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Sato M, Nagai K, Sato T, Yoshimoto R, Shibano Y, Shibahara M, Satokawa H, Anzai M, Uchida T, Tsutiya A, Takakuwa Y, Omoteyama K, Arito M, Suematsu N, Ooka S, Kawahata K, Kato T, Kurokawa MS. Aberrant oxidative modifications of neutrophil myeloperoxidase in anti-neutrophil cytoplasmic antibody-associated vasculitis. J Proteomics 2025; 315:105412. [PMID: 39993524 DOI: 10.1016/j.jprot.2025.105412] [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: 11/16/2024] [Revised: 02/20/2025] [Accepted: 02/21/2025] [Indexed: 02/26/2025]
Abstract
Anti-neutrophil cytoplasmic antibodies directed to myeloperoxidase (MPO-ANCA) are key molecules in the pathogenesis of ANCA-associated vasculitis (AAV), however, the mechanisms of autoantibody production have not been elucidated. We hypothesized that an aberrant PTM occurs in the MPO of MPO-ANCA-positive AAV (MPO-AAV), which induces immune responses to self MPO. To test this, we purified MPO proteins from neutrophils of 8 patients with MPO-AAV and 8 healthy subjects, digested them with trypsin, and comprehensively quantified PTMs of the MPO peptides using the sequential window acquisition of all theoretical fragment ion spectra (SWATH) method of LC-MS. Among the 1034 detected MPO peptides, 38 peptides were increased in the patients with MPO-AAV relative to the healthy subjects, whereas 10 peptides were decreased in the patients (p < 0.05). Interestingly, oxidative modifications were found in 11 of the 38 increased peptides (1.14- to 3.29-fold), but not in the decreased peptides. These included oxidation of Met577, Phe686, Met688 and Met719, dioxidation of Met409, Phe605, Trp679 and Met719, and kynurenylation of Trp255. Conversely, glycosylation was detected in 4 of the 10 decreased peptides (-1.32- to -2.32-fold), but not in the increased peptides. They were O-type glycans at Ser357 and Ser731, and N-type glycans at Asn355 and Asn729. In animal experiments, immunization of mice with in vitro oxidized or unoxidized mouse MPO (mMPO) showed that not only anti-oxidized mMPO antibodies but also anti-unoxidized mMPO antibodies were preferentially produced in the oxidized mMPO-immunized mice relative to the unoxidized mMPO-immunized mice (anti-oxidized mMPO antibodies, 6/8 vs 1/9, p < 0.05; anti-unoxidized mMPO antibodies, 4/8 vs 0/9, p < 0.05). Our results suggest that the increased oxidative modifications of MPO in MPO-AAV may break immune tolerance and trigger the MPO-ANCA production. SIGNIFICANCE: AAV is a systemic and refractory disease that causes life-threatening multi-organ involvement such as necrotizing glomerulonephritis and lung hemorrhage. MPO-ANCA is an autoantibody that plays a key role in the pathogenesis of AAV. Therefore, elucidation of the mechanism of MPO-ANCA production is crucial to overcoming this disease. In this study, we applied a SWATH-MS analysis to the detection of aberrant PTMs, and found increased oxidative modifications of neutrophil MPO in patients with MPO-AAV for the first time. Immunization of in vitro oxidized MPO induced autoantibodies to the intact unoxidized MPO, suggesting that the increased oxidative modifications of MPO may break the immune tolerance in MPO-AAV. This study suggests a novel trigger mechanism for MPO-ANCA production.
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Affiliation(s)
- Masaaki Sato
- Clinical Proteomics and Molecular Medicine, St. Marianna University Graduate School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511, Japan.
| | - Kouhei Nagai
- Graduate School of Biology-Oriented Science and Technology, Kindai University, 930 Nishimitani, Kinokawa, Wakayama 649-6493, Japan.
| | - Toshiyuki Sato
- Clinical Proteomics and Molecular Medicine, St. Marianna University Graduate School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511, Japan.
| | - Ryo Yoshimoto
- Graduate School of Biology-Oriented Science and Technology, Kindai University, 930 Nishimitani, Kinokawa, Wakayama 649-6493, Japan
| | - Yuto Shibano
- Faculty of Biology-Oriented Science and Technology, Kindai University, 930 Nishimitani, Kinokawa, Wakayama 649-6493, Japan
| | - Minori Shibahara
- Faculty of Biology-Oriented Science and Technology, Kindai University, 930 Nishimitani, Kinokawa, Wakayama 649-6493, Japan
| | - Haruka Satokawa
- Faculty of Biology-Oriented Science and Technology, Kindai University, 930 Nishimitani, Kinokawa, Wakayama 649-6493, Japan
| | - Masayuki Anzai
- Institute of Advanced Technology, Kindai University, 14-1, Minamiakasaka, Kainan, Wakayama 642-0017, Japan.
| | - Teisuke Uchida
- Disease Biomarker Analysis and Molecular Regulation, St. Marianna University Graduate School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511, Japan
| | - Atsuhiro Tsutiya
- Clinical Proteomics and Molecular Medicine, St. Marianna University Graduate School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511, Japan.
| | - Yukiko Takakuwa
- Department of Rheumatology and Allergology, St. Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511, Japan.
| | - Kazuki Omoteyama
- Clinical Proteomics and Molecular Medicine, St. Marianna University Graduate School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511, Japan.
| | - Mitsumi Arito
- Clinical Proteomics and Molecular Medicine, St. Marianna University Graduate School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511, Japan.
| | - Naoya Suematsu
- Clinical Proteomics and Molecular Medicine, St. Marianna University Graduate School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511, Japan.
| | - Seido Ooka
- Department of Rheumatology and Allergology, St. Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511, Japan.
| | - Kimito Kawahata
- Department of Rheumatology and Allergology, St. Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511, Japan.
| | - Tomohiro Kato
- Clinical Proteomics and Molecular Medicine, St. Marianna University Graduate School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511, Japan.
| | - Manae S Kurokawa
- Disease Biomarker Analysis and Molecular Regulation, St. Marianna University Graduate School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511, Japan.
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2
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Mahla RS. Epitope spreading and systemic sclerosis: comment on the article by Kotani et al. Arthritis Rheumatol 2025. [PMID: 40265297 DOI: 10.1002/art.43196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2025] [Accepted: 04/18/2025] [Indexed: 04/24/2025]
Affiliation(s)
- Ranjeet Singh Mahla
- Fred Hutchinson Cancer Center, Seattle, Washington
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom
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Mashhadiagha A, Khalili P, Ataollahi M, Karbasian F, Arman A, Geramizadeh B. COVID-19 Challenges in Autoimmune Hepatitis Management: A Successful Outcome With Intravenous Immune Globulin (IVIg). Case Rep Gastrointest Med 2025; 2025:4446896. [PMID: 40230407 PMCID: PMC11996283 DOI: 10.1155/crgm/4446896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 02/27/2025] [Accepted: 03/24/2025] [Indexed: 04/16/2025] Open
Abstract
Background: Several autoimmune diseases, such as autoimmune hepatitis (AIH), can arise or become decompensated following COVID-19 infection or vaccination; however, there is a lack of data regarding the management of concurrent COVID-19 infection and autoimmune diseases. Case Summary: In this paper, we present a case of a 9-year-old boy with yellowish discoloration of the skin and sclera, abnormal liver function test, followed by positive qRT-PCR for SARS-CoV-2 and progressive bicytopenia. After a lack of response to corticosteroids, intravenous immune globulin (IVIg) was administrated and a decline in liver enzymes, total bilirubin, and direct bilirubin was observed. Result and Discussion: This case illustrates how IVIg significantly improved the AIH symptoms in the patient with positive qRT-PCR for the SARS-CoV-2 test. We hope our report encourages further research on therapeutic approaches for AIH concomitant with COVID-19.
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Affiliation(s)
- Amirali Mashhadiagha
- Shiraz Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Parnian Khalili
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Maryam Ataollahi
- Department of Pediatric Gastroenterology, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Fereshteh Karbasian
- Department of Pediatric Gastroenterology, Shiraz University of Medical Sciences, Shiraz, Iran
- Ali-Asghar Children's Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Arman
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Bita Geramizadeh
- Shiraz Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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4
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Sabaka P, Timárová G, Dababseh M, Marešová E, Straka I. Autoimmune encephalitis associated with anti-SOX1 autoantibodies in COVID-19: A case report. IDCases 2025; 40:e02220. [PMID: 40330578 PMCID: PMC12052691 DOI: 10.1016/j.idcr.2025.e02220] [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: 02/08/2024] [Revised: 03/12/2025] [Accepted: 04/01/2025] [Indexed: 05/08/2025] Open
Abstract
Coronavirus disease 2019 (COVID-19) might be complicated by various non-respiratory conditions, including encephalitis. Encephalitis in COVID-19 represents a heterogenous group of diseases with variable aetiology. Autoimmune encephalitis (AIE) is the least common but one of the most severe causes of encephalopathy in COVID-19. AIE is a rare disease that is associated with different types of autoantibodies mostly directed against various neuronal antigens. Anti-Sry-like high mobility group box (SOX1) autoantibodies have been described in various clinical conditions, including Lambert-Eaton myasthenic syndrome, paraneoplastic cerebellar degeneration and rare cases of paraneoplastic AIE. We present the case of 28-year-old female patient with COVID-19 confirmed by the polymerase chain reaction (PCR) test. She was admitted with fever, headache, disorientation and new-onset refractory status epilepticus. Computed tomography and magnetic resonance imaging of the brain were unremarkable. Cerebrospinal fluid analysis showed pleocytosis, an increased total protein concentration and increased albumin and immunoglobulin G. Electroencephalography revealed findings suggestive of AIE. Serologic examination of antineuronal antibodies showed anti-SOX1 autoantibodies. A course of parenteral methylprednisolone and intravenous immunoglobulin led to rapid clinical improvement. The patient was discharged free of seizures as well as neurologic and psychiatric symptoms. After discharge, an oncologic screening was performed and ruled out a paraneoplastic aetiology.
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Affiliation(s)
- Peter Sabaka
- Department of Infectology and Geographical Medicine, Faculty of Medicine, Comenius University in Bratislava, Bratislava Slovakia
| | - Gabriela Timárová
- 2nd Department of Neurology, Faculty of Medicine, Comenius University in Bratislava, Bratislava, Slovakia
| | - Mohammad Dababseh
- Department of Infectology and Geographical Medicine, Faculty of Medicine, Comenius University in Bratislava, Bratislava Slovakia
| | - Eliška Marešová
- Department of Infectology and Geographical Medicine, Faculty of Medicine, Comenius University in Bratislava, Bratislava Slovakia
| | - Igor Straka
- 2nd Department of Neurology, Faculty of Medicine, Comenius University in Bratislava, Bratislava, Slovakia
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Segal Y, Soltys J, Clarkson BDS, Howe CL, Irani SR, Pittock SJ. Toward curing neurological autoimmune disorders: Biomarkers, immunological mechanisms, and therapeutic targets. Neuron 2025; 113:345-379. [PMID: 39809275 DOI: 10.1016/j.neuron.2024.12.006] [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: 08/21/2024] [Revised: 10/26/2024] [Accepted: 12/04/2024] [Indexed: 01/16/2025]
Abstract
Autoimmune neurology is a rapidly expanding field driven by the discovery of neuroglial autoantibodies and encompassing a myriad of conditions affecting every level of the nervous system. Traditionally, autoantibodies targeting intracellular antigens are considered markers of T cell-mediated cytotoxicity, while those targeting extracellular antigens are viewed as pathogenic drivers of disease. However, recent advances highlight complex interactions between these immune mechanisms, suggesting a continuum of immunopathogenesis. The breakdown of immune tolerance, central to these conditions, is affected by modifiable and non-modifiable risk factors such as genetic predisposition, infections, and malignancy. While significant therapeutic advancements have revolutionized treatment of certain diseases, such as neuromyelitis optica, our understanding of many others, particularly T cell-mediated conditions, remains limited, with fewer treatment options available. Future research should focus on improving effector function modeling and deepening our understanding of the factors influencing immune tolerance, with the goal of providing novel treatment options and improving patient care.
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Affiliation(s)
- Yahel Segal
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA; Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, MN, USA
| | - John Soltys
- Department of Neurosciences, Mayo Clinic, Jacksonville, FL, USA; Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, MN, USA
| | - Benjamin D S Clarkson
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA; Department of Neurology, Mayo Clinic, Rochester, MN, USA; Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, MN, USA
| | - Charles L Howe
- Department of Neurology, Mayo Clinic, Rochester, MN, USA; Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, MN, USA; Division of Experimental Neurology, Mayo Clinic, Rochester, MN, USA
| | - Sarosh R Irani
- Department of Neurosciences, Mayo Clinic, Jacksonville, FL, USA; Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, MN, USA; Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK; Department of Neurology, John Radcliffe Hospital, Oxford University Hospitals, Oxford, UK; Department of Neurology, Mayo Clinic, Jacksonville, FL, USA
| | - Sean J Pittock
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA; Department of Neurology, Mayo Clinic, Rochester, MN, USA; Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, MN, USA.
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6
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Korzeniowska A, Bryl E. Infectious agents in the pathogenesis of autoimmune rheumatic diseases. Transl Res 2025; 276:39-45. [PMID: 39742962 DOI: 10.1016/j.trsl.2024.12.004] [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: 03/14/2024] [Revised: 12/23/2024] [Accepted: 12/27/2024] [Indexed: 01/04/2025]
Abstract
Autoimmune rheumatic diseases (AIRDs) are diseases with complex outset and courses, in which both genetic and environmental factors participate. Many environmental factors can be committed to AIRDs outset and development. The most popular of them, with confirmed impact, are smoking, age, gender, and microorganisms. In light of recent research an assumption about the importance of various microorganisms in the pathogenesis of AIRDs is growing in popularity. The human immune system has various protective mechanisms against infectious antigens which in normal cases let organism manage potential infection faster and more effectively. Unfortunately in some situations, specific errors in those mechanisms can cause an autoreactive response despite mitigation of infection. Viruses including EBV, CMV, and even SARS-CoV2 can cause these errors. This in combination with genetic factors can lead to rheumatic disease development. This research aims to provide a brief review of the role of viruses in the outset and development of AIRDs.
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Affiliation(s)
| | - Ewa Bryl
- Department of Physiopathology, Faculty of Medicine, Medical University of Gdansk, Poland.
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7
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Platts-Mills TA, Keshavarz B, Wilson JM, Rifas-Shiman SL, Ailsworth SM, Sordillo JE, Workman L, Chapman M, Lidholm J, Oken E, Gold DR. High risk of asthma among early teens is associated with quantitative differences in mite and cat allergen specific IgE and IgG4: a modified Th2 related antibody response revisited. EBioMedicine 2025; 112:105556. [PMID: 39893721 PMCID: PMC11840499 DOI: 10.1016/j.ebiom.2024.105556] [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: 02/19/2024] [Revised: 12/06/2024] [Accepted: 12/31/2024] [Indexed: 02/04/2025] Open
Abstract
BACKGROUND Although proteins derived from cats are an important contributor to indoor allergen exposure in relation to asthma, it has been known for at least twenty years that some children who live in a house with a cat can become clinically tolerant to these animals. In 2001, we reported that children exposed to high levels of cat allergens made high levels of IgG4 antibodies to the cat allergen Fel d 1, and we coined the term "a modified Th2 response". However, this phenomenon is still poorly understood. METHODS We studied serum antibodies among 616 individuals in the Viva unselected birth cohort recruited at their early teen visit (mean age 13.1 SD 0.8). IgE and IgG4 antibodies were measured by ImmunoCAP to inhaled allergens as well as the best characterised component allergens of cat, Fel d 1, Fel d 2, Fel d 4, and Fel d 7, and the dust mite allergens Der p 1, Der p 2, Der p 10, and Der p 23. FINDINGS The results confirm that young teens living in a home with a cat make high levels of IgG4 specific for cat allergens, and that those antibodies, and specifically those to Fel d 1 are negatively associated with asthma. By contrast, the IgG4 responses to Fel d 4 and Fel d 7 are significantly lower and have no significant association with asthma. Perhaps more surprisingly, a similar effect is seen in relation to dust-mite allergens. Although the allergen Der p 1 is a major part of the IgE response to mite allergens, this protein also induced high prevalence and levels of IgG4 antibodies and has a less strong relationship to asthma than IgE to Der p 2 or Der p 23. Indeed, values of specific IgE to Der p 1 >3.5 IU/mL were not significantly related to asthma (OR 1.5 CI 0.8-2.8, p = 0.3, Chi2 test). The prevalence and levels of specific IgG4 to these less abundant allergens are significantly lower for Der p 2 and almost absent for Der p 23. INTERPRETATION High exposure to specific allergens in household dust can enhance production of both sIgE and sIgG4 antibodies, while allergens where abundance is significantly lower in dust can induce sIgE with limited or no sIgG4. The result is that the less abundant allergens, i.e., Fel d 4, Fel d 7, Der p 2, and Der p 23, may have a significantly higher relevance to asthma than expected because they induce less sIgG4. FUNDING This work was funded by R01-AI20565 (TPM) and support for the IgE and IgG4 assays provided by Phadia/Thermo Fisher Kalamazoo, Michigan. Project Viva is also supported by NIH R01HD034568 and R24ES.
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Affiliation(s)
- Thomas A Platts-Mills
- Division of Allergy & Clinical Immunology, Department of Medicine, University of Virginia, Charlottesville, VA, USA.
| | - Behnam Keshavarz
- Division of Allergy & Clinical Immunology, Department of Medicine, University of Virginia, Charlottesville, VA, USA
| | - Jeffrey M Wilson
- Division of Allergy & Clinical Immunology, Department of Medicine, University of Virginia, Charlottesville, VA, USA
| | - Sheryl L Rifas-Shiman
- The Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA
| | - Samuel M Ailsworth
- Division of Allergy & Clinical Immunology, Department of Medicine, University of Virginia, Charlottesville, VA, USA
| | - Joanne E Sordillo
- The Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA
| | - Lisa Workman
- Division of Allergy & Clinical Immunology, Department of Medicine, University of Virginia, Charlottesville, VA, USA
| | | | | | - Emily Oken
- The Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA
| | - Diane R Gold
- The Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; The Department of Environmental Medicine, Harvard T.H. Chan School of Public Health, Boston, MA, USA
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8
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Athanassiou P, Athanassiou L, Kostoglou-Athanassiou I, Shoenfeld Y. Targeted Cellular Treatment of Systemic Lupus Erythematosus. Cells 2025; 14:210. [PMID: 39937001 PMCID: PMC11816398 DOI: 10.3390/cells14030210] [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: 12/23/2024] [Revised: 01/18/2025] [Accepted: 01/30/2025] [Indexed: 02/13/2025] Open
Abstract
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease affecting all organ systems. The disease preferentially affects females of childbearing age. It runs a variable course. It may run a mild course that may never lead to severe disease and manifestations from critical organ systems. However, it may also run an undulating course with periods of mild and severe disease. It may run as a mild disease, quickly deteriorating to severe disease and affecting multiple organ systems. Various immune pathways related both to the innate and adaptive immune response are involved in the pathogenesis of SLE. Various drugs have been developed targeting cellular and molecular targets in these pathways. Interferons are involved in the pathogenesis of SLE, and various drugs have been developed to target this pathway. T and B lymphocytes are involved in the pathophysiology of SLE. Various treatment modalities targeting cellular targets are available for the treatment of SLE. These include biologic agents targeting B lymphocytes. However, some patients have disease refractory to these treatment modalities. For these patients, cell-based therapies may be used. Hematopoietic stem cell transplantation involving autologous cells is an option in the treatment of refractory SLE. Mesenchymal stem cells are also applied in the treatment of SLE. Chimeric antigen receptor (CAR)-T cell therapy is a novel treatment also used in SLE management. This novel treatment method holds major promise for the management of autoimmune diseases and, in particular, SLE. Major hurdles to be overcome are the logistics involved, as well as the need for specialized facilities. This review focuses on novel treatment modalities in SLE targeting cellular and molecular targets in the immune system.
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Affiliation(s)
| | - Lambros Athanassiou
- Department of Rheumatology, Asclepeion Hospital, Voula, 16673 Athens, Greece;
| | | | - Yehuda Shoenfeld
- Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Reichman University, Herzliya 4610101, Israel;
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9
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Kurien BT, Dave D, Tsaliki M, Quadri SMS, Lewis VM, Scofield RH. Experimental induction of anti-muscarinic type-3-receptor extracellular loop antibodies by immunization with 4-hydroxy-2-nonenal modified Ro60 and unmodified Ro60. Clin Exp Immunol 2025; 219:uxae114. [PMID: 39658078 PMCID: PMC11748001 DOI: 10.1093/cei/uxae114] [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: 05/25/2024] [Revised: 10/13/2024] [Accepted: 12/09/2024] [Indexed: 12/12/2024] Open
Abstract
OBJECTIVE Sjögren's Disease (SjD) subjects have decreased lacrimal/salivary gland function. Studies have proposed that autoantibodies targeting G-protein-coupled muscarinic acetylcholine-type-3-receptor (M3R) are potential clinical markers for SjD. We hypothesized that rabbits/mice immunized with 4-hydroxy-2-nonenal (HNE)-modified/unmodified Ro60 will develop an autoimmunity, specifically a SjD phenotype, thus expressing increased levels of anti-M3R antibodies. METHODS We immunized two rabbits each with 10 mM HNE-modified Ro60/unmodified Ro60 antigen or Ro274-290/Ro413-428/Ro500-517 Ro60 peptides. Two rabbits each were immunized with either M3R second extracellular loop (ECL2) or M3R ECL3 peptide. Finally, five groups of BALB/c mice were immunized as follows-Group-I immunized with Ro60, Groups-II-IV immunized with Ro60 modified with 0.4 mM (low), 2 mM (medium), and 10 mM (high) HNE, respectively and Group-V-Freund's adjuvant. Serum antibodies to M3R ECL2/ECL3/Ro60/La or Sm were detected by ELISA. Functional assays were also performed. RESULTS Immunization with HNE-modified Ro60/unmodified Ro60 antigen or Ro274/Ro 413/Ro500 peptides induced a rapid intermolecular epitope spreading to M3R ECL2/ECL3, especially to M3R ECL3 in HNE-Ro immunized rabbits. These animals did not bind to scrambled M3R peptides. Ro60-immunized rabbit IgG inhibited M3R activity in a functional assay. Rabbits immunized with ECL2/ECL3 developed high reactivity to Ro60 but not against Sm/RNP. We found a differential antibody-induction against M3R ECL2 with Group-3 mice developing significant reactivity. CONCLUSION Our data show induction of increasing anti-M3R antibodies in rabbits immunized with Ro60/HNE-Ro60 or Ro60 peptides and differential induction of these antibodies in mice immunized with Ro60 modified with increasing HNE. These findings suggest that M3R ECL2/ECL3 are involved in SjD autoimmunity progression.
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Affiliation(s)
- Biji T Kurien
- Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, OK, USA
- Department of Veterans Affairs Medical Center, Oklahoma City, Oklahoma, OK, USA
| | - Devavrat Dave
- Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, OK, USA
- Department of Veterans Affairs Medical Center, Oklahoma City, Oklahoma, OK, USA
| | - Martha Tsaliki
- Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, OK, USA
- Department of Veterans Affairs Medical Center, Oklahoma City, Oklahoma, OK, USA
| | - Syed M S Quadri
- Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, OK, USA
- Departments of Medicine and Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, OK, USA
| | - Valerie M Lewis
- Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, OK, USA
- Department of Veterans Affairs Medical Center, Oklahoma City, Oklahoma, OK, USA
| | - Robert Hal Scofield
- Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, OK, USA
- Department of Veterans Affairs Medical Center, Oklahoma City, Oklahoma, OK, USA
- Departments of Medicine and Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, OK, USA
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10
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Kutwin M, Kądziela M, Stein T, Kraska-Gacka M, Woźniacka A, Żebrowska A. Senear-Usher Syndrome or Coexistence of SLE with Pemphigus Vulgaris-A Case Report with Literature Review. J Clin Med 2025; 14:409. [PMID: 39860415 PMCID: PMC11765791 DOI: 10.3390/jcm14020409] [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: 11/25/2024] [Revised: 01/08/2025] [Accepted: 01/08/2025] [Indexed: 01/27/2025] Open
Abstract
Senear-Usher syndrome, or pemphigus erythematosus (PE), is a rare autoimmune disorder characterized by the coexistence of features from both lupus erythematosus (LE) and pemphigus foliaceus (PF). We describe a 41-year-old patient initially diagnosed with cutaneous and then systemic lupus erythematosus (SLE), who after a few years developed new skin lesions: erythematous and erosive eruptions partially covered by crusts located on the trunk and flaccid blisters on the extremities. Direct immunofluorescence of perilesional skin revealed deposits of IgG in the intercellular space of the epidermis and granular deposits of C3 at the dermo-epidermal junction. Additional testing, revealing autoantibodies against the intercellular space of the epidermis, and direct immunofluorescence (DIF) examination allowed a diagnosis of pemphigus vulgaris coexisting with lupus. Further, DIF study revealed granular deposits of immunoglobulin G (IgG) in the intercellular spaces of the epidermis and granular deposits of the C3 along the basement membrane. Clinical appearance led to suspicion of Senear-Usher syndrome. in this patient. This case report explores the diagnostic challenges posed by the patient's overlapping symptoms and immunological findings, suggesting an infrequent manifestation of Senear-Usher syndrome or a combination of SLE and pemphigus vulgaris. The case highlights the complexity of chronic inflammatory skin diseases and the need for tailored treatment approaches in such cases. Despite temporary improvement, the patient experienced relapses. We performed a descriptive literature review of the case reports of PE published in the last 24 years and prepared a summary of the characteristics, emphasizing the importance of proper recognition, clinical features, and treatment of this uncommon syndrome.
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Affiliation(s)
- Magdalena Kutwin
- Department of Dermatology and Venereology, Medical University of Lodz, pl. Hallera 1, 90-647 Lodz, Poland; (M.K.); (M.K.); (M.K.-G.); (A.W.)
| | - Marcelina Kądziela
- Department of Dermatology and Venereology, Medical University of Lodz, pl. Hallera 1, 90-647 Lodz, Poland; (M.K.); (M.K.); (M.K.-G.); (A.W.)
| | - Tomasz Stein
- Department of Dermatology, Poznan University of Medical Sciences, 60-806 Poznan, Poland;
| | - Marzena Kraska-Gacka
- Department of Dermatology and Venereology, Medical University of Lodz, pl. Hallera 1, 90-647 Lodz, Poland; (M.K.); (M.K.); (M.K.-G.); (A.W.)
| | - Anna Woźniacka
- Department of Dermatology and Venereology, Medical University of Lodz, pl. Hallera 1, 90-647 Lodz, Poland; (M.K.); (M.K.); (M.K.-G.); (A.W.)
| | - Agnieszka Żebrowska
- Department of Dermatology and Venereology, Medical University of Lodz, pl. Hallera 1, 90-647 Lodz, Poland; (M.K.); (M.K.); (M.K.-G.); (A.W.)
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11
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Postolache TT, Duncan E, Yen P, Potocki E, Barnhart M, Federline A, Massa N, Dagdag A, Joseph J, Wadhawan A, Capan CD, Forton C, Lowry CA, Ortmeyer HK, Brenner LA. Toxoplasma gondii, suicidal behaviour and suicide risk factors in US Veterans enrolled in mental health treatment. Folia Parasitol (Praha) 2025; 72:2025.002. [PMID: 39817778 DOI: 10.14411/fp.2025.002] [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: 09/01/2024] [Accepted: 10/21/2024] [Indexed: 01/18/2025]
Abstract
Markers of chronic infection Toxoplasma gondii (Nicolle et Manceaux, 1908) have been associated with suicidal self-directed violence (SSDV). We present the results of the first study relating T. gondii IgG serology with suicide attempts and suicidal ideation in United States Veterans, known to have higher suicide rates than members of the general population. We also related T. gondii serology to SSDV risk factors, including valid and reliable measures of trait impulsivity, aggression, self-reported depression, and sleep disturbance. We recruited 407 Veterans enrolled at three Veterans Affairs Medical Centers with mean (S.D.) age = 45.6 (11.6) years; 304 men (74.7%); 203 with a history of SSDV and 204 with no history of any self-directed violence (SDV). Seropositivity and serointensity, categorised as high (top quartile) or low (lower three quartiles), were analysed in relationship to SSDV, suicidal ideation and clinical risk factors using age and gender-adjusted linear and logistic methods, after transformations and nonparametric tests when appropriate. Associations between seropositivity and SSDV and its risk factors were not significant in all groups. High serointensity, while not associated with SSDV or repeat suicide attempts, was positively associated with suicidal ideation, depression, impulsivity, and daytime dysfunction due to sleepiness (p < 0.05), but only in Veterans with a history of SSDV. In Veterans without a history of SDV, no associations were significant. These associations remained significant after adjustment for certain socioeconomic factors (i.e., income, homelessness, military rank). Including education in the model downgraded the statistical significance of suicidal ideation and depression to statistical trends, but the significance of associations with impulsivity and daytime dysfunction due to sleepiness remained. Major limitations include the cross-sectional design, overall low seropositivity within the sample, and potentially spurious results due to multiple comparisons. Thus, the results of this report need to be replicated in larger samples, ideally longitudinally.
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Affiliation(s)
- Teodor T Postolache
- Share senior authorship *Address for correspondence: Teodor T. Postolache, MD; 685 West Baltimore Street, MSTF Building, Room 930 Baltimore, MD 21201, USA
| | - Erica Duncan
- Atlanta Veterans Affairs Health Care System, Decatur, GA, USA
- Emory University School of Medicine, Department of Psychiatry and Behavioral Sciences, Atlanta, GA, USA
- Share senior authorship *Address for correspondence: Teodor T. Postolache, MD; 685 West Baltimore Street, MSTF Building, Room 930 Baltimore, MD 21201, USA
| | - Poyu Yen
- Mood and Anxiety Program, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Eileen Potocki
- VA Maryland Healthcare System, Baltimore VA Medical Center, Baltimore, MD, USA
| | - Meghan Barnhart
- Veterans Health Administration, Rocky Mountain Mental Illness Research Education and Clinical Center (MIRECC), Veterans Integrated Service Network (VISN) 19, Aurora, CO, USA
| | - Amanda Federline
- Mental Illness Research, Education and Clinical Center (MIRECC), Veterans Integrated Service Network (VISN) 5, VA Capitol Health Care Network, Baltimore, MD, USA
| | - Nicholas Massa
- Atlanta Veterans Affairs Health Care System, Decatur, GA, USA
| | - Aline Dagdag
- Mood and Anxiety Program, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Joshua Joseph
- Mood and Anxiety Program, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Abhishek Wadhawan
- Mood and Anxiety Program, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA
- Saint Elizabeths Hospital, Department of Psychiatry, Washington, DC, USA
| | - Colt D Capan
- Department for Neurodegenerative Sciences, Van Andel Research Institute, Grand Rapids, MI, USA
| | - Cameron Forton
- Department for Neurodegenerative Sciences, Van Andel Research Institute, Grand Rapids, MI, USA
| | - Christopher A Lowry
- Veterans Health Administration, Rocky Mountain Mental Illness Research Education and Clinical Center (MIRECC), Veterans Integrated Service Network (VISN) 19, Aurora, CO, USA
- Military and Veteran Microbiome: Consortium for Research and Education (MVM-CoRE), Aurora, CO, USA
- Department of Integrative Physiology and Center for Neuroscience, University of Colorado Boulder, Boulder, CO, USA
| | - Heidi K Ortmeyer
- Baltimore VA Medical Center, Baltimore, MD, USA
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Lisa A Brenner
- Veterans Health Administration, Rocky Mountain Mental Illness Research Education and Clinical Center (MIRECC), Veterans Integrated Service Network (VISN) 19, Aurora, CO, USA
- Military and Veteran Microbiome: Consortium for Research and Education (MVM-CoRE), Aurora, CO, USA
- Departments of Physical Medicine and Rehabilitation, Psychiatry and Neurology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Share senior authorship *Address for correspondence: Teodor T. Postolache, MD; 685 West Baltimore Street, MSTF Building, Room 930 Baltimore, MD 21201, USA
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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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Lim E, Kim YH, Jeong NY, Kim SH, Won H, Bae JS, Choi NK. The association between acute transverse myelitis and COVID-19 vaccination in Korea: Self-controlled case series study. Eur J Neurol 2025; 32:e70020. [PMID: 39739424 DOI: 10.1111/ene.70020] [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: 05/17/2024] [Accepted: 12/01/2024] [Indexed: 01/02/2025]
Abstract
BACKGROUND Acute transverse myelitis (ATM) has been reported as a potential association between COVID-19 vaccination. In this study, we aimed to investigate the association between the COVID-19 vaccination and ATM. METHODS A self-controlled case series study was performed using a large database that combine the COVID-19 vaccine registry and the national claims database. The COVID-19 vaccination data included information on individuals aged 18 and above who received COVID-19 vaccination from February 26, 2021, to August 31, 2022. The claims database covered the entire Korean population for the period between January 1, 2002 to August 31, 2022. Patients who develop ATM within 1-42 days following COVID-19 vaccination were included. The observation period was 270 days after the first dose of the COVID-19 vaccine. The incidence rate ratio (IRR) and 95% confidence interval (CI) were estimated using a conditional Poisson regression model. RESULTS A total of 159 ATM patients were included. Among them, 82 (51.6%) were male, and mean age was 55.4 (±17.4) years. The IRR was 2.41 (95% CI: 1.76-3.30) for the ATM risk within 1-42 days after COVID-19 vaccination. The IRR by vaccine product was 3.31 (95% CI: 1.81-6.05) for ChAdOx1-S; 1.99 (95% CI: 1.30-3.03) for BNT162b2; 2.57 (95% CI: 1.14-5.97) for mRNA-1273; and 3.33 (95% CI: 0.30-36.44) for Ad26.COV2.S. CONCLUSION These findings indicated an increased risk of ATM following COVID-19 vaccination within 42 days. An association with the risk of ATM was found both for viral vector and mRNA vaccines.
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Affiliation(s)
- Eunsun Lim
- Department of Health Convergence, College of Science and Industry Convergence, Ewha Womans University, Seoul, Republic of Korea
| | - Yoo Hwan Kim
- Department of Neurology, Hallym University Sacred Heart Hospital, College of Medicine, Hallym Universit, Anyang, Republic of Korea
| | - Na-Young Jeong
- Department of Health Convergence, College of Science and Industry Convergence, Ewha Womans University, Seoul, Republic of Korea
| | - Su-Hyun Kim
- Department of Neurology, Research Institute and Hospital of National Cancer Center, Goyang, Republic of Korea
| | - Heehyun Won
- Department of Health Convergence, College of Science and Industry Convergence, Ewha Womans University, Seoul, Republic of Korea
| | - Jong-Seok Bae
- Department of Neurology, Kangdong Sacred Heart Hospital, College of Medicine, Hallym University, Seoul, Republic of Korea
| | - Nam-Kyong Choi
- Department of Health Convergence, College of Science and Industry Convergence, Ewha Womans University, Seoul, Republic of Korea
- Graduate School of Industrial Pharmaceutical Science, College of Pharmacy, Ewha Womans University, Seoul, Republic of Korea
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14
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Kotani H, Matsuda KM, Yamaguchi K, Ono C, Kogo E, Ogawa K, Kobayashi Y, Hisamoto T, Kawanabe R, Kuzumi A, Fukasawa T, Yoshizaki‐Ogawa A, Goshima N, Sato S, Yoshizaki A. Diversity and Epitope Spreading of Anti-RNA Polymerase III Antibodies in Systemic Sclerosis: A Potential Biomarker for Skin and Lung Involvement. Arthritis Rheumatol 2025; 77:67-79. [PMID: 39219033 PMCID: PMC11684998 DOI: 10.1002/art.42975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 06/07/2024] [Accepted: 08/19/2024] [Indexed: 09/04/2024]
Abstract
OBJECTIVE Epitope spreading (ES), involving autoantibodies, plays a crucial role in the development and persistence of autoimmune reactions in various autoimmune diseases. This study aimed to investigate the relationship between ES of anti-RNA polymerase III (RNAP III) antibodies (ARAs) and the clinical manifestations of systemic sclerosis (SSc). METHODS We investigated whether intermolecular ES occurs in the subunits of the RNAP III complex and whether intramolecular ES targets the major antigen, RNA polymerase III subunit A (RPC1), in patients with SSc. To achieve this, we synthesized 17 full-length subunit proteins of the RNAP III complex and 5 truncated forms of RPC1 in vitro using a wheat germ cell-free translation system. Subsequently, we prepared antigen-binding plates and measured autoantibodies in the serum of patients with SSc. RESULTS Autoantibodies against different RNAP III complex subunits were found in patients who were ARA-positive with SSc. The intermolecular ES indicators significantly correlated with the modified Rodnan skin thickness score (mRSS) and surfactant protein-D, a biomarker of interstitial lung disease. However, the extent of disease on high-resolution computed tomography or pulmonary function tests did not show any significant correlation. Intramolecular ES indicator against RPC1 were significantly correlated with mRSS and renal crisis. Furthermore, longitudinal assessment of ES in RNAP III complex subunits correlated with mRSS and exhibited potential as a disease activity biomarker. CONCLUSION Our findings indicate a correlation between ES levels and the severity of skin sclerosis or the risk of other complications in SSc. This study suggests that measuring ES in SSc serves as a novel biomarker for disease activity.
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Affiliation(s)
| | | | | | | | - Emi Kogo
- ProteoBridge CorporationKoto‐kuJapan
| | | | | | | | | | | | | | | | - Naoki Goshima
- ProteoBridge Corporation and the University of MusashinoKoto‐kuJapan
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15
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Carter PJ, Quarmby V. Immunogenicity risk assessment and mitigation for engineered antibody and protein therapeutics. Nat Rev Drug Discov 2024; 23:898-913. [PMID: 39424922 DOI: 10.1038/s41573-024-01051-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/10/2024] [Indexed: 10/21/2024]
Abstract
Remarkable progress has been made in recent decades in engineering antibodies and other protein therapeutics, including enhancements to existing functions as well as the advent of novel molecules that confer biological activities previously unknown in nature. These protein therapeutics have brought major benefits to patients across multiple areas of medicine. One major ongoing challenge is that protein therapeutics can elicit unwanted immune responses (immunogenicity) in treated patients, including the generation of anti-drug antibodies. In rare and unpredictable cases, anti-drug antibodies can seriously compromise therapeutic safety and/or efficacy. Systematic deconvolution of this immunogenicity problem is confounded by the complexity of its many contributing factors and the inherent limitations of available experimental and computational methods. Nevertheless, continued progress with the assessment and mitigation of immunogenicity risk at the preclinical stage has the potential to reduce the incidence and severity of clinical immunogenicity events. This Review focuses on identifying key unsolved anti-drug antibody-related challenges and offers some pragmatic approaches towards addressing them. Examples are drawn mainly from antibodies, given that the majority of available clinical data are from this class of protein therapeutics. Plausible and seemingly tractable solutions are in sight for some immunogenicity problems, whereas other challenges will likely require completely new approaches.
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Affiliation(s)
- Paul J Carter
- Department of Antibody Engineering, Genentech, Inc., South San Francisco, CA, USA.
| | - Valerie Quarmby
- Department of BioAnalytical Sciences, Genentech, Inc., South San Francisco, CA, USA.
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16
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Mok CC, Cheung CCL, Chan KL, Tse SM, To CH. Effect of SARS-CoV2 infection on disease flares in patients with systemic lupus erythematosus: a case-control study. Rheumatology (Oxford) 2024; 63:3390-3396. [PMID: 37947324 DOI: 10.1093/rheumatology/kead601] [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: 08/06/2023] [Revised: 10/08/2023] [Accepted: 10/27/2023] [Indexed: 11/12/2023] Open
Abstract
OBJECTIVES To study the effect of SARS-CoV2 infection on flares of systemic lupus erythematosus (SLE). METHODS Patients who fulfilled the ACR/SLICC criteria for SLE and had documented COVID-19 between February and November 2022 were identified retrospectively from our hospital COVID-19 registry. SLE controls who did not have SARS-CoV2 infection were randomly matched for age, sex and the time of infection in a 2:1 ratio with those infected. The primary outcome of interest was clinical flare of SLE within 90 days of COVID-19. The rate of SLE flares (mild/moderate or severe) was compared between SARS-CoV2-infected SLE patients and controls. RESULTS Ninety-one SLE patients with COVID-19 (age 48.6 (14.0) years; 95.6% women) and 182 SLE controls (age 48.7 (13.8) years; 95.6% women) were studied. Eleven of 91 (12.1%) SARS-CoV2-infected patients had serious manifestations. One (1.1%) patient died and 7 (7.7%) developed severe complications. Within 90 days of SARS-CoV2 infection, 14 (15.4%) patients developed mild/moderate clinical SLE flares and two (2.2%) patients had severe SLE flares. The incidence of SLE flares in SARS-CoV2-infected patients was significantly higher than in those without the infection (17.6% vs 5.5%; odds ratio 3.67 [95% CI: 1.59, 8.46]; P = 0.001). The changes in anti-dsDNA and complement levels, however, were not significantly different between the two groups. Among SARS-CoV2-infected SLE patients, those with clinical SLE flares had significantly lower C3 values (P = 0.004) before the infection than those without. CONCLUSION Clinical flares within 90 days were significantly more common in SLE patients infected with SARS-CoV2 than matched non-infected SLE controls.
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Affiliation(s)
- Chi Chiu Mok
- Department of Medicine, Tuen Mun Hospital, Hong Kong SAR, China
| | - Chris Ching Lam Cheung
- Department of Medicine, Tuen Mun Hospital, Hong Kong SAR, China
- Rutonjee Hospital, Hong Kong SAR, China
| | - Kar Li Chan
- Department of Medicine, Tuen Mun Hospital, Hong Kong SAR, China
| | - Sau Mei Tse
- Department of Medicine, Tuen Mun Hospital, Hong Kong SAR, China
| | - Chi Hung To
- Department of Medicine, Tuen Mun Hospital, Hong Kong SAR, China
- Pok Oi Hospital, Hong Kong SAR, China
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17
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Yuan J, Yao X, Liu L, Zhang J. Coexistence of Pemphigus Foliaceus and Bullous Pemphigoid: A Case Report. Clin Cosmet Investig Dermatol 2024; 17:2725-2731. [PMID: 39629046 PMCID: PMC11611744 DOI: 10.2147/ccid.s486976] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Accepted: 11/15/2024] [Indexed: 12/06/2024]
Abstract
Pemphigus foliaceus (PF) and bullous pemphigoid (BP) are distinct autoimmune bullous skin diseases mediated by autoantibodies targeting adhesion molecules in desmosomes and hemidesmosomes structural proteins in the epidermal-basement membrane zone, respectively. The coexistence of PF and BP is rare. We present the case of a 72-year-old male with clinical and histological features of both PF and BP. Treatment with immunoglobulin (10 g/day for 3 days), intravenous dexamethasone sodium phosphate (5 mg/day for 10 days), oral triamcinolone (30 mg/day for 10 days), and minocycline hydrochloride (20 mg/day for 10 days) resulted in significant improvement. This rare case highlights the importance of accurate diagnosis and effective treatment strategies for the coexistence of PF and BP.
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Affiliation(s)
- Jinxiang Yuan
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, People’s Republic of China
| | - Xinyi Yao
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, People’s Republic of China
| | - Lvye Liu
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, People’s Republic of China
| | - Junling Zhang
- Department of Dermatology, Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital, Tianjin, People’s Republic of China
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18
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Antoine JC. Antibodies in immune-mediated peripheral neuropathies. Where are we in 2024? Rev Neurol (Paris) 2024; 180:876-887. [PMID: 39322491 DOI: 10.1016/j.neurol.2024.09.002] [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: 06/14/2024] [Revised: 08/28/2024] [Accepted: 09/09/2024] [Indexed: 09/27/2024]
Abstract
Over the past 30 years, about 20 antibodies have been identified in immune-mediated neuropathies, recognizing membrane or intracellular proteins or glycolipids of neuron and Schwann cells. This article reviews the different methods used for their detection, what we know about their pathogenic role, how they have helped identify several disorders, and how they are essential for diagnosis. Despite sustained efforts, some immune-mediated disorders still lack identified autoantibodies, notably the classical form of Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy. The reasons for this are discussed. The article also tries to determine potential future developments in antibody research, particularly the use of omic approaches and the search for other types of biomarkers beyond diagnostic ones, such as those that can identify patients who will respond to a given treatment.
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Affiliation(s)
- J-C Antoine
- Service de neurologie, CHU de Saint-Étienne, 42055 Saint-Étienne cedex, France; Inserm CNRS, laboratoire SynAtac, MeliS, université Jean-Monnet, Saint-Étienne, France.
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19
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Strizzi CT, Ambrogio M, Zanoni F, Bonerba B, Bracaccia ME, Grandaliano G, Pesce F. Epitope Spreading in Immune-Mediated Glomerulonephritis: The Expanding Target. Int J Mol Sci 2024; 25:11096. [PMID: 39456878 PMCID: PMC11507388 DOI: 10.3390/ijms252011096] [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: 09/28/2024] [Revised: 10/04/2024] [Accepted: 10/14/2024] [Indexed: 10/28/2024] Open
Abstract
Epitope spreading is a critical mechanism driving the progression of autoimmune glomerulonephritis. This phenomenon, where immune responses broaden from a single epitope to encompass additional targets, contributes to the complexity and severity of diseases such as membranous nephropathy (MN), lupus nephritis (LN), and ANCA-associated vasculitis (AAV). In MN, intramolecular spreading within the phospholipase A2 receptor correlates with a worse prognosis, while LN exemplifies both intra- and intermolecular spreading, exacerbating renal involvement. Similarly, ANCA reactivity in AAV highlights the destructive potential of epitope diversification. Understanding these immunological cascades reveals therapeutic opportunities-targeting early epitope spreading could curb disease progression. Despite promising insights, the clinical utility of epitope spreading as a prognostic tool remains debated. This review provides a complete overview of the current evidence, exploring the dual-edged nature of epitope spreading, the intricate immune mechanisms behind it, and its therapeutic implications. By elucidating these dynamics, we aim to pave the way for more precise, targeted interventions in autoimmune glomerular diseases.
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Affiliation(s)
- Camillo Tancredi Strizzi
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (M.A.); (B.B.); (G.G.)
- Nephrology, Dialysis and Transplantation Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Martina Ambrogio
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (M.A.); (B.B.); (G.G.)
- Nephrology, Dialysis and Transplantation Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Francesca Zanoni
- Department of Nephrology, Dialysis, and Kidney Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy;
| | - Bibiana Bonerba
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (M.A.); (B.B.); (G.G.)
- Nephrology, Dialysis and Transplantation Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Maria Elena Bracaccia
- Division of Renal Medicine, Ospedale Isola Tiberina-Gemelli Isola, 00186 Rome, Italy;
| | - Giuseppe Grandaliano
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (M.A.); (B.B.); (G.G.)
- Nephrology, Dialysis and Transplantation Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Francesco Pesce
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (M.A.); (B.B.); (G.G.)
- Division of Renal Medicine, Ospedale Isola Tiberina-Gemelli Isola, 00186 Rome, Italy;
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Zhang Y, Zhou Y, Guan H, Yu M. Exploring PLA2R and HLA in membranous nephropathy: A narrative review of pathogenic mechanisms and emerging therapeutic potentials. Int J Biol Macromol 2024; 280:136200. [PMID: 39366594 DOI: 10.1016/j.ijbiomac.2024.136200] [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: 07/31/2023] [Revised: 09/28/2024] [Accepted: 09/29/2024] [Indexed: 10/06/2024]
Abstract
Membranous Nephropathy (MN), a non-inflammatory autoimmune glomerulopathy, is a prominent cause of nephrotic syndrome, predominantly affecting Caucasian adults. It is characterized by significant thickening of the glomerular basement membrane, a direct result of immune complex deposition. Fundamental to its pathogenesis are the Phospholipase A2 receptor (PLA2R) and Human Leukocyte Antigens (HLA), which play crucial and interconnected roles. Specifically, PLA2R serves as the primary antigen, while HLA molecules facilitate MN-specific immune responses, thereby providing key insights into the disease's etiology. This study critically examines the roles of PLA2R and HLA in MN, with a particular focus on the antigenic epitopes of PLA2R. Given MN's complex nature, personalized therapeutic interventions are essential. Accordingly, targeting immunogenic epitopes has emerged as a transformative approach, aimed at modulating specific immune responses without disrupting overall immune function. Numerous studies and clinical trials have been advancing the application of these epitopes in therapeutic strategies. Nevertheless, challenges such as identifying effective epitopes, enhancing epitope-specific responses, and optimizing therapeutic dosing remain. This narrative review addresses these challenges in depth, offering a comprehensive insight into the pathology and emerging treatment strategies for MN.
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Affiliation(s)
- Yang Zhang
- Heilongjiang University of Chinese Medicine, No. 24 Heping Road, Xiangfang District, Harbin, Heilongjiang Province, China
| | - Yanyan Zhou
- Heilongjiang University of Chinese Medicine, No. 24 Heping Road, Xiangfang District, Harbin, Heilongjiang Province, China
| | - Huibo Guan
- Heilongjiang University of Chinese Medicine, No. 24 Heping Road, Xiangfang District, Harbin, Heilongjiang Province, China
| | - Miao Yu
- Heilongjiang University of Chinese Medicine, No. 24 Heping Road, Xiangfang District, Harbin, Heilongjiang Province, China.
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21
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Pitner RA, Chao JL, Dahl NP, Fan MN, Cai X, Avery NG, Roe K, Spiegel PC, Miao CH, Gerner MY, James RG, Rawlings DJ. Blunting specific T-dependent antibody responses with engineered "decoy" B cells. Mol Ther 2024; 32:3453-3469. [PMID: 39192583 PMCID: PMC11489556 DOI: 10.1016/j.ymthe.2024.08.023] [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: 07/17/2024] [Accepted: 08/23/2024] [Indexed: 08/29/2024] Open
Abstract
Antibody inhibitors pose an ongoing challenge to the treatment of subjects with inherited protein deficiency disorders, limiting the efficacy of both protein replacement therapy and corrective gene therapy. Beyond their central role as producers of serum antibody, B cells also exhibit many unique properties that could be exploited in cell therapy applications, notably including antigen-specific recognition and the linked capacity for antigen presentation. Here we employed CRISPR-Cas9 to demonstrate that ex vivo antigen-primed Blimp1-knockout "decoy" B cells, incapable of differentiation into plasma cells, participated in and downregulated host antigen-specific humoral responses after adoptive transfer. Following ex vivo antigen pulse, adoptively transferred high-affinity antigen-specific decoy B cells were diverted into germinal centers en masse, thereby reducing participation by endogenous antigen-specific B cells in T-dependent humoral responses and suppressing both cognate and linked antigen-specific immunoglobulin (Ig)G following immunization with conjugated antigen. This effect was dose-dependent and, importantly, did not impact concurrent unrelated antibody responses. We demonstrated the therapeutic potential of this approach by treating factor VIII (FVIII)-knockout mice with antigen-pulsed decoy B cells prior to immunization with an FVIII conjugate protein, thereby blunting the production of serum FVIII-specific IgG by an order of magnitude as well as reducing the proportion of animals exhibiting functional FVIII inhibition by 6-fold.
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Affiliation(s)
- Ragan A Pitner
- Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA; Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA 98101, USA
| | - Jaime L Chao
- Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA
| | - Noelle P Dahl
- Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA 98101, USA
| | - Meng-Ni Fan
- Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA 98101, USA
| | - Xiaohe Cai
- Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA 98101, USA
| | - Nathan G Avery
- Department of Chemistry, Western Washington University, Bellingham, WA 98225, USA
| | - Kelsey Roe
- Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA 98101, USA
| | - P Clint Spiegel
- Department of Chemistry, Western Washington University, Bellingham, WA 98225, USA
| | - Carol H Miao
- Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA 98101, USA; Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195, USA
| | - Michael Y Gerner
- Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA
| | - Richard G James
- Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA 98101, USA; Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195, USA
| | - David J Rawlings
- Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA; Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA 98101, USA; Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195, USA.
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22
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Guo M, Shang S, Li M, Cai G, Li P, Chen X, Li Q. Understanding autoimmune response after SARS-CoV-2 infection and the pathogenesis/mechanisms of long COVID. MEDICAL REVIEW (2021) 2024; 4:367-383. [PMID: 39444797 PMCID: PMC11495526 DOI: 10.1515/mr-2024-0013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Accepted: 05/04/2024] [Indexed: 10/25/2024]
Abstract
COVID-19 posed a major challenge to the healthcare system and resources worldwide. The popularization of vaccines and the adoption of numerous prevention and control measures enabled the gradual end of the COVID-19 pandemic. However, successive occurrence of autoimmune diseases in patients with COVID-19 cannot be overlooked. Long COVID has been the major focus of research due to the long duration of different symptoms and the variety of systems involved. Autoimmunity may play a crucial role in the pathogenesis of long COVID. Here, we reviewed several autoimmune disorders occurring after COVID-19 infection and the pathogenesis of long COVID.
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Affiliation(s)
- Ming Guo
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, Beijing 100853, China
| | - Shunlai Shang
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, Beijing 100853, China
- Department of Nephrology, China-Japan Friendship Hospital, Beijing, China
| | - Mengfei Li
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, Beijing 100853, China
| | - Guangyan Cai
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, Beijing 100853, China
| | - Ping Li
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, Beijing 100853, China
| | - Xiangmei Chen
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, Beijing 100853, China
- Haihe Laboratory of CellEcosystem, China
| | - Qinggang Li
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, Beijing 100853, China
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23
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Xu J, Hu H, Sun Y, Zhao Z, Zhang D, Yang L, Lu Q. The fate of immune complexes in membranous nephropathy. Front Immunol 2024; 15:1441017. [PMID: 39185424 PMCID: PMC11342396 DOI: 10.3389/fimmu.2024.1441017] [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: 05/30/2024] [Accepted: 07/24/2024] [Indexed: 08/27/2024] Open
Abstract
The most characteristic feature of membranous nephropathy (MN) is the presence of subepithelial electron dense deposits and the consequential thickening of the glomerular basement membrane. There have been great advances in the understanding of the destiny of immune complexes in MN by the benefit of experimental models represented by Heymann nephritis. Subepithelial immune complexes are formed in situ by autoantibodies targeting native autoantigens or exogenous planted antigens such as the phospholipase A2 receptor (PLA2R) and cationic BSA respectively. The nascent immune complexes would not be pathogenic until they develop into immune deposits. Podocytes are the major source of autoantigens in idiopathic membranous nephropathy. They also participate in the modulation and removal of the immune complexes to a large extent. The balance between deposition and clearance is regulated by a wide range of factors such as the composition and physicochemical properties of the immune complexes and the complement system. Complement components such as C3 and C1q have been reported to be precipitated with the deposits whereas a complement regulatory protein CR1 expressed by podocytes is involved in the phagocytosis of immune complexes by podocytes. Podocytes regulate the dynamic change of immune complexes which is disturbed in membranous nephropathy. To elucidate the precise fate of the immune complexes is essential for developing more rational and novel therapies for membranous nephropathy.
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Affiliation(s)
- Jie Xu
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Haikun Hu
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Yuhe Sun
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Zihan Zhao
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Danyuan Zhang
- Qi Huang of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Lei Yang
- Department of Nephropathy, The Third Affiliated Hospital of Beijing University of Chinese Medicine, Beijing, China
| | - Qingyi Lu
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
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24
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Strandmoe AL, Bremer J, Diercks GFH, Gostyński A, Ammatuna E, Pas HH, Wouthuyzen-Bakker M, Huls GA, Heeringa P, Laman JD, Horváth B. Beyond the skin: B cells in pemphigus vulgaris, tolerance and treatment. Br J Dermatol 2024; 191:164-176. [PMID: 38504438 DOI: 10.1093/bjd/ljae107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 03/08/2024] [Accepted: 03/08/2024] [Indexed: 03/21/2024]
Abstract
Pemphigus vulgaris (PV) is a rare autoimmune bullous disease characterized by blistering of the skin and mucosa owing to the presence of autoantibodies against the desmosome proteins desmoglein 3 and occasionally in conjunction with desmoglein 1. Fundamental research into the pathogenesis of PV has revolutionized its treatment and outcome with rituximab, a B-cell-depleting therapy. The critical contribution of B cells to the pathogenesis of pemphigus is well accepted. However, the exact pathomechanism, mechanisms of onset, disease course and relapse remain unclear. In this narrative review, we provide an overview of the fundamental research progress that has unfolded over the past few centuries to give rise to current and emerging therapies. Furthermore, we summarize the multifaceted roles of B cells in PV, including their development, maturation and antibody activity. Finally, we explored how these various aspects of B-cell function contribute to disease pathogenesis and pave the way for innovative therapeutic interventions.
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Affiliation(s)
- Anne-Lise Strandmoe
- Departments of Medical Biology and Pathology
- Dermatology (Centre for Blistering Diseases)
| | | | - Gilles F H Diercks
- Departments of Medical Biology and Pathology
- Dermatology (Centre for Blistering Diseases)
| | - Antoni Gostyński
- Dermatology (Centre for Blistering Diseases)
- Department of Dermatology, Maastricht University Medical Centre, Maastricht, the Netherlands
| | | | | | - Marjan Wouthuyzen-Bakker
- Medical Microbiology and Infection Prevention; University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands
| | | | | | - Jon D Laman
- Departments of Medical Biology and Pathology
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25
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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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26
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Smith CT, Wang Z, Lewis JS. Engineering antigen-presenting cells for immunotherapy of autoimmunity. Adv Drug Deliv Rev 2024; 210:115329. [PMID: 38729265 DOI: 10.1016/j.addr.2024.115329] [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: 11/03/2023] [Revised: 03/05/2024] [Accepted: 05/03/2024] [Indexed: 05/12/2024]
Abstract
Autoimmune diseases are burdensome conditions that affect a significant fraction of the global population. The hallmark of autoimmune disease is a host's immune system being licensed to attack its tissues based on specific antigens. There are no cures for autoimmune diseases. The current clinical standard for treating autoimmune diseases is the administration of immunosuppressants, which weaken the immune system and reduce auto-inflammatory responses. However, people living with autoimmune diseases are subject to toxicity, fail to mount a sufficient immune response to protect against pathogens, and are more likely to develop infections. Therefore, there is a concerted effort to develop more effective means of targeting immunomodulatory therapies to antigen-presenting cells, which are involved in modulating the immune responses to specific antigens. In this review, we highlight approaches that are currently in development to target antigen-presenting cells and improve therapeutic outcomes in autoimmune diseases.
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Affiliation(s)
- Clinton T Smith
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL 32611, USA
| | - Zhenyu Wang
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL 32611, USA
| | - Jamal S Lewis
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL 32611, USA; Department of Biomedical Engineering, University of California, Davis, CA 95616, USA.
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27
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Al-Hawary SIS, Jasim SA, Hjazi A, Ullah H, Bansal P, Deorari M, Sapaev IB, Ami AA, Mohmmed KH, Abosaoda MK. A new perspective on therapies involving B-cell depletion in autoimmune diseases. Mol Biol Rep 2024; 51:629. [PMID: 38717637 DOI: 10.1007/s11033-024-09575-6] [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: 03/26/2024] [Accepted: 04/22/2024] [Indexed: 06/30/2024]
Abstract
It has been rediscovered in the last fifteen years that B-cells play an active role in autoimmune etiology rather than just being spectators. The clinical success of B-cell depletion therapies (BCDTs) has contributed to this. BCDTs, including those that target CD20, CD19, and BAFF, were first developed to eradicate malignant B-cells. These days, they treat autoimmune conditions like multiple sclerosis and systemic lupus erythematosus. Particular surprises have resulted from the use of BCDTs in autoimmune diseases. For example, even in cases where BCDT is used to treat the condition, its effects on antibody-secreting plasma cells and antibody levels are restricted, even though these cells are regarded to play a detrimental pathogenic role in autoimmune diseases. In this Review, we provide an update on our knowledge of the biology of B-cells, examine the outcomes of clinical studies employing BCDT for autoimmune reasons, talk about potential explanations for the drug's mode of action, and make predictions about future approaches to targeting B-cells other than depletion.
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Affiliation(s)
| | | | - Ahmed Hjazi
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam Bin Abdulaziz University, 11942, Al-Kharj, Saudi Arabia
| | - Himayat Ullah
- College of Medicine, Shaqra University, 15526, Shaqra, Saudi Arabia.
| | - Pooja Bansal
- Department of Biotechnology and Genetics, Jain (Deemed-to-Be) University, Bengaluru, Karnataka, 560069, India
- Department of Allied Healthcare and Sciences, Vivekananda Global University, Jaipur, Rajasthan, 303012, India
| | - Mahamedha Deorari
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
| | - I B Sapaev
- Tashkent Institute of Irrigation and Agricultural Mechanization Engineers National Research University, Tashkent, Uzbekistan
- Scientific Researcher, Western Caspian University, Baku, Azerbaijan
| | - Ahmed Ali Ami
- Department of Medical Laboratories Technology, Al-Nisour University College, Baghdad, Iraq
| | | | - Munther Kadhim Abosaoda
- College of Pharmacy, The Islamic University, Najaf, Iraq
- College of Pharmacy, The Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- College of Pharmacy, The Islamic University of Babylon, Hillah, Iraq
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28
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Ruggenenti P, Reinhard L, Ruggiero B, Perna A, Perico L, Peracchi T, Fidone D, Gennarini A, Benigni A, Cortinovis M, Hoxha E, Remuzzi G. Anti-Phospholipase A2 Receptor 1 and Anti-Cysteine Rich Antibodies, Domain Recognition and Rituximab Efficacy in Membranous Nephropathy: A Prospective Cohort Study. Am J Kidney Dis 2024; 83:588-600.e1. [PMID: 38151224 DOI: 10.1053/j.ajkd.2023.10.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 09/08/2023] [Accepted: 10/15/2023] [Indexed: 12/29/2023]
Abstract
RATIONALE & OBJECTIVE Proteinuria and anti-phospholipase A2 receptor 1 (anti-PLA2R1) antibody titers are associated with primary membranous nephropathy (MN) outcomes. We evaluated the association of antibodies against the cysteine-rich (CysR) and C-type lectin 1, 7, and 8 (CTLD1, CTLD7, and CTLD8) domains of PLA2R1 with MN outcomes. STUDY DESIGN Prospective cohort study. SETTING & PARTICIPANTS One-hundred-thirteen consecutive, consenting patients referred to the Nephology Unit of the Azienda-Socio-Sanitaria-Territoriale (ASST) Papa Giovanni XXIII (Bergamo, Italy) with PLA2R1-related, biopsy-proven MN whose persistent nephrotic syndrome (NS) was managed conservatively for>6 months and were monitored with serial evaluations of proteinuria, autoantibodies (by enzyme-linked immunosorbent assay), and clinical outcomes. EXPOSURE Rituximab. OUTCOME Complete (proteinuria<0.3g/24h) or partial (proteinuria≥0.3g/24h and<3.0g/24h with>50% reduction vs basal) NS remission. ANALYTICAL APPROACH Univariable and multivariable Cox regression analyses. RESULTS All patients had anti-CysR antibodies; 62 (54.9%) were multidomain recognizers. Anti-PLA2R1 and anti-CysR antibody titers were strongly correlated at baseline (P<0.001, r=0.934), 6 months (P<0.001, r=0.964), and 12 months (P<0.001, r=0.944). During a median follow-up of 37.1 (IQR, 20.3-56.9) months, 71 patients (62.8%) achieved either complete or partial remission of their NS. Lower baseline anti-PLA2R1 (HR, 0.997 [95% CI, 0.996-0.999], P=0.002) and anti-CysR [HR, 0.996 [95% CI, 0.993-0.998], P=0.001) titers were associated with a higher probability of remission, along with female sex, lower proteinuria, and lower serum creatinine levels (P<0.05 for all comparisons). Anti-CTLD antibodies were not associated with outcomes. At 6 and 12 months, compared to baseline, anti-PLA2R1 and anti-CysR antibody titers decreased more in patients progressing to partial or complete remission than in those without remission (P<0.05 for all comparisons). LIMITATIONS Observational design. CONCLUSIONS In PLA2R1-related MN, anti-PLA2R1 and anti-CysR antibodies similarly predict rituximab efficacy independent of PLA2R1 domain recognition. The choice between these tests should be dictated by feasibility and costs. Evaluating anti-CTLD antibodies appears unnecessary. PLAIN-LANGUAGE SUMMARY Primary membranous nephropathy (MN), a leading cause of nephrotic syndrome (NS) in adults, is an autoimmune disease caused by autoantibodies binding to the podocyte antigen phospholipase A2 receptor 1 (PLA2R1). We assessed whether the effects of anti-CD20 cytolytic therapy with the monoclonal antibody rituximab are associated with detection rates and levels of anti-PLA2R1 antibodies and antibodies against PLA2R1 domains such as cysteine-rich (CysR), and C-type lectin 1, 7, and 8 (CTLD1, 7, and 8), in patients with PLA2R1-related MN and persistent NS. The probability of rituximab-induced complete or partial NS remission was associated with baseline anti-PLA2R1 and anti-CysR antibody titers, but not with anti-CTLD1, 7 and 8 antibodies or multidomain recognition. Integrated evaluation of anti-PLA2R1 or anti-CysR antibodies with proteinuria and kidney function may play a role in monitoring the effects of rituximab in patients with PLA2R1-related NS and MN.
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Affiliation(s)
- Piero Ruggenenti
- Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale (ASST) Papa Giovanni XXIII, Bergamo, Italy; Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Linda Reinhard
- 3III, Department of Internal Medicine, University Medical Center Hamburg, Eppendorf, Hamburg, Germany
| | - Barbara Ruggiero
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Annalisa Perna
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Luca Perico
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Tobia Peracchi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Diego Fidone
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Alessia Gennarini
- Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale (ASST) Papa Giovanni XXIII, Bergamo, Italy
| | - Ariela Benigni
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Monica Cortinovis
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Elion Hoxha
- 3III, Department of Internal Medicine, University Medical Center Hamburg, Eppendorf, Hamburg, Germany.
| | - Giuseppe Remuzzi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy.
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29
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Zhou YJ, Jin QF, Wang C, Zhang XJ, Liu H, Bao J. Onset of acute severe autoimmune hepatitis after severe acute respiratory syndrome coronavirus 2 infection: a case report. J Int Med Res 2024; 52:3000605241233450. [PMID: 38502002 PMCID: PMC10953009 DOI: 10.1177/03000605241233450] [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: 08/20/2023] [Accepted: 01/29/2024] [Indexed: 03/20/2024] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can trigger autoimmune inflammation in the liver, leading to acute autoimmune hepatitis (AIH). We herein report a case involving a 39-year-old woman with a 23-day history of yellow skin and urine. Using the revised original scoring system of the International AIH Group, we definitively diagnosed the patient with acute severe AIH (AS-AIH). She began treatment with 80 mg/day intravenous methylprednisolone, which was gradually reduced and followed by eventual transition to oral methylprednisolone. The patient finally achieved a biochemical response after 30 days of therapy, and liver transplantation was avoided. Clinicians should be aware that the onset of AS-AIH after SARS-CoV-2 infection differs from the onset of conventional AIH with respect to its clinical and pathological features. Early diagnosis and timely glucocorticoid treatment are crucial in improving outcomes.
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Affiliation(s)
- Yi-Jun Zhou
- Department of Hepatology, Affiliated Hangzhou Xixi Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Qiao-Fei Jin
- Department of Hepatology, Affiliated Hangzhou Xixi Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Chen Wang
- Department of Hepatology, Affiliated Hangzhou Xixi Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Xiao-Jing Zhang
- Department of Hepatology, Affiliated Hangzhou Xixi Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Hong Liu
- Department of Pathology, Affiliated Hangzhou Xixi Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Jianfeng Bao
- Department of Hepatology, Affiliated Hangzhou Xixi Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
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30
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Zhao XC, Ju B, Xiu NN, Sun XY, Meng FJ. When inflammatory stressors dramatically change, disease phenotypes may transform between autoimmune hematopoietic failure and myeloid neoplasms. Front Immunol 2024; 15:1339971. [PMID: 38426096 PMCID: PMC10902444 DOI: 10.3389/fimmu.2024.1339971] [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: 11/17/2023] [Accepted: 01/24/2024] [Indexed: 03/02/2024] Open
Abstract
Aplastic anemia (AA) and hypoplastic myelodysplastic syndrome are paradigms of autoimmune hematopoietic failure (AHF). Myelodysplastic syndrome and acute myeloid leukemia are unequivocal myeloid neoplasms (MNs). Currently, AA is also known to be a clonal hematological disease. Genetic aberrations typically observed in MNs are detected in approximately one-third of AA patients. In AA patients harboring MN-related genetic aberrations, a poor response to immunosuppressive therapy (IST) and an increased risk of transformation to MNs occurring either naturally or after IST are predicted. Approximately 10%-15% of patients with severe AA transform the disease phenotype to MNs following IST, and in some patients, leukemic transformation emerges during or shortly after IST. Phenotypic transformations between AHF and MNs can occur reciprocally. A fraction of advanced MN patients experience an aplastic crisis during which leukemic blasts are repressed. The switch that shapes the disease phenotype is a change in the strength of extramedullary inflammation. Both AHF and MNs have an immune-active bone marrow (BM) environment (BME). In AHF patients, an inflamed BME can be evoked by infiltrated immune cells targeting neoplastic molecules, which contributes to the BM-specific autoimmune impairment. Autoimmune responses in AHF may represent an antileukemic mechanism, and inflammatory stressors strengthen antileukemic immunity, at least in a significant proportion of patients who have MN-related genetic aberrations. During active inflammatory episodes, normal and leukemic hematopoieses are suppressed, which leads to the occurrence of aplastic cytopenia and leukemic cell regression. The successful treatment of underlying infections mitigates inflammatory stress-related antileukemic activities and promotes the penetration of leukemic hematopoiesis. The effect of IST is similar to that of treating underlying infections. Investigating inflammatory stress-powered antileukemic immunity is highly important in theoretical studies and clinical practice, especially given the wide application of immune-activating agents and immune checkpoint inhibitors in the treatment of hematological neoplasms.
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Affiliation(s)
- Xi-Chen Zhao
- Department of Hematology, The Central Hospital of Qingdao West Coast New Area, Qingdao, Shandong, China
| | - Bo Ju
- Department of Hematology, The Central Hospital of Qingdao West Coast New Area, Qingdao, Shandong, China
| | - Nuan-Nuan Xiu
- Department of Hematology, The Central Hospital of Qingdao West Coast New Area, Qingdao, Shandong, China
| | - Xiao-Yun Sun
- Department of Hematology, The Central Hospital of Qingdao West Coast New Area, Qingdao, Shandong, China
| | - Fan-Jun Meng
- Department of Hematology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
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DiToro D, Murakami N, Pillai S. T-B Collaboration in Autoimmunity, Infection, and Transplantation. Transplantation 2024; 108:386-398. [PMID: 37314442 PMCID: PMC11345790 DOI: 10.1097/tp.0000000000004671] [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] [Indexed: 06/15/2023]
Abstract
We have attempted here to provide an up-to-date review of the collaboration between helper T cells and B cells in response to protein and glycoprotein antigens. This collaboration is essential as it not only protects from many pathogens but also contributes to a litany of autoimmune and immune-mediated diseases.
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Affiliation(s)
- Daniel DiToro
- Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard, Cambridge, MA
- Department of Pathology, Brigham and Women’s Hospital, Boston, MA
| | - Naoka Murakami
- Department of Medicine, Brigham and Women’s Hospital, Boston, MA
| | - Shiv Pillai
- Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard, Cambridge, MA
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Ramos MJ, Lui AJ, Hollern DP. The Evolving Landscape of B Cells in Cancer Metastasis. Cancer Res 2023; 83:3835-3845. [PMID: 37815800 PMCID: PMC10914383 DOI: 10.1158/0008-5472.can-23-0620] [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: 02/23/2023] [Revised: 06/28/2023] [Accepted: 10/05/2023] [Indexed: 10/11/2023]
Abstract
Metastasis is the leading cause of cancer mortality. Functional and clinical studies have documented diverse B-cell and antibody responses in cancer metastasis. The presence of B cells in tumor microenvironments and metastatic sites has been associated with diverse effects that can promote or inhibit metastasis. Specifically, B cells can contribute to the spread of cancer cells by enhancing tumor cell motility, invasion, angiogenesis, lymphangiogenesis, and extracellular matrix remodeling. Moreover, they can promote metastatic colonization by triggering pathogenic immunoglobulin responses and recruiting immune suppressive cells. Contrastingly, B cells can also exhibit antimetastatic effects. For example, they aid in enhanced antigen presentation, which helps activate immune responses against cancer cells. In addition, B cells play a crucial role in preventing the dissemination of metastatic cells from the primary tumor and secrete antibodies that can aid in tumor recognition. Here, we review the complex roles of B cells in metastasis, delineating the heterogeneity of B-cell activity and subtypes by metastatic site, antibody class, antigen (if known), and molecular phenotype. These important attributes of B cells emphasize the need for a deeper understanding and characterization of B-cell phenotypes to define their effects in metastasis.
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Affiliation(s)
- Monika J. Ramos
- Salk Institute for Biological Sciences
- The University of California San Diego School of Biological Sciences
| | - Asona J. Lui
- Salk Institute for Biological Sciences
- Radiation Medicine and Applied Sciences, The University of California School of Medicine
| | - Daniel P. Hollern
- Salk Institute for Biological Sciences
- The University of California San Diego School of Biological Sciences
- Radiation Medicine and Applied Sciences, The University of California School of Medicine
- NOMIS Center for Immunobiology and Microbial Pathogenesis
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33
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Fitzcharles MA, Cohen SP, Häuser W. A step towards better understanding chronic overlapping pain conditions. Pain 2023:00006396-990000000-00469. [PMID: 38112644 DOI: 10.1097/j.pain.0000000000003129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Accepted: 10/13/2023] [Indexed: 12/21/2023]
Affiliation(s)
- Mary-Ann Fitzcharles
- Department of Rheumatology, McGill University, Montreal, QC, Canada
- Alan Edwards Pain Management Unit, McGill University, Montreal, QC, Canada
| | - Steven P Cohen
- Department of Anesthesiology and Critical Care Medicine, Neurology and Physical Medicine and Rehabilitation at Johns Hopkins Hospital, Baltimore, MD, United States
- Uniformed Services University of the Health Sciences, Bethesda, MD, United States
| | - Winfried Häuser
- Department of Psychosomatic Medicine and Psychotherapy, Technische Universität München, München, Germany
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34
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Kokubu H, Takahashi T, Tateishi C, Hashimoto T, Tsuruta D, Fujimoto N. Associations of autoimmune bullous diseases and autoantibodies against epidermal autoantigens in patients with inflammatory myopathy. Mod Rheumatol 2023; 33:1207-1208. [PMID: 36527416 DOI: 10.1093/mr/roac159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 12/16/2022] [Indexed: 11/08/2023]
Affiliation(s)
- Hiraku Kokubu
- Department of Dermatology, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Toshifumi Takahashi
- Department of Dermatology, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Chiharu Tateishi
- Department of Dermatology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Takashi Hashimoto
- Department of Dermatology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Daisuke Tsuruta
- Department of Dermatology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Noriki Fujimoto
- Department of Dermatology, Shiga University of Medical Science, Otsu, Shiga, Japan
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35
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Collins MP, Hadden RDM, Shahnoor N. Primary perineuritis, a rare but treatable neuropathy: Review of perineurial anatomy, clinicopathological features, and differential diagnosis. Muscle Nerve 2023; 68:696-713. [PMID: 37602939 DOI: 10.1002/mus.27949] [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: 04/02/2023] [Revised: 07/10/2023] [Accepted: 07/16/2023] [Indexed: 08/22/2023]
Abstract
The perineurium surrounds each fascicle in peripheral nerves, forming part of the blood-nerve barrier. We describe its normal anatomy and function. "Perineuritis" refers to both a nonspecific histopathological finding and more specific clinicopathological entity, primary perineuritis (PP). Patients with PP are often assumed to have nonsystemic vasculitic neuropathy until nerve biopsy is performed. We systematically reviewed the literature on PP and developed a differential diagnosis for histopathologically defined perineuritis. We searched PubMed, Embase, Scopus, and Web of Science for "perineuritis." We identified 20 cases (11 M/9F) of PP: progressive, unexplained neuropathy with biopsy showing perineuritis without vasculitis or other known predisposing condition. Patients ranged in age from 18 to 75 (mean 53.7) y and had symptoms 2-24 (median 4.5) mo before diagnosis. Neuropathy was usually sensory-motor (15/20), painful (18/19), multifocal (16/20), and distal-predominant (16/17) with legs more affected than arms. Truncal numbness occurred in 6/17; 10/18 had elevated cerebrospinal fluid (CSF) protein. Electromyography (EMG) and nerve conduction studies (NCS) demonstrated primarily axonal changes. Nerve biopsies showed T-cell-predominant inflammation, widening, and fibrosis of perineurium; infiltrates in epineurium in 10/20 and endoneurium in 7/20; and non-uniform axonal degeneration. Six had epithelioid cells. 19/20 received corticosteroids, 8 with additional immunomodulators; 18/19 improved. Two patients did not respond to intravenous immunoglobulin (IVIg). At final follow-up, 13/16 patients had mild and 2/16 moderate disability; 1/16 died. Secondary causes of perineuritis include leprosy, vasculitis, neurosarcoidosis, neuroborreliosis, neurolymphomatosis, toxic oil syndrome, eosinophilia-myalgia syndrome, and rarer conditions. PP appears to be an immune-mediated, corticosteroid-responsive disorder. It mimics nonsystemic vasculitic neuropathy. Cases with epithelioid cells might represent peripheral nervous system (PNS)-restricted forms of sarcoidosis.
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Affiliation(s)
- Michael P Collins
- Department of Neurology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | | | - Nazima Shahnoor
- Neuromuscular Pathology Laboratory, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
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Trier NH, Houen G. Antibody Cross-Reactivity in Auto-Immune Diseases. Int J Mol Sci 2023; 24:13609. [PMID: 37686415 PMCID: PMC10487534 DOI: 10.3390/ijms241713609] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 08/25/2023] [Accepted: 08/29/2023] [Indexed: 09/10/2023] Open
Abstract
Autoimmunity is defined by the presence of antibodies and/or T cells directed against self-components. Although of unknown etiology, autoimmunity commonly is associated with environmental factors such as infections, which have been reported to increase the risk of developing autoimmune diseases. Occasionally, similarities between infectious non-self and self-tissue antigens may contribute to immunological cross-reactivity in autoimmune diseases. These reactions may be interpreted as molecular mimicry, which describes cross-reactivity between foreign pathogens and self-antigens that have been reported to cause tissue damage and to contribute to the development of autoimmunity. By focusing on the nature of antibodies, cross-reactivity in general, and antibody-antigen interactions, this review aims to characterize the nature of potential cross-reactive immune reactions between infectious non-self and self-tissue antigens which may be associated with autoimmunity but may not actually be the cause of disease onset.
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Affiliation(s)
- Nicole Hartwig Trier
- Department of Neurology, Rigshospitalet Glostrup, Valdemar Hansens Vej 1-23, 2600 Glostrup, Denmark
| | - Gunnar Houen
- Department of Neurology, Rigshospitalet Glostrup, Valdemar Hansens Vej 1-23, 2600 Glostrup, Denmark
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark
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Sahlolbei M, Azangou-Khyavy M, Khanali J, Khorsand B, Shiralipour A, Ahmadbeigi N, Madjd Z, Ghanbarian H, Ardjmand A, Hashemi SM, Kiani J. Engineering chimeric autoantibody receptor T cells for targeted B cell depletion in multiple sclerosis model: An in-vitro study. Heliyon 2023; 9:e19763. [PMID: 37809446 PMCID: PMC10559048 DOI: 10.1016/j.heliyon.2023.e19763] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 08/18/2023] [Accepted: 08/31/2023] [Indexed: 10/10/2023] Open
Abstract
Background Recent evidence suggests that B cells and autoantibodies have a substantial role in the pathogenesis of Multiple sclerosis. T cells could be engineered to express chimeric autoantibody receptors (CAARs), which have an epitope of autoantigens in their extracellular domain acting as bait for trapping autoreactive B cells. This study aims to assess the function of designed CAAR T cells against B cell clones reactive to the myelin basic protein (MBP) autoantigen. Methods T cells were transduced to express a CAAR consisting of MBP as the extracellular domain. experimental autoimmune encephalomyelitis (EAE) was induced by injecting MBP into mice. The cytotoxicity, proliferation, and cytokine production of the MBP-CAAR T cells were investigated in co-culture with B cells. Results MBP-CAAR T cells showed higher cytotoxic activity against autoreactive B cells in all effector-to-target ratios compared to Mock T cell (empty vector-transduced T cell) and Un-T cells (un-transduced T cell). In co-cultures containing CAAR T cells, there was more proliferation and inflammatory cytokine release as compared to Un-T and Mock T cell groups. Conclusion Based on these findings, CAAR T cells are promising for curing or modulating autoimmunity and can be served as a new approach for clone-specific B cell depletion therapy in multiple sclerosis.
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Affiliation(s)
- Maryam Sahlolbei
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | | | - Javad Khanali
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Babak Khorsand
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Computer Engineering Department, Faculty of Engineering, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Aref Shiralipour
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Naser Ahmadbeigi
- Gene Therapy Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Zahra Madjd
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Hossein Ghanbarian
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Seyed Mahmoud Hashemi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Jafar Kiani
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
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Shin DS, Ratnapriya S, Cashin CN, Kuhn LF, Rahimi RA, Anthony RM, Moon JJ. Lung injury induces a polarized immune response by self-antigen-specific CD4 + Foxp3 + regulatory T cells. Cell Rep 2023; 42:112839. [PMID: 37471223 PMCID: PMC10529088 DOI: 10.1016/j.celrep.2023.112839] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 06/11/2023] [Accepted: 07/05/2023] [Indexed: 07/22/2023] Open
Abstract
Self-antigen-specific T cells are prevalent in the mature adaptive immune system but are regulated through multiple mechanisms of tolerance. However, inflammatory conditions such as tissue injury may allow these T cells to break tolerance and trigger autoimmunity. To understand how the T cell repertoire responds to the presentation of self-antigen under highly stimulatory conditions, we use peptide:major histocompatibility complex (MHC) class II tetramers to track the behavior of endogenous CD4+ T cells with specificity to a lung-expressed self-antigen in mouse models of immune-mediated lung injury. Acute injury results in the exclusive expansion of CD4+ regulatory T cells (Tregs) that is dependent on self-antigen recognition and interleukin-2 (IL-2). Conversely, conventional CD4+ T cells of the same self-antigen specificity remain unresponsive even following Treg ablation. Thus, the self-antigen-specific CD4+ T cell repertoire is poised to serve a regulatory function during acute tissue damage to limit further damage and the possibility of autoimmunity.
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Affiliation(s)
- Daniel S Shin
- Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Charlestown, MA 02129, USA; Division of Immunology, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA
| | - Sneha Ratnapriya
- Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Charlestown, MA 02129, USA; Harvard Medical School, Boston, MA 02115, USA
| | - Creel Ng Cashin
- Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Charlestown, MA 02129, USA; Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Lucy F Kuhn
- Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Charlestown, MA 02129, USA
| | - Rod A Rahimi
- Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Charlestown, MA 02129, USA; Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA
| | - Robert M Anthony
- Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Charlestown, MA 02129, USA; Harvard Medical School, Boston, MA 02115, USA
| | - James J Moon
- Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Charlestown, MA 02129, USA; Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA.
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Chancharoenthana W, Traitanon O, Leelahavanichkul A, Tasanarong A. Molecular immune monitoring in kidney transplant rejection: a state-of-the-art review. Front Immunol 2023; 14:1206929. [PMID: 37675106 PMCID: PMC10477600 DOI: 10.3389/fimmu.2023.1206929] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2023] [Accepted: 07/31/2023] [Indexed: 09/08/2023] Open
Abstract
Although current regimens of immunosuppressive drugs are effective in renal transplant recipients, long-term renal allograft outcomes remain suboptimal. For many years, the diagnosis of renal allograft rejection and of several causes of renal allograft dysfunction, such as chronic subclinical inflammation and infection, was mostly based on renal allograft biopsy, which is not only invasive but also possibly performed too late for proper management. In addition, certain allograft dysfunctions are difficult to differentiate from renal histology due to their similar pathogenesis and immune responses. As such, non-invasive assays and biomarkers may be more beneficial than conventional renal biopsy for enhancing graft survival and optimizing immunosuppressive drug regimens during long-term care. This paper discusses recent biomarker candidates, including donor-derived cell-free DNA, transcriptomics, microRNAs, exosomes (or other extracellular vesicles), urine chemokines, and nucleosomes, that show high potential for clinical use in determining the prognosis of long-term outcomes of kidney transplantation, along with their limitations.
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Affiliation(s)
- Wiwat Chancharoenthana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
- Tropical Immunology and Translational Research Unit (TITRU), Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
- Thammasat Multi-Organ Transplant Center, Thammasat University Hospital, Faculty of Medicine, Thammasat University, Pathumthani, Thailand
| | - Opas Traitanon
- Thammasat Multi-Organ Transplant Center, Thammasat University Hospital, Faculty of Medicine, Thammasat University, Pathumthani, Thailand
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Thammasat University, Pathumthani, Thailand
| | - Asada Leelahavanichkul
- Center of Excellence on Translational Research in Inflammation and Immunology (CETRII), Department of Microbiology, Chulalongkorn University, Bangkok, Thailand
- Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Adis Tasanarong
- Thammasat Multi-Organ Transplant Center, Thammasat University Hospital, Faculty of Medicine, Thammasat University, Pathumthani, Thailand
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Thammasat University, Pathumthani, Thailand
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Lerner A, Benzvi C, Vojdani A. SARS-CoV-2 Gut-Targeted Epitopes: Sequence Similarity and Cross-Reactivity Join Together for Molecular Mimicry. Biomedicines 2023; 11:1937. [PMID: 37509576 PMCID: PMC10376948 DOI: 10.3390/biomedicines11071937] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 07/02/2023] [Accepted: 07/06/2023] [Indexed: 07/30/2023] Open
Abstract
The gastrointestinal tract can be heavily infected by SARS-CoV-2. Being an auto-immunogenic virus, SARS-CoV-2 represents an environmental factor that might play a role in gut-associated autoimmune diseases. However, molecular mimicry between the virus and the intestinal epitopes is under-investigated. The present study aims to elucidate sequence similarity between viral antigens and human enteric sequences, based on known cross-reactivity. SARS-CoV-2 epitopes that cross-react with human gut antigens were explored, and sequence alignment was performed against self-antigens implicated in enteric autoimmune conditions. Experimental SARS-CoV-2 epitopes were aggregated from the Immune Epitope Database (IEDB), while enteric antigens were obtained from the UniProt Knowledgebase. A Pairwise Local Alignment tool, EMBOSS Matcher, was employed for the similarity search. Sequence similarity and targeted cross-reactivity were depicted between 10 pairs of immunoreactive epitopes. Similar pairs were found in four viral proteins and seven enteric antigens related to ulcerative colitis, primary biliary cholangitis, celiac disease, and autoimmune hepatitis. Antibodies made against the viral proteins that were cross-reactive with human gut antigens are involved in several essential cellular functions. The relationship and contribution of those intestinal cross-reactive epitopes to SARS-CoV-2 or its potential contribution to gut auto-immuno-genesis are discussed.
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Affiliation(s)
- Aaron Lerner
- Chaim Sheba Medical Center, The Zabludowicz Research Center for Autoimmune Diseases, Ramat Gan 52621, Israel;
- Research Department, Ariel University, Ariel 40700, Israel
| | - Carina Benzvi
- Chaim Sheba Medical Center, The Zabludowicz Research Center for Autoimmune Diseases, Ramat Gan 52621, Israel;
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Fuse K, Araki A, Morozumi S, Yasui K. [A patient with anti-myelin oligodendrocyte glycoprotein antibody-associated combined central and peripheral demyelination with anti-galactocerebroside and anti-GM1 antibodies]. Rinsho Shinkeigaku 2023:cn-001850. [PMID: 37394490 DOI: 10.5692/clinicalneurol.cn-001850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/04/2023]
Abstract
A 48-year-old male was admitted to our hospital because of chronic progressive demyelination of the peripheral nerves of the upper limbs, as well as acute myelitis presenting with sensory disturbance from the left chest to the left leg. We established a diagnosis of combined central and peripheral demyelination (CCPD). The patient was positive for serum anti-myelin oligodendrocyte glycoprotein (MOG), anti-galactocerebroside IgG, and anti-GM1 IgG antibodies. Intravenous methylprednisolone therapy and plasma exchange improved myelitis, and the subsequent administration of oral prednisolone yielded a gradual improvement of the peripheral nerve damage with a mostly negative result for the antibodies. However, the patient experienced a relapse of radiculitis eight months later. Relapses of anti-MOG antibody-associated disease can provoke new immune reactions, leading to CCPD.
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Affiliation(s)
- Kenshiro Fuse
- Department of Neurology, Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital
| | - Amane Araki
- Department of Neurology, Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital
| | - Saori Morozumi
- Department of Neurology, Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital
| | - Keizo Yasui
- Department of Neurology, Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital
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Ignatz RM, Zirkenbach VA, Kaya M, Stroikova V, Öttl R, Frey N, Kaya Z. No Evidence for Myocarditis or Other Organ Affection by Induction of an Immune Response against Critical SARS-CoV-2 Protein Epitopes in a Mouse Model Susceptible for Autoimmunity. Int J Mol Sci 2023; 24:9873. [PMID: 37373021 DOI: 10.3390/ijms24129873] [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: 05/15/2023] [Revised: 06/02/2023] [Accepted: 06/05/2023] [Indexed: 06/29/2023] Open
Abstract
After Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) developed into a global pandemic, not only the infection itself but also several immune-mediated side effects led to additional consequences. Immune reactions such as epitope spreading and cross-reactivity may also play a role in the development of long-COVID, although the exact pathomechanisms have not yet been elucidated. Infection with SARS-CoV-2 can not only cause direct damage to the lungs but can also lead to secondary indirect organ damage (e.g., myocardial involvement), which is often associated with high mortality. To investigate whether an immune reaction against the viral peptides can lead to organ affection, a mouse strain known to be susceptible to the development of autoimmune diseases, such as experimental autoimmune myocarditis (EAM), was used. First, the mice were immunized with single or pooled peptide sequences of the virus's spike (SP), membrane (MP), nucleocapsid (NP), and envelope protein (EP), then the heart and other organs such as the liver, kidney, lung, intestine, and muscle were examined for signs of inflammation or other damage. Our results showed no significant inflammation or signs of pathology in any of these organs as a result of the immunization with these different viral protein sequences. In summary, immunization with different SARS-CoV-2 spike-, membrane-, nucleocapsid-, and envelope-protein peptides does not significantly affect the heart or other organ systems adversely, even when using a highly susceptible mouse strain for experimental autoimmune diseases. This suggests that inducing an immune reaction against these peptides of the SARS-CoV-2 virus alone is not sufficient to cause inflammation and/or dysfunction of the myocardium or other studied organs.
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Affiliation(s)
| | | | - Mansur Kaya
- Department of Cardiology, University of Heidelberg, 69120 Heidelberg, Germany
| | - Vera Stroikova
- Department of Cardiology, University of Heidelberg, 69120 Heidelberg, Germany
| | - Renate Öttl
- Department of Cardiology, University of Heidelberg, 69120 Heidelberg, Germany
| | - Norbert Frey
- Department of Cardiology, University of Heidelberg, 69120 Heidelberg, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, University of Heidelberg, 69120 Heidelberg, Germany
| | - Ziya Kaya
- Department of Cardiology, University of Heidelberg, 69120 Heidelberg, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, University of Heidelberg, 69120 Heidelberg, Germany
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43
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Czaja AJ. Incorporating the Molecular Mimicry of Environmental Antigens into the Causality of Autoimmune Hepatitis. Dig Dis Sci 2023:10.1007/s10620-023-07967-5. [PMID: 37160542 PMCID: PMC10169207 DOI: 10.1007/s10620-023-07967-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Accepted: 05/01/2023] [Indexed: 05/11/2023]
Abstract
Molecular mimicry between foreign and self-antigens has been implicated as a cause of autoimmune hepatitis in experimental models and cross-reacting antibodies in patients. This review describes the experimental and clinical evidence for molecular mimicry as a cause of autoimmune hepatitis, indicates the limitations and uncertainties of this premise, and encourages investigations that assess diverse environmental antigens as sources of disease-relevant molecular mimics. Pertinent articles were identified in PubMed using multiple search phrases. Several pathogens have linear or conformational epitopes that mimic the self-antigens of autoimmune hepatitis. The occurrence of an acute immune-mediated hepatitis after vaccination for severe acute respiratory syndrome (SARS)-associated coronavirus 2 (SARS-CoV-2) has suggested that vaccine-induced peptides may mimic disease-relevant tissue antigens. The intestinal microbiome is an under-evaluated source of gut-derived antigens that could also engage in molecular mimicry. Chaperone molecules may enhance the pathogenicity of molecular mimics, and they warrant investigation. Molecular mimics of immune dominant epitopes within cytochrome P450 IID6, the autoantigen most closely associated with autoimmune hepatitis, should be sought in diverse environmental antigens and assessed for pathogenicity. Avoidance strategies, dietary adjustments, vaccine improvement, and targeted manipulation of the intestinal microbiota may emerge as therapeutic possibilities. In conclusion, molecular mimicry may be a missing causality of autoimmune hepatitis. Molecular mimics of key immune dominant epitopes of disease-specific antigens must be sought in diverse environmental antigens. The ubiquity of molecular mimicry compels rigorous assessments of peptide mimics for immunogenicity and pathogenicity in experimental models. Molecular mimicry may complement epigenetic modifications as causative mechanisms of autoimmune hepatitis.
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Affiliation(s)
- Albert J Czaja
- Professor Emeritus of Medicine, Mayo Clinic College of Medicine and Science, 200 First Street SW, Rochester, MN, 55905, USA.
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44
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Huang J, Xu Y. Autoimmunity: A New Focus on Nasal Polyps. Int J Mol Sci 2023; 24:ijms24098444. [PMID: 37176151 PMCID: PMC10179643 DOI: 10.3390/ijms24098444] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 04/28/2023] [Accepted: 05/02/2023] [Indexed: 05/15/2023] Open
Abstract
Chronic rhinosinusitis with nasal polyps (CRSwNP) has long been considered a benign, chronic inflammatory, and hyperplastic disease. Recent studies have shown that autoimmune-related mechanisms are involved in the pathology of nasal polyps. Activated plasma cells, eosinophils, basophils, innate type 2 lymphocytes, mast cells, and proinflammatory cytokine in polyp tissue indicate the mobilization of innate and adaptive immune pathways during polyp formation. The discovery of a series of autoantibodies further supports the autoimmune nature of nasal polyps. Local homeostasis dysregulation, infection, and chronic inflammation may trigger autoimmunity through several mechanisms, including autoantigens overproduction, microbial translocation, molecular mimicry, superantigens, activation or inhibition of receptors, bystander activation, dysregulation of Toll-Like Receptors (TLRs), epitope spreading, autoantigens complementarity. In this paper, we elaborated on the microbiome-mediated mechanism, abnormal host immunity, and genetic changes to update the role of autoimmunity in the pathogenesis of chronic rhinosinusitis with nasal polyps.
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Affiliation(s)
- Jingyu Huang
- Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Yu Xu
- Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, China
- Research Institute of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, China
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45
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Guo M, Liu X, Chen X, Li Q. Insights into new-onset autoimmune diseases after COVID-19 vaccination. Autoimmun Rev 2023; 22:103340. [PMID: 37075917 PMCID: PMC10108562 DOI: 10.1016/j.autrev.2023.103340] [Citation(s) in RCA: 43] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 04/13/2023] [Indexed: 04/21/2023]
Abstract
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in more than 670 million infections and almost 7 million deaths globally. The emergence of numerous SARS-CoV-2 has heightened public concern regarding the future course of the epidemic. Currently, the SARS-CoV-2 Omicron variant has rapidly become globally dominant in the COVID-19 pandemic due to its high infectivity and immune evasion. Consequently, vaccination implementation is critically significant. However, growing evidence suggests that COVID-19 vaccination may cause new-onset autoimmune diseases, including autoimmune glomerulonephritis, autoimmune rheumatic diseases, and autoimmune hepatitis. Nevertheless, the causal relationship between COVID-19 vaccines and these autoimmune diseases remains to be demonstrated. In this review, we provide evidence that vaccination induces autoimmunity and summarize possible mechanisms of action, such as molecular mimicry, activation by bystanders, and adjuvants. Our objective is not to refute the importance of vaccines, but to raise awareness about the potential risks of COVID-19 vaccination. In fact, we believe that the benefits of vaccination far outweigh the possible risks and encourage people to get vaccinated.
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Affiliation(s)
- Ming Guo
- Hebei General Hosptial, Shijiazhuang, China; Hebei Medical University, Shijiazhuang, China
| | - Xiaoxiao Liu
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing 100853, China
| | - Xiangmei Chen
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing 100853, China
| | - Qinggang Li
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing 100853, China.
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46
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Ryan FJ, Norton TS, McCafferty C, Blake SJ, Stevens NE, James J, Eden GL, Tee YC, Benson SC, Masavuli MG, Yeow AEL, Abayasingam A, Agapiou D, Stevens H, Zecha J, Messina NL, Curtis N, Ignjatovic V, Monagle P, Tran H, McFadyen JD, Bull RA, Grubor-Bauk B, Lynn MA, Botten R, Barry SE, Lynn DJ. A systems immunology study comparing innate and adaptive immune responses in adults to COVID-19 mRNA and adenovirus vectored vaccines. Cell Rep Med 2023; 4:100971. [PMID: 36871558 PMCID: PMC9935276 DOI: 10.1016/j.xcrm.2023.100971] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 12/23/2022] [Accepted: 02/13/2023] [Indexed: 02/19/2023]
Abstract
Identifying the molecular mechanisms that promote optimal immune responses to coronavirus disease 2019 (COVID-19) vaccination is critical for future rational vaccine design. Here, we longitudinally profile innate and adaptive immune responses in 102 adults after the first, second, and third doses of mRNA or adenovirus-vectored COVID-19 vaccines. Using a multi-omics approach, we identify key differences in the immune responses induced by ChAdOx1-S and BNT162b2 that correlate with antigen-specific antibody and T cell responses or vaccine reactogenicity. Unexpectedly, we observe that vaccination with ChAdOx1-S, but not BNT162b2, induces an adenoviral vector-specific memory response after the first dose, which correlates with the expression of proteins with roles in thrombosis with potential implications for thrombosis with thrombocytopenia syndrome (TTS), a rare but serious adverse event linked to adenovirus-vectored vaccines. The COVID-19 Vaccine Immune Responses Study thus represents a major resource that can be used to understand the immunogenicity and reactogenicity of these COVID-19 vaccines.
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Affiliation(s)
- Feargal J Ryan
- Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA 5001, Australia; Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA 5042, Australia
| | - Todd S Norton
- Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA 5001, Australia
| | - Conor McCafferty
- Haematology Research, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3010, Australia
| | - Stephen J Blake
- Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA 5001, Australia; Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA 5042, Australia
| | - Natalie E Stevens
- Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA 5001, Australia; Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA 5042, Australia
| | - Jane James
- Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA 5001, Australia
| | - Georgina L Eden
- Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA 5001, Australia
| | - Yee C Tee
- Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA 5001, Australia; Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA 5042, Australia
| | - Saoirse C Benson
- Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA 5001, Australia; Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA 5042, Australia
| | - Makutiro G Masavuli
- Viral Immunology Group, Adelaide Medical School, University of Adelaide and Basil Hetzel Institute for Translational Health Research, Adelaide, SA 5011, Australia
| | - Arthur E L Yeow
- Viral Immunology Group, Adelaide Medical School, University of Adelaide and Basil Hetzel Institute for Translational Health Research, Adelaide, SA 5011, Australia
| | - Arunasingam Abayasingam
- School of Medical Sciences, Faculty of Medicine, UNSW, Sydney, NSW 2052, Australia; The Kirby Institute, Sydney, NSW 2052, Australia
| | | | - Hannah Stevens
- Clinical Haematology Department, Alfred Hospital, Melbourne, VIC 3004, Australia; Australian Centre for Blood Diseases, Monash University, Melbourne, VIC 3800, Australia
| | - Jana Zecha
- Dynamic Omics, Centre for Genomics Research, Discovery Sciences, R&D, AstraZeneca, Gaithersburg, MD 20878, USA
| | - Nicole L Messina
- Department of Paediatrics, University of Melbourne, Melbourne, VIC 3010, Australia; Infectious Diseases Group, Murdoch Children's Research Institute, Parkville, VIC 3052, Australia
| | - Nigel Curtis
- Department of Paediatrics, University of Melbourne, Melbourne, VIC 3010, Australia; Infectious Diseases Group, Murdoch Children's Research Institute, Parkville, VIC 3052, Australia
| | - Vera Ignjatovic
- Haematology Research, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3010, Australia
| | - Paul Monagle
- Haematology Research, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3010, Australia
| | - Huyen Tran
- Clinical Haematology Department, Alfred Hospital, Melbourne, VIC 3004, Australia; Australian Centre for Blood Diseases, Monash University, Melbourne, VIC 3800, Australia
| | - James D McFadyen
- Clinical Haematology Department, Alfred Hospital, Melbourne, VIC 3004, Australia; Atherothrombosis and Vascular Biology Program, Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia; Baker Department of Cardiometabolic Health, The University of Melbourne, Parkville, VIC 3010, Australia
| | - Rowena A Bull
- School of Medical Sciences, Faculty of Medicine, UNSW, Sydney, NSW 2052, Australia; The Kirby Institute, Sydney, NSW 2052, Australia
| | - Branka Grubor-Bauk
- Viral Immunology Group, Adelaide Medical School, University of Adelaide and Basil Hetzel Institute for Translational Health Research, Adelaide, SA 5011, Australia
| | - Miriam A Lynn
- Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA 5001, Australia; Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA 5042, Australia
| | - Rochelle Botten
- Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA 5001, Australia
| | - Simone E Barry
- Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, SA 5000, Australia
| | - David J Lynn
- Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA 5001, Australia; Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA 5042, Australia.
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47
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Sundaresan B, Shirafkan F, Ripperger K, Rattay K. The Role of Viral Infections in the Onset of Autoimmune Diseases. Viruses 2023; 15:v15030782. [PMID: 36992490 PMCID: PMC10051805 DOI: 10.3390/v15030782] [Citation(s) in RCA: 63] [Impact Index Per Article: 31.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 03/16/2023] [Accepted: 03/17/2023] [Indexed: 03/31/2023] Open
Abstract
Autoimmune diseases (AIDs) are the consequence of a breach in immune tolerance, leading to the inability to sufficiently differentiate between self and non-self. Immune reactions that are targeted towards self-antigens can ultimately lead to the destruction of the host's cells and the development of autoimmune diseases. Although autoimmune disorders are comparatively rare, the worldwide incidence and prevalence is increasing, and they have major adverse implications for mortality and morbidity. Genetic and environmental factors are thought to be the major factors contributing to the development of autoimmunity. Viral infections are one of the environmental triggers that can lead to autoimmunity. Current research suggests that several mechanisms, such as molecular mimicry, epitope spreading, and bystander activation, can cause viral-induced autoimmunity. Here we describe the latest insights into the pathomechanisms of viral-induced autoimmune diseases and discuss recent findings on COVID-19 infections and the development of AIDs.
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Affiliation(s)
- Bhargavi Sundaresan
- Institute of Pharmacology, Biochemical Pharmacological Center, University of Marburg, 35043 Marburg, Germany
| | - Fatemeh Shirafkan
- Institute of Pharmacology, Biochemical Pharmacological Center, University of Marburg, 35043 Marburg, Germany
| | - Kevin Ripperger
- Institute of Pharmacology, Biochemical Pharmacological Center, University of Marburg, 35043 Marburg, Germany
| | - Kristin Rattay
- Institute of Pharmacology, Biochemical Pharmacological Center, University of Marburg, 35043 Marburg, Germany
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48
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Yan T, Zhang Z. Adaptive and innate immune pathogenesis of bullous pemphigoid: A review. Front Immunol 2023; 14:1144429. [PMID: 36993969 PMCID: PMC10041874 DOI: 10.3389/fimmu.2023.1144429] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Accepted: 02/24/2023] [Indexed: 03/12/2023] Open
Abstract
Bullous pemphigoid (BP) is an autoimmune blistering disease that primarily affects elderly individuals. The presentation of BP is heterogeneous, typically manifesting as microscopic subepidermal separation with a mixed inflammatory infiltrate. The mechanism of pemphigoid development is unclear. B cells play a major role in pathogenic autoantibody production, and T cells, type II inflammatory cytokines, eosinophils, mast cells, neutrophils, and keratinocytes are also implicated in the pathogenesis of BP. Here, we review the roles of and crosstalk between innate and adaptive immune cells in BP.
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Affiliation(s)
- Tianmeng Yan
- Department of Dermatology, The University of Hong Kong Shenzhen Hospital, Shenzhen, China
| | - Zhenying Zhang
- Department of Dermatology, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
- *Correspondence: Zhenying Zhang,
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49
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Liu W, Li H, Jin Y, Cheng L, Shi L, Gao Y, Zhou Z, Feng S, Qian H, Hashimoto T, Li X. Case report: Mucous membrane pemphigoid with complicated autoantibody profile indicating the necessity of comprehensive diagnostic methods and the contribution of IgA autoantibodies. Front Immunol 2023; 14:1149119. [PMID: 36969205 PMCID: PMC10033602 DOI: 10.3389/fimmu.2023.1149119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Accepted: 02/27/2023] [Indexed: 03/11/2023] Open
Abstract
Mucous membrane pemphigoid (MMP) is a type of subepithelial autoimmune bullous disease, affecting various mucosae, occasionally with skin lesions. Both diagnosis and treatment of MMP are difficult. Although multiple autoantigens have been identified for MMP, the pathogenesis of MMP is still unclear. In this study, we presented a female MMP case with extensive oral mucosal lesions and skin lesions, particularly on the extremities. IgG and IgA autoantibodies against multiple autoantigens including BP180, laminin 332, integrinα6β4 and desmoglein 3, and IgM autoantibodies against BP180 were identified during the disease course. Compared with IgG autoantibodies, the levels of IgA autoantibodies against various autoantigens decreased more significantly with improvement of clinical features after the initiation of treatments. Our findings indicated the importance of comprehensive autoantibody screening for different immunoglobulin types and autoantigens at multiple time points for the precise diagnosis of various autoimmune bullous diseases, and the significant involvement of IgA autoantibodies into the pathogenesis of MMP.
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Affiliation(s)
- Weijun Liu
- Dermatology Hospital of Jiangxi Province, Jiangxi Provincial Clinical Research Center for Skin Diseases, Candidate Branch of National Clinical Research Center for Skin Diseases, Dermatology Institute of Jiangxi Province, The Affiliated Dermatology Hospital of Nanchang University, Nanchang, China
| | - Huicheng Li
- Dermatology Hospital of Jiangxi Province, Jiangxi Provincial Clinical Research Center for Skin Diseases, Candidate Branch of National Clinical Research Center for Skin Diseases, Dermatology Institute of Jiangxi Province, The Affiliated Dermatology Hospital of Nanchang University, Nanchang, China
| | - Yun Jin
- Dermatology Hospital of Jiangxi Province, Jiangxi Provincial Clinical Research Center for Skin Diseases, Candidate Branch of National Clinical Research Center for Skin Diseases, Dermatology Institute of Jiangxi Province, The Affiliated Dermatology Hospital of Nanchang University, Nanchang, China
- Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
| | - Lifang Cheng
- Dermatology Hospital of Jiangxi Province, Jiangxi Provincial Clinical Research Center for Skin Diseases, Candidate Branch of National Clinical Research Center for Skin Diseases, Dermatology Institute of Jiangxi Province, The Affiliated Dermatology Hospital of Nanchang University, Nanchang, China
| | - Luhuai Shi
- Dermatology Hospital of Jiangxi Province, Jiangxi Provincial Clinical Research Center for Skin Diseases, Candidate Branch of National Clinical Research Center for Skin Diseases, Dermatology Institute of Jiangxi Province, The Affiliated Dermatology Hospital of Nanchang University, Nanchang, China
| | - Yangmin Gao
- Dermatology Hospital of Jiangxi Province, Jiangxi Provincial Clinical Research Center for Skin Diseases, Candidate Branch of National Clinical Research Center for Skin Diseases, Dermatology Institute of Jiangxi Province, The Affiliated Dermatology Hospital of Nanchang University, Nanchang, China
| | - Zhijun Zhou
- Dermatology Hospital of Jiangxi Province, Jiangxi Provincial Clinical Research Center for Skin Diseases, Candidate Branch of National Clinical Research Center for Skin Diseases, Dermatology Institute of Jiangxi Province, The Affiliated Dermatology Hospital of Nanchang University, Nanchang, China
| | - Suying Feng
- Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
| | - Hua Qian
- Department of Laboratory Medicine, Chronic Disease Research Center, Medical College, Dalian University, Dalian, China
- *Correspondence: Xiaoguang Li, ; Takashi Hashimoto, ; Hua Qian,
| | - Takashi Hashimoto
- Department of Dermatology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
- *Correspondence: Xiaoguang Li, ; Takashi Hashimoto, ; Hua Qian,
| | - Xiaoguang Li
- Department of Laboratory Medicine, Chronic Disease Research Center, Medical College, Dalian University, Dalian, China
- *Correspondence: Xiaoguang Li, ; Takashi Hashimoto, ; Hua Qian,
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50
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Shin DS, Ratnapriya S, Cashin CN, Kuhn LF, Rahimi RA, Anthony RM, Moon JJ. Lung injury induces a polarized immune response by self antigen-specific Foxp3 + regulatory T cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.02.09.527896. [PMID: 36798259 PMCID: PMC9934659 DOI: 10.1101/2023.02.09.527896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/12/2023]
Abstract
Self antigen-specific T cells are prevalent in the mature adaptive immune system, but are regulated through multiple mechanisms of tolerance. However, inflammatory conditions such as tissue injury may provide these T cells with an opportunity to break tolerance and trigger autoimmunity. To understand how the T cell repertoire responds to the presentation of self antigen under highly stimulatory conditions, we used peptide:MHCII tetramers to track the behavior of endogenous CD4 + T cells with specificity to a lung-expressed self antigen in mouse models of immune-mediated lung injury. Acute injury resulted in the exclusive expansion of regulatory T cells (Tregs) that was dependent on self antigen recognition and IL-2. Conversely, conventional T cells of the same self antigen specificity remained unresponsive, even following Treg ablation. Thus, the self antigen-specific T cell repertoire is poised to serve a regulatory function during acute tissue damage to limit further damage and the possibility of autoimmunity.
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