70 hACE2 Tg) mice for SARS-CoV-2 infection. We noted that this model is highly permissive to SARS-CoV-2 with values of 50% lethal dose and infectious dose as ~ 3 and ~ 0.5 TCID50 of SARS-CoV-2, respectively. Mice infected with 105 TCID50 of SARS-CoV-2 rapidly succumbed to infection with 100% mortality within 5 days. Lung and brain were the prime tissues harboring high viral titers, accompanied by histopathology. However, viral RNA and inflammatory mediators could be detectable in other organs, suggesting the nature of a systemic infection. Lethal challenge of AC70 hACE2 Tg mice caused acute onset of leukopenia, lymphopenia, along with an increased neutrophil-to-lymphocyte ratio (NLR). Importantly, infected animals recapitulated key features of COVID-19-associated coagulopathy. SARS-CoV-2 could induce the release of circulating neutrophil extracellular traps (NETs), along with activated platelet/endothelium marker. Immunohistochemical staining with anti-platelet factor-4 (PF4) antibody revealed profound platelet aggregates especially within blocked veins of the lungs. We showed that acute SARS-CoV-2 infection triggered a hypercoagulable state coexisting with ill-regulated fibrinolysis. Finally, we highlighted the potential role of Annexin A2 (ANXA2) in fibrinolytic failure. ANXA2 is a calcium-dependent phospholipid-binding protein that forms a heterotertrameric complexes localized at the extracellular membranes with two S100A10 small molecules acting as a co-receptor for tissue-plasminogen activator (t-PA), tightly involved in cell surface fibrinolysis. Thus, our results revealing elevated IgG type anti-ANXA2 antibody production, downregulated de novo ANXA2/S100A10 synthesis, and reduced ANXA2/S100A10 association in infected mice, this protein might serve as druggable targets for development of antithrombotic and/or anti-fibrinolytic agents to attenuate pathogenesis of COVID-19.
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Affiliation(s)
- Aleksandra K. Drelich
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America
| | - Kempaiah Rayavara
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America
| | - Jason Hsu
- Department of Biochemistry, Cell and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, United States of America
| | - Panatda Saenkham-Huntsinger
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America
| | - Barbara M. Judy
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America
| | - Vivian Tat
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America
| | - Thomas G. Ksiazek
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America
- World Reference Center for Emerging Viruses and Arboviruses, Institute for Human Infection and Immunity, University of Texas Medical Branch, Galveston, Texas, United States of America
| | - Bi-Hung Peng
- Neurosciences, Cell Biology, and Anatomy, University of Texas Medical Branch Galveston, Texas, United States of America
| | - Chien-Te K. Tseng
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America
- Department of Biochemistry, Cell and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, United States of America
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America
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Calcaterra V, Zanelli S, Foppiani A, Verduci E, Benatti B, Bollina R, Bombaci F, Brucato A, Cammarata S, Calabrò E, Cirnigliaro G, Della Torre S, Dell’osso B, Moltrasio C, Marzano AV, Nostro C, Romagnuolo M, Trotta L, Savasi V, Smiroldo V, Zuccotti G. Long COVID in Children, Adults, and Vulnerable Populations: A Comprehensive Overview for an Integrated Approach. Diseases 2024; 12:95. [PMID: 38785750 PMCID: PMC11120262 DOI: 10.3390/diseases12050095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 04/27/2024] [Accepted: 05/03/2024] [Indexed: 05/25/2024] Open
Abstract
Long COVID affects both children and adults, including subjects who experienced severe, mild, or even asymptomatic SARS-CoV-2 infection. We have provided a comprehensive overview of the incidence, clinical characteristics, risk factors, and outcomes of persistent COVID-19 symptoms in both children and adults, encompassing vulnerable populations, such as pregnant women and oncological patients. Our objective is to emphasize the critical significance of adopting an integrated approach for the early detection and appropriate management of long COVID. The incidence and severity of long COVID symptoms can have a significant impact on the quality of life of patients and the course of disease in the case of pre-existing pathologies. Particularly, in fragile and vulnerable patients, the presence of PASC is related to significantly worse survival, independent from pre-existing vulnerabilities and treatment. It is important try to achieve an early recognition and management. Various mechanisms are implicated, resulting in a wide range of clinical presentations. Understanding the specific mechanisms and risk factors involved in long COVID is crucial for tailoring effective interventions and support strategies. Management approaches involve comprehensive biopsychosocial assessments and treatment of symptoms and comorbidities, such as autonomic dysfunction, as well as multidisciplinary rehabilitation. The overall course of long COVID is one of gradual improvement, with recovery observed in the majority, though not all, of patients. As the research on long-COVID continues to evolve, ongoing studies are likely to shed more light on the intricate relationship between chronic diseases, such as oncological status, cardiovascular diseases, psychiatric disorders, and the persistent effects of SARS-CoV-2 infection. This information could guide healthcare providers, researchers, and policymakers in developing targeted interventions.
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Affiliation(s)
- Valeria Calcaterra
- Department of Internal Medicine and Therapeutics, Università degli Sudi di Pavia, 27100 Pavia, Italy;
- Pediatric Department, Buzzi Children’s Hospital, 20154 Milano, Italy; (S.Z.); (E.V.)
| | - Sara Zanelli
- Pediatric Department, Buzzi Children’s Hospital, 20154 Milano, Italy; (S.Z.); (E.V.)
| | - Andrea Foppiani
- International Center for the Assessment of Nutritional Status and the Development of Dietary Intervention Strategies (ICANS-DIS), Department of Food, Environmental and Nutritional Sciences (DeFENS), Università degli Studi di Milano, 20157 Milano, Italy;
- IRCCS Istituto Auxologico Italiano, Department of Endocrine and Metabolic Medicine, Clinical Nutrition Unit, 20145 Milano, Italy
| | - Elvira Verduci
- Pediatric Department, Buzzi Children’s Hospital, 20154 Milano, Italy; (S.Z.); (E.V.)
- Department of Health Sciences, Università degli Studi di Milano, 20157 Milano, Italy
| | - Beatrice Benatti
- “Aldo Ravelli” Center for Nanotechnology and Neurostimulation, Università degli Studi di Milano, 20157 Milano, Italy; (B.B.); (B.D.)
- Department of Psychiatry, ASST Fatebenefratelli-Sacco, University of Milano, 20154 Milano, Italy; (G.C.); (C.N.)
| | - Roberto Bollina
- Department of Medical Oncology, ASST Rhodense, 20024 Milano, Italy; (R.B.); (S.D.T.); (V.S.)
| | - Francesco Bombaci
- Department of Radiology, ASST Fatebenefratelli Sacco, 20154 Milano, Italy;
| | - Antonio Brucato
- Department of Internal Medicine, ASST Fatebenefratelli-Sacco, 20154 Milano, Italy; (A.B.); (E.C.); (L.T.)
| | - Selene Cammarata
- Department of Woman, Mother and Neonate, Luigi Sacco Hospital, ASST Fatebenefratelli-Sacco, 20154 Milano, Italy; (S.C.); (V.S.)
| | - Elisa Calabrò
- Department of Internal Medicine, ASST Fatebenefratelli-Sacco, 20154 Milano, Italy; (A.B.); (E.C.); (L.T.)
| | - Giovanna Cirnigliaro
- Department of Psychiatry, ASST Fatebenefratelli-Sacco, University of Milano, 20154 Milano, Italy; (G.C.); (C.N.)
| | - Silvia Della Torre
- Department of Medical Oncology, ASST Rhodense, 20024 Milano, Italy; (R.B.); (S.D.T.); (V.S.)
| | - Bernardo Dell’osso
- “Aldo Ravelli” Center for Nanotechnology and Neurostimulation, Università degli Studi di Milano, 20157 Milano, Italy; (B.B.); (B.D.)
- Department of Psychiatry, ASST Fatebenefratelli-Sacco, University of Milano, 20154 Milano, Italy; (G.C.); (C.N.)
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA
- Centro per lo Studio dei Meccanismi Molecolari alla Base delle Patologie Neuro-Psico-Geriatriche, Università degli Studi di Milano, 20157 Milano, Italy
| | - Chiara Moltrasio
- Dermatology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy; (C.M.); (A.V.M.); (M.R.)
| | - Angelo Valerio Marzano
- Dermatology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy; (C.M.); (A.V.M.); (M.R.)
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122 Milano, Italy
| | - Chiara Nostro
- Department of Psychiatry, ASST Fatebenefratelli-Sacco, University of Milano, 20154 Milano, Italy; (G.C.); (C.N.)
| | - Maurizio Romagnuolo
- Dermatology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy; (C.M.); (A.V.M.); (M.R.)
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122 Milano, Italy
| | - Lucia Trotta
- Department of Internal Medicine, ASST Fatebenefratelli-Sacco, 20154 Milano, Italy; (A.B.); (E.C.); (L.T.)
| | - Valeria Savasi
- Department of Woman, Mother and Neonate, Luigi Sacco Hospital, ASST Fatebenefratelli-Sacco, 20154 Milano, Italy; (S.C.); (V.S.)
- Department of Biomedical and Clinical Science, Università degli Studi di Milano, 20157 Milano, Italy
| | - Valeria Smiroldo
- Department of Medical Oncology, ASST Rhodense, 20024 Milano, Italy; (R.B.); (S.D.T.); (V.S.)
| | - Gianvincenzo Zuccotti
- Pediatric Department, Buzzi Children’s Hospital, 20154 Milano, Italy; (S.Z.); (E.V.)
- Department of Biomedical and Clinical Science, Università degli Studi di Milano, 20157 Milano, Italy
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Roghani SA, Dastbaz M, Lotfi R, Shamsi A, Abdan Z, Rostampour R, Soleymani B, Zamanian MH, Soufivand P, Pournazari M, Taghadosi M. The development of anticyclic citrullinated peptide (anti-CCP) antibody following severe COVID-19. Immun Inflamm Dis 2024; 12:e1276. [PMID: 38780036 PMCID: PMC11112627 DOI: 10.1002/iid3.1276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 04/10/2024] [Accepted: 05/06/2024] [Indexed: 05/25/2024] Open
Abstract
OBJECTIVES The dysregulated immune response is one of the cardinal features of severe coronavirus disease 2019 (COVID-19). This study was conducted to clarify the occurrence of autoantibodies (AABs) associated with systemic autoimmune rheumatic diseases (SARDs) in hospitalized patients with a moderate, severe, and critical form of COVID-19. METHODS The serum samples obtained from 176 hospitalized COVID-19 patients were investigated in this study, including patients with moderate (N = 90), severe (N = 50), and critical (N = 36) forms of COVID-19. Also, the serum samples collected from healthy subjects before the COVID-19 pandemic were used as controls (N = 176). The antinuclear antibodies (ANAs), antidouble-stranded DNA (anti-dsDNA), cytoplasmic-anti neutrophil cytoplasmic antibody (c-ANCA), perinuclear ANCA (p-ANCA), antiphospholipid antibodies (aPLs), and anticyclic citrullinated peptide (anti-CCP) occurrence was evaluated using a solid-phase enzyme-linked immunosorbent assay (ELISA). RESULTS The results showed that the occurrence of ANAs, anti-dsDNA, anti-CCP, c-ANCA, and p-ANCA was significantly higher in the COVID-19 patients compared to serum obtained from healthy subjects (p < .0001, p < .0001, p < .0001, p < .05, and p < .001, respectively). The positive number of anti-CCP tests increased significantly in severe COVID-19 compared to the moderate group (p < .01). CONCLUSION Our study further supports the development of autoantibodies related to systemic autoimmune rheumatologic diseases. To the best of our knowledge, this is the first study with a large sample size that reported the occurrence of anti-CCP in a severe form of COVID-19.
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Affiliation(s)
- Seyed Askar Roghani
- Immunology Department, Faculty of MedicineKermanshah University of Medical SciencesKermanshahIran
- Clinical Research Development Center, Imam Reza HospitalKermanshah University of Medical SciencesKermanshahIran
- Medical Biology Research Center, Health Technology InstituteKermanshah University of Medical SciencesKermanshahIran
| | - Mohammad Dastbaz
- Immunology Department, Faculty of MedicineKermanshah University of Medical SciencesKermanshahIran
| | - Ramin Lotfi
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion MedicineKurdistan Regional Blood Transfusion CenterSanandajIran
- Clinical Research Development Center, Tohid HospitalKurdistan University of Medical SciencesSanandajIran
| | - Afsaneh Shamsi
- Immunology Department, Faculty of MedicineKermanshah University of Medical SciencesKermanshahIran
| | - Zahra Abdan
- Clinical Research Development Center, Imam Reza HospitalKermanshah University of Medical SciencesKermanshahIran
| | - Rezvan Rostampour
- Clinical Research Development Center, Imam Reza HospitalKermanshah University of Medical SciencesKermanshahIran
- Department of Clinical Biochemistry, Medical SchoolKermanshah University of Medical SciencesKermanshahIran
| | - Bijan Soleymani
- Medical Biology Research Center, Health Technology InstituteKermanshah University of Medical SciencesKermanshahIran
| | - Mohammad Hossein Zamanian
- Clinical Research Development Center, Imam Reza HospitalKermanshah University of Medical SciencesKermanshahIran
| | - Parviz Soufivand
- Clinical Research Development Center, Imam Reza HospitalKermanshah University of Medical SciencesKermanshahIran
| | - Mehran Pournazari
- Clinical Research Development Center, Imam Reza HospitalKermanshah University of Medical SciencesKermanshahIran
| | - Mahdi Taghadosi
- Immunology Department, Faculty of MedicineKermanshah University of Medical SciencesKermanshahIran
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Casanova JL, Peel J, Donadieu J, Neehus AL, Puel A, Bastard P. The ouroboros of autoimmunity. Nat Immunol 2024; 25:743-754. [PMID: 38698239 DOI: 10.1038/s41590-024-01815-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Accepted: 03/13/2024] [Indexed: 05/05/2024]
Abstract
Human autoimmunity against elements conferring protective immunity can be symbolized by the 'ouroboros', a snake eating its own tail. Underlying infection is autoimmunity against three immunological targets: neutrophils, complement and cytokines. Autoantibodies against neutrophils can cause peripheral neutropenia underlying mild pyogenic bacterial infections. The pathogenic contribution of autoantibodies against molecules of the complement system is often unclear, but autoantibodies specific for C3 convertase can enhance its activity, lowering complement levels and underlying severe bacterial infections. Autoantibodies neutralizing granulocyte-macrophage colony-stimulating factor impair alveolar macrophages, thereby underlying pulmonary proteinosis and airborne infections, type I interferon viral diseases, type II interferon intra-macrophagic infections, interleukin-6 pyogenic bacterial diseases and interleukin-17A/F mucocutaneous candidiasis. Each of these five cytokine autoantibodies underlies a specific range of infectious diseases, phenocopying infections that occur in patients with the corresponding inborn errors. In this Review, we analyze this ouroboros of immunity against immunity and posit that it should be considered as a factor in patients with unexplained infection.
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Affiliation(s)
- Jean-Laurent Casanova
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, New York, NY, USA.
- Howard Hughes Medical Institute, New York, NY, USA.
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, Necker Hospital for Sick Children, Paris, France.
- Paris Cité University, Imagine Institute, Paris, France.
- Pediatric Hematology-Immunology and Rheumatology Unit, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
| | - Jessica Peel
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, New York, NY, USA
| | - Jean Donadieu
- Trousseau Hospital for Sick Children, Centre de référence des neutropénies chroniques, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
| | - Anna-Lena Neehus
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, Necker Hospital for Sick Children, Paris, France
- Paris Cité University, Imagine Institute, Paris, France
| | - Anne Puel
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, New York, NY, USA
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, Necker Hospital for Sick Children, Paris, France
- Paris Cité University, Imagine Institute, Paris, France
| | - Paul Bastard
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, New York, NY, USA
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, Necker Hospital for Sick Children, Paris, France
- Paris Cité University, Imagine Institute, Paris, France
- Pediatric Hematology-Immunology and Rheumatology Unit, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
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40
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Vera IM, Kessler A, Harawa V, Ahmadu A, Keller TE, Ray ST, Taylor TE, Rogerson SJ, Mandala WL, Reyes Gil M, Seydel KB, Kim K. Prothrombotic autoantibodies targeting platelet factor 4/polyanion are associated with pediatric cerebral malaria. J Clin Invest 2024; 134:e176466. [PMID: 38652559 PMCID: PMC11142751 DOI: 10.1172/jci176466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 04/09/2024] [Indexed: 04/25/2024] Open
Abstract
BACKGROUNDFeatures of consumptive coagulopathy and thromboinflammation are prominent in cerebral malaria (CM). We hypothesized that thrombogenic autoantibodies contribute to a procoagulant state in CM.METHODSPlasma from children with uncomplicated malaria (UM) (n = 124) and CM (n = 136) was analyzed by ELISA for a panel of 8 autoantibodies including anti-platelet factor 4/polyanion (anti-PF4/P), anti-phospholipid, anti-phosphatidylserine, anti-myeloperoxidase, anti-proteinase 3, anti-dsDNA, anti-β-2-glycoprotein I, and anti-cardiolipin. Plasma samples from individuals with nonmalarial coma (NMC) (n = 49) and healthy controls (HCs) (n = 56) were assayed for comparison. Associations with clinical and immune biomarkers were determined using univariate and logistic regression analyses.RESULTSMedian anti-PF4/P and anti-PS IgG levels were elevated in individuals with malaria infection relative to levels in HCs (P < 0.001) and patients with NMC (PF4/P: P < 0.001). Anti-PF4/P IgG levels were elevated in children with CM (median = 0.27, IQR: 0.19-0.41) compared with those with UM (median = 0.19, IQR: 0.14-0.22, P < 0.0001). Anti-PS IgG levels did not differ between patients with UM and those with CM (P = 0.39). When patients with CM were stratified by malaria retinopathy (Ret) status, the levels of anti-PF4/P IgG correlated negatively with the peripheral platelet count in patients with Ret+ CM (Spearman's rho [Rs] = 0.201, P = 0.04) and associated positively with mortality (OR = 15.2, 95% CI: 1.02-275, P = 0.048). Plasma from patients with CM induced greater platelet activation in an ex vivo assay relative to plasma from patients with UM (P = 0.02), and the observed platelet activation was associated with anti-PF4/P IgG levels (Rs= 0.293, P = 0.035).CONCLUSIONSThrombosis mediated by elevated anti-PF4/P autoantibodies may be one mechanism contributing to the clinical complications of CM.
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Affiliation(s)
- Iset M. Vera
- Division of Infectious Disease and International Medicine, Department of Internal Medicine, University of South Florida, Tampa, Florida, USA
| | - Anne Kessler
- Center for Genomics and Systems Biology, Department of Biology, New York University, New York, New York, USA
| | - Visopo Harawa
- Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi
- Biomedical Department, University of Malawi College of Medicine, Blantyre, Malawi
- Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi
| | - Ajisa Ahmadu
- Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi
| | - Thomas E. Keller
- Division of Infectious Disease and International Medicine, Department of Internal Medicine, University of South Florida, Tampa, Florida, USA
| | - Stephen T.J. Ray
- Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi
- Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi
- Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, United Kingdom
- Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, United Kingdom
| | - Terrie E. Taylor
- Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi
- Department of Osteopathic Medical Specialties, Michigan State University, East Lansing, Michigan, USA
| | - Stephen J. Rogerson
- Department of Medicine (RMH), and
- Department of Infectious Diseases, Doherty Institute, The University of Melbourne, Melbourne, Australia
| | - Wilson L. Mandala
- Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi
- Biomedical Department, University of Malawi College of Medicine, Blantyre, Malawi
- Academy of Medical Sciences, Malawi University of Science and Technology, Thyolo, Malawi
| | - Morayma Reyes Gil
- Department of Pathology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, USA
| | - Karl B. Seydel
- Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi
- Department of Osteopathic Medical Specialties, Michigan State University, East Lansing, Michigan, USA
| | - Kami Kim
- Division of Infectious Disease and International Medicine, Department of Internal Medicine, University of South Florida, Tampa, Florida, USA
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41
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Li Q, Li J, Zhou M, Ge Y, Liu Z, Li T, Zhang L. Antiphospholipid antibody-related hepatic vasculitis in a juvenile after non-severe COVID-19: a case report and literature review. Front Immunol 2024; 15:1354349. [PMID: 38707895 PMCID: PMC11066154 DOI: 10.3389/fimmu.2024.1354349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 03/29/2024] [Indexed: 05/07/2024] Open
Abstract
Antiphospholipid antibodies (aPL) are both laboratory evidence and causative factors for a broad spectrum of clinical manifestations of antiphospholipid syndrome (APS), with thrombotic and obstetric events being the most prevalent. Despite the aPL-triggered vasculopathy nature of APS, vasculitic-like manifestations rarely exist in APS and mainly appear associated with other concurrent connective tissue diseases like systemic lupus erythematous. Several studies have characterized pulmonary capillaritis related to pathogenic aPL, suggesting vasculitis as a potential associated non-thrombotic manifestation. Here, we describe a 15-year-old girl who develops hepatic infarction in the presence of highly positive aPL, temporally related to prior non-severe COVID-19 infection. aPL-related hepatic vasculitis, which has not been reported before, contributes to liver ischemic necrosis. Immunosuppression therapy brings about favorable outcomes. Our case together with retrieved literature provides supportive evidence for aPL-related vasculitis, extending the spectrum of vascular changes raised by pathogenic aPL. Differentiation between thrombotic and vasculitic forms of vascular lesions is essential for appropriate therapeutic decision to include additional immunosuppression therapy. We also perform a systematic review to characterize the prevalence and clinical features of new-onset APS and APS relapses after COVID-19 for the first time, indicating the pathogenicity of aPL in a subset of COVID-19 patients.
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Affiliation(s)
- Qingyu Li
- Tsinghua Medicine, School of Medicine, Tsinghua University, Beijing, China
- Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Jingya Li
- Tsinghua Medicine, School of Medicine, Tsinghua University, Beijing, China
- Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Menglan Zhou
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Beijing, China
| | - Ying Ge
- Department of Infectious Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Zhengyin Liu
- Department of Infectious Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Taisheng Li
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Beijing, China
- Department of Infectious Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Li Zhang
- Department of Infectious Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
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42
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Safhi AY, Albariqi AH, Sabei FY, Alsalhi A, Khalil FMA, Waheed A, Arbi FM, White A, Anthony S, Alissa M. Journey into tomorrow: cardiovascular wellbeing transformed by nano-scale innovations. Curr Probl Cardiol 2024; 49:102428. [PMID: 38311274 DOI: 10.1016/j.cpcardiol.2024.102428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Accepted: 01/29/2024] [Indexed: 02/10/2024]
Abstract
Worldwide, cardiovascular diseases (CVDs) account for the vast majority of deaths and place enormous financial strains on healthcare systems. Gold nanoparticles, quantum dots, polymeric nanoparticles, carbon nanotubes, and lipids are innovative nanomaterials promising in tackling CVDs. In the setting of CVDs, these nanomaterials actively impact cellular responses due to their distinctive properties, including surface energy and topographies. Opportunities to more precisely target CVDs have arisen due to recent developments in nanomaterial science, which have introduced fresh approaches. An in-depth familiarity with the illness and its targeted mechanisms is necessary to use nanomaterials in CVDs effectively. We support the academic community's efforts to prioritize Nano-technological techniques in addressing risk factors linked with cardiovascular diseases, acknowledging the far-reaching effects of these conditions. The significant impact of nanotechnology on the early detection and treatment of cardiovascular diseases highlights the critical need for novel approaches to this pressing health problem, which is affecting people worldwide.
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Affiliation(s)
- Awaji Y Safhi
- Department of Pharmaceutics, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia
| | - Ahmed H Albariqi
- Department of Pharmaceutics, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia
| | - Fahad Y Sabei
- Department of Pharmaceutics, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia
| | - Abdullah Alsalhi
- Department of Pharmaceutics, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia
| | - Fatma Mohamed Ameen Khalil
- King Khalid University, Collage of Science and Art, Department of Biology, Mohayil Asir Abha 61421, Saudi Arabia
| | | | - Fawad Mueen Arbi
- Quaid-e-Azam Medical College, Bahawalpur, Punjab 63100, Pakistan
| | - Alexandra White
- Liaoning Provincial Key Laboratory of Cerebral Diseases, Department of Physiology, Dalian Medical University Liaoning Provence China, PR China
| | - Stefan Anthony
- Cardiovascular Center of Excellence at Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
| | - Mohammed Alissa
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
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Tóth E, Fagyas M, Nagy B, Siket IM, Szőke B, Mártha L, Mahdi M, Erdősi G, Pólik Z, Kappelmayer J, Papp Z, Borbély A, Szabó T, Balla J, Balla G, Bácsi A, Szekanecz Z, Bai P, Tóth A. Distinct subsets of anti-pulmonary autoantibodies correlate with disease severity and survival in severe COVID-19 patients. GeroScience 2024; 46:1561-1574. [PMID: 37656328 PMCID: PMC10828368 DOI: 10.1007/s11357-023-00887-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 07/24/2023] [Indexed: 09/02/2023] Open
Abstract
Autoantibodies targeting the lung tissue were identified in severe COVID-19 patients in this retrospective study. Fifty-three percent of 104 patients developed anti-pulmonary antibodies, the majority of which were IgM class, suggesting that they developed upon infection with SARS-CoV-2. Anti-pulmonary antibodies correlated with worse pulmonary function and a higher risk of multiorgan failure that was further aggravated if 3 or more autoantibody clones were simultaneously present (multi-producers). Multi-producer patients were older than the patients with less or no autoantibodies. One of the identified autoantibodies (targeting a pulmonary protein of ~ 50 kDa) associated with worse clinical outcomes, including mortality. In summary, severe COVID-19 is associated with the development of lung-specific autoantibodies, which may worsen the clinical outcome. Tissue proteome-wide tests, such as the ones applied here, can be used to detect autoimmunity in the post-COVID state to identify the cause of symptoms and to reveal a new target for treatment.
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Affiliation(s)
- Emese Tóth
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032, Debrecen, Hungary
- Center of Excellence, The Hungarian Academy of Sciences, Budapest, Hungary
| | - Miklós Fagyas
- Division of Cardiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Béla Nagy
- Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Ivetta Mányiné Siket
- Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Blanka Szőke
- Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Lilla Mártha
- Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Mohamed Mahdi
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Gábor Erdősi
- Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Zsófia Pólik
- Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - János Kappelmayer
- Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Zoltán Papp
- Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- ELKH-UD Vascular Biology and Myocardial Pathophysiology Research Group, Hungarian Academy of Sciences, Budapest, Hungary
- Research Center for Molecular Medicine, Faculty of Medicine, University of Debrecen, 4032, Debrecen, Hungary
| | - Attila Borbély
- Division of Cardiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Tamás Szabó
- Department of Pediatrics, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - József Balla
- ELKH-UD Vascular Biology and Myocardial Pathophysiology Research Group, Hungarian Academy of Sciences, Budapest, Hungary
- Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - György Balla
- ELKH-UD Vascular Biology and Myocardial Pathophysiology Research Group, Hungarian Academy of Sciences, Budapest, Hungary
- Department of Pediatrics, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Attila Bácsi
- Department of Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Zoltán Szekanecz
- Department of Rheumatology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Péter Bai
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032, Debrecen, Hungary.
- Center of Excellence, The Hungarian Academy of Sciences, Budapest, Hungary.
- Research Center for Molecular Medicine, Faculty of Medicine, University of Debrecen, 4032, Debrecen, Hungary.
- MTA-DE Cell Biology and Signaling Research Group ELKH, Debrecen, 4032, Hungary.
- MTA-DE Lendület Laboratory of Cellular Metabolism, 4032, Debrecen, Hungary.
| | - Attila Tóth
- Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
- ELKH-UD Vascular Biology and Myocardial Pathophysiology Research Group, Hungarian Academy of Sciences, Budapest, Hungary.
- Research Center for Molecular Medicine, Faculty of Medicine, University of Debrecen, 4032, Debrecen, Hungary.
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Bergaglio T, Synhaivska O, Nirmalraj PN. 3D Holo-tomographic Mapping of COVID-19 Microclots in Blood to Assess Disease Severity. CHEMICAL & BIOMEDICAL IMAGING 2024; 2:194-204. [PMID: 39474148 PMCID: PMC11503935 DOI: 10.1021/cbmi.3c00126] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Revised: 12/13/2023] [Accepted: 12/15/2023] [Indexed: 04/15/2025]
Abstract
The coronavirus disease 2019 (COVID-19) has impacted health globally. Cumulative evidence points to long-term effects of COVID-19 such as cardiovascular and cognitive disorders, diagnosed in patients even after the recovery period. In particular, micrometer-sized blood clots and hyperactivated platelets have been identified as potential indicators of long COVID. Here, we resolve microclot structures in the plasma of patients with different subphenotypes of COVID-19 in a label-free manner, using 3D digital holo-tomographic microscopy (DHTM). Based on 3D refractive index (RI) tomograms, the size, dry mass, and prevalence of microclot composites were quantified and then parametrically differentiated from fibrin-rich microclots and platelet aggregates in the plasma of COVID-19 patients. Importantly, fewer microclots and platelet aggregates were detected in the plasma of healthy controls compared to COVID-19 patients. Our imaging and analysis workflow is built around a commercially available DHT microscope capable of operation in clinical settings with a 2 h time period from sample preparation and data acquisition to results.
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Affiliation(s)
- Talia Bergaglio
- Transport
at Nanoscale Interfaces Laboratory, Swiss
Federal Laboratories for Materials Science and Technology, Dübendorf CH-8600, Switzerland
- Graduate
School for Cellular and Biomedical Sciences, University of Bern, Bern CH-3012, Switzerland
| | - Olena Synhaivska
- Transport
at Nanoscale Interfaces Laboratory, Swiss
Federal Laboratories for Materials Science and Technology, Dübendorf CH-8600, Switzerland
| | - Peter Niraj Nirmalraj
- Transport
at Nanoscale Interfaces Laboratory, Swiss
Federal Laboratories for Materials Science and Technology, Dübendorf CH-8600, Switzerland
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Müller-Calleja N, Grunz K, Nguyen TS, Posma J, Pedrosa D, Meineck M, Hollerbach A, Braun J, Muth S, Schild H, Saar K, Hübner N, Krishnaswamy S, Royce J, Teyton L, Lemmermann N, Weinmann-Menke J, Lackner KJ, Ruf W. Targeting the tissue factor coagulation initiation complex prevents antiphospholipid antibody development. Blood 2024; 143:1167-1180. [PMID: 38142429 PMCID: PMC10972716 DOI: 10.1182/blood.2023022276] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 12/08/2023] [Accepted: 12/13/2023] [Indexed: 12/26/2023] Open
Abstract
ABSTRACT Antiphospholipid antibodies (aPL) in primary or secondary antiphospholipid syndrome (APS) are a major cause for acquired thrombophilia, but specific interventions preventing autoimmune aPL development are an unmet clinical need. Although autoimmune aPL cross react with various coagulation regulatory proteins, lipid-reactive aPL, including those derived from patients with COVID-19, recognize the endolysosomal phospholipid lysobisphosphatidic acid presented by the cell surface-expressed endothelial protein C receptor. This specific recognition leads to complement-mediated activation of tissue factor (TF)-dependent proinflammatory signaling and thrombosis. Here, we show that specific inhibition of the TF coagulation initiation complex with nematode anticoagulant protein c2 (NAPc2) prevents the prothrombotic effects of aPL derived from patients with COVID-19 in mice and the aPL-induced proinflammatory and prothrombotic activation of monocytes. The induction of experimental APS is dependent on the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex, and NAPc2 suppresses monocyte endosomal reactive oxygen species production requiring the TF cytoplasmic domain and interferon-α secretion from dendritic cells. Latent infection with murine cytomegalovirus causes TF cytoplasmic domain-dependent development of persistent aPL and circulating phospholipid-reactive B1 cells, which is prevented by short-term intervention with NAPc2 during acute viral infection. In addition, treatment of lupus prone MRL-lpr mice with NAPc2, but not with heparin, suppresses dendritic-cell activation in the spleen, aPL production and circulating phospholipid-reactive B1 cells, and attenuates lupus pathology. These data demonstrate a convergent TF-dependent mechanism of aPL development in latent viral infection and autoimmune disease and provide initial evidence that specific targeting of the TF initiation complex has therapeutic benefits beyond currently used clinical anticoagulant strategies.
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Affiliation(s)
- Nadine Müller-Calleja
- Center for Thrombosis and Hemostasis, Johannes Gutenberg University Medical Center, Mainz, Germany
- Institute of Clinical Chemistry and Laboratory Medicine, Johannes Gutenberg University Medical Center, Mainz, Germany
| | - Kristin Grunz
- Center for Thrombosis and Hemostasis, Johannes Gutenberg University Medical Center, Mainz, Germany
| | - T. Son Nguyen
- Center for Thrombosis and Hemostasis, Johannes Gutenberg University Medical Center, Mainz, Germany
| | - Jens Posma
- Center for Thrombosis and Hemostasis, Johannes Gutenberg University Medical Center, Mainz, Germany
| | - Denise Pedrosa
- Center for Thrombosis and Hemostasis, Johannes Gutenberg University Medical Center, Mainz, Germany
| | - Myriam Meineck
- Department of Medicine I, Johannes Gutenberg University Medical Center, Mainz, Germany
| | - Anne Hollerbach
- Institute of Clinical Chemistry and Laboratory Medicine, Johannes Gutenberg University Medical Center, Mainz, Germany
| | - Johannes Braun
- Center for Thrombosis and Hemostasis, Johannes Gutenberg University Medical Center, Mainz, Germany
| | - Sabine Muth
- Institute for Immunology, Johannes Gutenberg University Medical Center, Mainz, Germany
| | - Hansjörg Schild
- Institute for Immunology, Johannes Gutenberg University Medical Center, Mainz, Germany
| | - Kathrin Saar
- Max Delbrück Center for Molecular Medicine, Berlin, Germany
- Charite-Universitätsmedizin Berlin, Berlin, Germany
- German Center for Cardiovascular Research (DZHK), Partner site Berlin, Berlin, Germany
| | - Norbert Hübner
- Max Delbrück Center for Molecular Medicine, Berlin, Germany
- Charite-Universitätsmedizin Berlin, Berlin, Germany
- German Center for Cardiovascular Research (DZHK), Partner site Berlin, Berlin, Germany
| | - Sriram Krishnaswamy
- Department of Pediatrics, Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA
| | - Jennifer Royce
- Department of Immunology and Microbiology, Scripps Research, La Jolla, CA
| | - Luc Teyton
- Department of Immunology and Microbiology, Scripps Research, La Jolla, CA
| | - Niels Lemmermann
- Institute for Virology, Johannes Gutenberg University Medical Center, Mainz, Germany
- Institute of Virology, University Hospital Bonn, Bonn, Germany
| | - Julia Weinmann-Menke
- Department of Medicine I, Johannes Gutenberg University Medical Center, Mainz, Germany
| | - Karl J. Lackner
- Institute of Clinical Chemistry and Laboratory Medicine, Johannes Gutenberg University Medical Center, Mainz, Germany
| | - Wolfram Ruf
- Center for Thrombosis and Hemostasis, Johannes Gutenberg University Medical Center, Mainz, Germany
- Department of Immunology and Microbiology, Scripps Research, La Jolla, CA
- German Center for Cardiovascular Research (DZHK), Partner site Rhein-Main, Mainz, Germany
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46
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Geanes ES, McLennan R, LeMaster C, Bradley T. Autoantibodies to ACE2 and immune molecules are associated with COVID-19 disease severity. COMMUNICATIONS MEDICINE 2024; 4:47. [PMID: 38491326 PMCID: PMC10943194 DOI: 10.1038/s43856-024-00477-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Accepted: 03/05/2024] [Indexed: 03/18/2024] Open
Abstract
BACKGROUND Increased inflammation caused by SARS-CoV-2 infection can lead to severe coronavirus disease 2019 (COVID-19) and long-term disease manifestations. The mechanisms of this variable long-term immune activation are poorly defined. One feature of this increased inflammation is elevated levels of proinflammatory cytokines and chemokines. Autoantibodies targeting immune factors such as cytokines, as well as the viral host cell receptor, angiotensin-converting enzyme 2 (ACE2), have been observed after SARS-CoV-2 infection. Autoantibodies to immune factors and ACE2 could interfere with normal immune regulation and lead to increased inflammation, severe COVID-19, and long-term complications. METHODS Here, we deeply profiled the features of ACE2, cytokine, and chemokine autoantibodies in samples from patients recovering from severe COVID-19. We measured the levels of immunoglobulin subclasses (IgG, IgA, IgM) in the peripheral blood against ACE2 and 23 cytokines and other immune molecules. We then utilized an ACE2 peptide microarray to map the linear epitopes targeted by ACE2 autoantibodies. RESULTS We demonstrate that ACE2 autoantibody levels are increased in individuals with severe COVID-19 compared with those with mild infection or no prior infection. We identify epitopes near the catalytic domain of ACE2 targeted by these antibodies. Levels of autoantibodies targeting ACE2 and other immune factors could serve as determinants of COVID-19 disease severity, and represent a natural immunoregulatory mechanism in response to viral infection. CONCLUSIONS These results demonstrate that SARS-CoV-2 infection can increase autoantibody levels to ACE2 and other immune factors. The levels of these autoantibodies are associated with COVID-19 disease severity.
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Affiliation(s)
- Eric S Geanes
- Genomic Medicine Center, Children's Mercy Research Institute, Kansas City, MO, USA
| | - Rebecca McLennan
- Genomic Medicine Center, Children's Mercy Research Institute, Kansas City, MO, USA
| | - Cas LeMaster
- Genomic Medicine Center, Children's Mercy Research Institute, Kansas City, MO, USA
| | - Todd Bradley
- Genomic Medicine Center, Children's Mercy Research Institute, Kansas City, MO, USA.
- Department of Pediatrics, University of Missouri, Kansas City, MO, USA.
- Department of Pediatrics, University of Kansas Medical Center, Kansas City, KS, USA.
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
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47
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Kuo YM, Kang CM, Lai ZY, Huang TY, Tzeng SJ, Hsu CC, Chen SY, Hsieh SC, Chia JS, Jung CJ, Hsueh PR. Temporal changes in biomarkers of neutrophil extracellular traps and NET-promoting autoantibodies following adenovirus-vectored, mRNA, and recombinant protein COVID-19 vaccination. J Med Virol 2024; 96:e29556. [PMID: 38511554 DOI: 10.1002/jmv.29556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 03/01/2024] [Accepted: 03/12/2024] [Indexed: 03/22/2024]
Abstract
Neutrophil extracellular traps (NETs) play a role in innate pathogen defense and also trigger B-cell response by providing antigens. NETs have been linked to vaccine-induced thrombotic thrombocytopenia. We postulated a potential link between NET biomarkers, NET-promoting autoantibodies, and adverse events (AEs) after COVID-19 vaccine boosters. Healthy donors (HDs) who received ChAdOx1-S (A), mRNA-1273 (M), or recombinant protein (MVC-COV1901) vaccines at the National Taiwan University Hospital between 2021 and 2022 were recruited. We measured serial NET-associated biomarkers, citrullinated-histone3 (citH3), and myeloperoxidase (MPO)-DNA. Serum citH3 and MPO-DNA were significantly or numerically higher in HDs who reported AEs (n = 100, booster Day 0/Day 30, p = 0.01/p = 0.03 and p = 0.30/p = 0.35, respectively). We also observed a positive correlation between rash occurrence in online diaries and elevated citH3. A linear mixed model also revealed significantly higher citH3 levels in mRNA-1273/ChAdOx1-S recipients than MVC-COV1901 recipients. Significant positive correlations were observed between the ratios of anti-heparin platelet factor 4 and citH3 levels on Booster Day 0 and naïve and between the ratios of anti-NET IgM and citH3 on Booster Day 30/Day 0 in the AA-M and MM-M group, respectively. The increased levels of citH3/MPO-DNA accompanied by NET-promoting autoantibodies suggest a potential connection between mRNA-1273/ChAdOx1-S vaccines and cardiovascular complications. These findings provide insights for risk assessments of future vaccines.
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Affiliation(s)
- Yu-Min Kuo
- Department of Internal Medicine, Division of Allergy, Immunology and Rheumatology, National Taiwan University, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chun-Min Kang
- Department of Laboratory Medicine, National Taiwan University, Taipei, Taiwan
| | - Zhi-Yun Lai
- Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Ting-Yu Huang
- Department of Internal Medicine, Division of Infection, National Taiwan University, Taipei, Taiwan
| | - Shiang-Jong Tzeng
- Department and Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chih-Chieh Hsu
- Department of Internal Medicine, Division of Infection, National Taiwan University, Taipei, Taiwan
| | - Shey-Ying Chen
- Department of Emergency Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Song-Chou Hsieh
- Department of Internal Medicine, Division of Allergy, Immunology and Rheumatology, National Taiwan University, Taipei, Taiwan
| | - Jean-San Chia
- Department of Dentistry, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chiau-Jing Jung
- Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Po-Ren Hsueh
- Departments of Laboratory Medicine and Internal Medicine, China Medical University Hospital, China Medical University, Taichung, Taiwan
- Departments of Laboratory Medicine and Internal Medicine, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan
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48
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Thachil J, Favaloro EJ, Lippi G. Are Antiphospholipid Antibodies a Surrogate Risk Factor for Thrombosis in Sepsis? Semin Thromb Hemost 2024; 50:284-287. [PMID: 37506732 DOI: 10.1055/s-0043-1771268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/30/2023]
Abstract
Antiphospholipid syndrome (APS) is a hypercoagulable state caused by antiphospholipid antibodies (aPL). APS clinically manifests with arterial or venous or microvascular thrombi and/or pregnancy complications. It is well-known that the development of aPL can be a transient phenomenon and thus the current diagnostic criterion for APS requires repeat laboratory testing several weeks apart before a definitive diagnosis is made. However, transient presence of aPL may also be pathogenic. In this article, we attempt to give historical and clinical evidence for the importance of these antibodies, even when transient, and call for further research into mechanisms by which these antibodies may promote thrombosis and pregnancy morbidities.
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Affiliation(s)
- Jecko Thachil
- Department of Haematology, Manchester University Hospitals, Manchester, United Kingdom
| | - Emmanuel J Favaloro
- Department of Haematology, Institute of Clinical Pathology and Medical Research (ICPMR), NSW Health Pathology, Westmead Hospital, Westmead, NSW, Australia
- Sydney Centres for Thrombosis and Haemostasis, Westmead, NSW, Australia
- Faculty of Science and Health, Charles Sturt University, Wagga Wagga, NSW, Australia
- School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Westmead Hospital, Westmead, New South Wales, Australia
| | - Giuseppe Lippi
- Section of Clinical Biochemistry, University of Verona, Verona, Italy
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49
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Rao S, Gross RS, Mohandas S, Stein CR, Case A, Dreyer B, Pajor NM, Bunnell HT, Warburton D, Berg E, Overdevest JB, Gorelik M, Milner J, Saxena S, Jhaveri R, Wood JC, Rhee KE, Letts R, Maughan C, Guthe N, Castro-Baucom L, Stockwell MS. Postacute Sequelae of SARS-CoV-2 in Children. Pediatrics 2024; 153:e2023062570. [PMID: 38321938 PMCID: PMC10904902 DOI: 10.1542/peds.2023-062570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/01/2023] [Indexed: 02/08/2024] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic has caused significant medical, social, and economic impacts globally, both in the short and long term. Although most individuals recover within a few days or weeks from an acute infection, some experience longer lasting effects. Data regarding the postacute sequelae of severe acute respiratory syndrome coronavirus 2 infection (PASC) in children, or long COVID, are only just emerging in the literature. These symptoms and conditions may reflect persistent symptoms from acute infection (eg, cough, headaches, fatigue, and loss of taste and smell), new symptoms like dizziness, or exacerbation of underlying conditions. Children may develop conditions de novo, including postural orthostatic tachycardia syndrome, myalgic encephalomyelitis/chronic fatigue syndrome, autoimmune conditions and multisystem inflammatory syndrome in children. This state-of-the-art narrative review provides a summary of our current knowledge about PASC in children, including prevalence, epidemiology, risk factors, clinical characteristics, underlying mechanisms, and functional outcomes, as well as a conceptual framework for PASC based on the current National Institutes of Health definition. We highlight the pediatric components of the National Institutes of Health-funded Researching COVID to Enhance Recovery Initiative, which seeks to characterize the natural history, mechanisms, and long-term health effects of PASC in children and young adults to inform future treatment and prevention efforts. These initiatives include electronic health record cohorts, which offer rapid assessments at scale with geographical and demographic diversity, as well as longitudinal prospective observational cohorts, to estimate disease burden, illness trajectory, pathobiology, and clinical manifestations and outcomes.
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Affiliation(s)
- Suchitra Rao
- Department of Pediatrics, University of Colorado School of Medicine and Children’s Hospital Colorado, Aurora, Colorado
| | - Rachel S. Gross
- Departments of Pediatrics
- Population Health, NYU Grossman School of Medicine, New York, New York
| | - Sindhu Mohandas
- Division of Infectious Diseases
- Department of Pediatrics and Radiology, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Cheryl R. Stein
- Child and Adolescent Psychiatry, New York University Grossman School of Medicine, New York, New York
| | - Abigail Case
- Department of Pediatrics and Rehabilitation Medicine, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Benard Dreyer
- Department of Pediatrics and Radiology, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Nathan M. Pajor
- Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - H. Timothy Bunnell
- Biomedical Research Informatics Center, Nemours Children’s Health, Nemours Children’s Hospital, Delaware, Wilmington, Delaware
| | - David Warburton
- Department of Pediatrics and Radiology, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Elizabeth Berg
- Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons, New York, New York
| | - Jonathan B. Overdevest
- Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons, New York, New York
| | - Mark Gorelik
- Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons, New York, New York
| | - Joshua Milner
- Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons, New York, New York
| | - Sejal Saxena
- Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons, New York, New York
| | - Ravi Jhaveri
- Division of Infectious Diseases, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois
| | - John C. Wood
- Department of Pediatrics and Radiology, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Kyung E. Rhee
- Department of Pediatrics, University of California, San Diego, School of Medicine, San Diego, California
| | - Rebecca Letts
- Population Health, NYU Grossman School of Medicine, New York, New York
| | - Christine Maughan
- Population Health, NYU Grossman School of Medicine, New York, New York
| | - Nick Guthe
- Population Health, NYU Grossman School of Medicine, New York, New York
| | | | - Melissa S. Stockwell
- Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons, New York, New York
- Department of Population and Family Health, Columbia University Mailman School of Public Health, New York, New York
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50
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Verma A, Manojkumar A, Dhasmana A, Tripathi MK, Jaggi M, Chauhan SC, Chauhan DS, Yallapu MM. Recurring SARS-CoV-2 variants: an update on post-pandemic, co-infections and immune response. Nanotheranostics 2024; 8:247-269. [PMID: 38444741 PMCID: PMC10911975 DOI: 10.7150/ntno.91910] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Accepted: 01/30/2024] [Indexed: 03/07/2024] Open
Abstract
The post-pandemic era following the global spread of the SARS-CoV-2 virus has brought about persistent concerns regarding recurring coinfections. While significant strides in genome mapping, diagnostics, and vaccine development have controlled the pandemic and reduced fatalities, ongoing virus mutations necessitate a deeper exploration of the interplay between SARS-CoV-2 mutations and the host's immune response. Various vaccines, including RNA-based ones like Pfizer and Moderna, viral vector vaccines like Johnson & Johnson and AstraZeneca, and protein subunit vaccines like Novavax, have played critical roles in mitigating the impact of COVID-19. Understanding their strengths and limitations is crucial for tailoring future vaccines to specific variants and individual needs. The intricate relationship between SARS-CoV-2 mutations and the immune response remains a focus of intense research, providing insights into personalized treatment strategies and long-term effects like long-COVID. This article offers an overview of the post-pandemic landscape, highlighting emerging variants, summarizing vaccine platforms, and delving into immunological responses and the phenomenon of long-COVID. By presenting clinical findings, it aims to contribute to the ongoing understanding of COVID-19's progression in the aftermath of the pandemic.
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Affiliation(s)
- Ashmit Verma
- Divyasampark iHub Roorkee for Devices Materials and Technology Foundation, Indian Institute of Technology Roorkee, Uttarakhand, 247667, India
- Samrat Ashok Technological Institute, Vidisha, Madhya Pradesh, 464001, India
| | - Anjali Manojkumar
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, Texas 78504, USA
- Department of Biology, College of Science, University of Texas Rio Grande Valley, McAllen, Texas 78504, USA
| | - Anupam Dhasmana
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, Texas 78504, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, Texas 78504, USA
| | - Manish K. Tripathi
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, Texas 78504, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, Texas 78504, USA
| | - Meena Jaggi
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, Texas 78504, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, Texas 78504, USA
| | - Subhash C. Chauhan
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, Texas 78504, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, Texas 78504, USA
| | - Deepak S. Chauhan
- Faculté de Pharmacie, Université de Montréal, Montréal H3C 3J7, QC, Canada
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada
- Department of Pediatrics, IWK Research Center, Halifax, NS, Canada
| | - Murali M. Yallapu
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, Texas 78504, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, Texas 78504, USA
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