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Rokni M, Khomeijani-Farahani M, Soltani T, Jamshidi A, Mahmoudi M, Farhadi E. Understanding the pleiotropic effects of CXCL10/IP-10 in the immunopathogenesis of inflammatory rheumatic diseases: Implications for better understanding disease mechanisms. Int Immunopharmacol 2025; 153:114456. [PMID: 40121742 DOI: 10.1016/j.intimp.2025.114456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2024] [Revised: 02/16/2025] [Accepted: 03/08/2025] [Indexed: 03/25/2025]
Abstract
Chemokines play a critical role in immune responses, acting as chemotactic factors and effectors in different immune processes. CXCL10/IFN-gamma-inducible protein 10 (IP-10) is an inflammatory chemokine that regulates immune cell activation and recruitment by binding to its receptor CXCR3. Additionally, CXCL10 inhibits angiogenesis by interacting with endothelial cells (ECs). In the context of inflammatory rheumatic diseases, CXCL10 influences multiple pathways including chemotaxis, angiostasis, bone destruction, joint inflammation, and regulation of fibroblast-like synoviocyte properties. High levels of CXCL10 have been detected in the serum and tissues of individuals with autoimmune conditions like systemic sclerosis (SSc), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and among others (ankylosing spondylitis, Behçet's syndrome). The CXCL10 may inhibit fibroblast recruitment after tissue injury, delaying wound healing; inhibiting angiogenesis, and uncontrolled pulmonary fibrosis in SSc. In RA disease, the CXCL10-CXCR3 axis could increase the inflammatory cell infiltration, including T lymphocytes and macrophages, into inflamed joints, enhancing arthritis severity and bone and cartilage destruction. The interaction between CXCR3 and ligand-CXCL10 on directing the CD4+ T lymphocytes polarization and observed that CXCL10 skew T lymphocytes polarization into Th1/Th17 effector cells that could lead to an increase in the inflammatory responses in the SLE. This study aims to explore the role of CXCL10 in rheumatic diseases and its potential as both a therapeutic target and a biomarker for these conditions. Understanding the involvement of CXCL10 in the immunopathogenesis of inflammatory rheumatic diseases may provide valuable insights for the development of targeted therapies and diagnostic strategies.
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Affiliation(s)
- Mohsen Rokni
- Department of Immunology, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Taha Soltani
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Ahmadreza Jamshidi
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahdi Mahmoudi
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran; Research Center for Chronic Inflammatory Diseases, Tehran University of Medical Sciences, Tehran, Iran.
| | - Elham Farhadi
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran; Research Center for Chronic Inflammatory Diseases, Tehran University of Medical Sciences, Tehran, Iran.
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Zhang S, Li X, Chen H, Gao X, Cai Z, Zeng H. Assay for interferon gamma release as a novel marker in pediatric patients with systemic lupus erythematosus. Pediatr Rheumatol Online J 2024; 22:70. [PMID: 39090639 PMCID: PMC11292859 DOI: 10.1186/s12969-024-01008-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 07/25/2024] [Indexed: 08/04/2024] Open
Abstract
BACKGROUND The interferon-gamma (IFN-γ) release assay (IGRA) is an important laboratory diagnosis for latent Mycobacterium tuberculosis (TB) infection. The TB-IGRA measures the release of IFN-γ from peripheral blood cells, who are exposed to TB antigen (Ag), mitogen (MT), or negative/nil control (NL) in vitro. While, an exceptional higher TB Ag-NL level will reflect an elevation of peripheral lymphocytes released IFN-γ in a same condition. Therefore, we found that the elevated levels of TB Ag-NL could become a new biomarker for the diagnosis and treatment of pediatric systemic lupus erythematosus (SLE) patients. METHODS We have analyzed the clinical data of 776 children who are underwent TB-IGRA testing in the Department of Allergy and Rheumatology of Guangzhou Women and Children's Medical Center from 2018 to 2020. To investigate the association between TB Ag-NL and SLE, we have analyzed the clinical data of 47 SLE patients and TB Ag-NL testing results, and then evaluated the association between TB Ag-NL and SLE disease activity. RESULTS The TB Ag-NL levels were significantly higher in patients with active SLE than those in inactive SLE (p = 0.0002). The TB Ag-NL levels were positively correlated with the SLE disease activity index (SLEDAI) and laboratory diagnosis parameters. The mean value of TB Ag-NL in SLE patients (0.04191 ± 0.07955, IU/mL) were significantly higher than those in patients with juvenile dermatomyositis (JDM) (0.0158 ± 0.0337, IU/mL, p = 0.036), juvenile idiopathic arthritis (JIA) (0.0162 ± 0.0388, IU/mL, p = 0.001), and healthy controls (HC) (0.0001 ± 0.0027, IU/mL, p = 0.0003). Therefore, the elevated TB Ag-NL levels could serve as a potential diagnostic biomarker of SLE, especially for the active SLE. CONCLUSION The detection of IFN-γ release levels by the TB-IGRA may be useful to assess SLE disease activity in pediatric patients with active SLE.
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Affiliation(s)
- Song Zhang
- Department of Allergy, Immunology and Rheumatology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University，Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, 510623, China
| | - Xue Li
- Department of Rheumatology and Immunology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510623, China
| | - Huishan Chen
- Department of Allergy, Immunology and Rheumatology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University，Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, 510623, China
| | - Xianfei Gao
- Department of Allergy, Immunology and Rheumatology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University，Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, 510623, China
| | - Zhe Cai
- Department of Allergy, Immunology and Rheumatology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University，Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, 510623, China.
- Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China.
| | - Huasong Zeng
- Department of Allergy, Immunology and Rheumatology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University，Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, 510623, China.
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Zou H, Ma S, Li L, Xia X, Zhou Y, Zhang R. Downregulation of circular RNA ETS1 promotes SLE activity and inhibits Treg cell differentiation through miR-1205/FoxP3 molecular axis. Int Immunopharmacol 2024; 128:111539. [PMID: 38244519 DOI: 10.1016/j.intimp.2024.111539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 01/10/2024] [Accepted: 01/11/2024] [Indexed: 01/22/2024]
Abstract
PURPOSE This study aimed to explore the mechanism by which systemic lupus erythematosus (SLE) activity is promoted through Treg inhibition from the perspective of ceRNA. METHODS qRT-PCR was used to detect the expressions of circETS1, miR-1205, and FoxP3 in clinical SLE patient samples. Overexpression of circETS1and miR-1205, along with knockdown of miR-1205 and FoxP3 were conducted in CD4+ T cells, while the proliferation of helper T cell 17 (Th17) and regulatory T cell (Treg) was detected. Arescue assay was performed to verify the molecular mechanism of circETS1/miR-1205/Foxp3 mRNA axis in regulating CD4+ T cell differentiation. In the in vivo experiment, the expression of miR-1205 in SLE mice was intervened, and renal function, inflammatory factors, and serum complement were measured. Additionally, Treg/Th17 cell ratio was detected by flow cytometry. RESULTS In SLE patients, Treg cells were found to decrease, while Th17 cells increased. Transfection with circETS1 overexpression led to CD4+ T cells differentiating into Treg cells, causing an imbalance in the Th17/Treg ratio. Transfection of miR-1205 mimic and si-FoxP3 could reverse the effect of circETS1 overexpression. Moreover, inhibiting the expression of miR-1205 showed therapeutic effects on SLE mice. CONCLUSION circETS1 inhibits Treg via the miR-1205/FoxP3 axis, thereby promoting SLE activity, which may become a new target for SLE treatment.
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Affiliation(s)
- Hongju Zou
- Department of Disease Control and Prevention, The First People's Hospital of Yunnan Province The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan 650034, China
| | - Sha Ma
- Department of Rheumatology, The First People's Hospital of Yunnan Province The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan 650034, China
| | - Li Li
- School of Public Health, Dali University, Dali, Yunnan 671013, China
| | - Xixi Xia
- Department of Laboratory Medicine, The First People's Hospital of Yunnan Province The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan 650034, China
| | - Yan Zhou
- Department of Nephrology, The First People's Hospital of Yunnan Province The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan 650034, China.
| | - Ruixian Zhang
- Department of Disease Control and Prevention, The First People's Hospital of Yunnan Province The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan 650034, China.
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Cao L, Qian W, Li W, Ma Z, Xie S. Type III interferon exerts thymic stromal lymphopoietin in mediating adaptive antiviral immune response. Front Immunol 2023; 14:1250541. [PMID: 37809098 PMCID: PMC10556530 DOI: 10.3389/fimmu.2023.1250541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Accepted: 09/07/2023] [Indexed: 10/10/2023] Open
Abstract
Previously, it was believed that type III interferon (IFN-III) has functions similar to those of type I interferon (IFN-I). However, recently, emerging findings have increasingly indicated the non-redundant role of IFN-III in innate antiviral immune responses. Still, the regulatory activity of IFN-III in adaptive immune response has not been clearly reported yet due to the low expression of IFN-III receptors on most immune cells. In the present study, we reviewed the adjuvant, antiviral, antitumor, and disease-moderating activities of IFN-III in adaptive immunity; moreover, we further elucidated the mechanisms of IFN-III in mediating the adaptive antiviral immune response in a thymic stromal lymphopoietin (TSLP)-dependent manner, a pleiotropic cytokine involved in mucosal adaptive immunity. Research has shown that IFN-III can enhance the antiviral immunogenic response in mouse species by activating germinal center B (GC B) cell responses after stimulating TSLP production by microfold (M) cells, while in human species, TSLP exerts OX40L for regulating GC B cell immune responses, which may also depend on IFN-III. In conclusion, our review highlights the unique role of the IFN-III/TSLP axis in mediating host adaptive immunity, which is mechanically different from IFN-I. Therefore, the IFN-III/TSLP axis may provide novel insights for clinical immunotherapy.
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Affiliation(s)
- Luhong Cao
- Department of Otolaryngology Head and Neck Surgery Surgery, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Weiwei Qian
- Department of Emergency Medicine, Laboratory of Emergency Medicine, West China Hospital, and Disaster Medical Center, Sichuan University, Chengdu, Sichuan, China
| | - Wanlin Li
- National Clinical Research Center for Infectious Disease, Shenzhen Third People’s Hospital, Shenzhen, China
| | - Zhiyue Ma
- Department of Otolaryngology Head and Neck Surgery Surgery, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Shenglong Xie
- Department of Thoracic Surgery, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
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Mohan C, Zhang T, Putterman C. Pathogenic cellular and molecular mediators in lupus nephritis. Nat Rev Nephrol 2023:10.1038/s41581-023-00722-z. [PMID: 37225921 DOI: 10.1038/s41581-023-00722-z] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/21/2023] [Indexed: 05/26/2023]
Abstract
Kidney involvement in patients with systemic lupus erythematosus - lupus nephritis (LN) - is one of the most important and common clinical manifestations of this disease and occurs in 40-60% of patients. Current treatment regimens achieve a complete kidney response in only a minority of affected individuals, and 10-15% of patients with LN develop kidney failure, with its attendant morbidity and considerable prognostic implications. Moreover, the medications most often used to treat LN - corticosteroids in combination with immunosuppressive or cytotoxic drugs - are associated with substantial side effects. Advances in proteomics, flow cytometry and RNA sequencing have led to important new insights into immune cells, molecules and mechanistic pathways that are instrumental in the pathogenesis of LN. These insights, together with a renewed focus on the study of human LN kidney tissue, suggest new therapeutic targets that are already being tested in lupus animal models and early-phase clinical trials and, as such, are hoped to eventually lead to meaningful improvements in the care of patients with systemic lupus erythematosus-associated kidney disease.
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Affiliation(s)
- Chandra Mohan
- Department of Biomedical Engineering, University of Houston, Houston, TX, USA.
| | - Ting Zhang
- Division of Rheumatology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Chaim Putterman
- Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel.
- Division of Rheumatology and Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.
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Petrić M, Radić M. Is Th17-Targeted Therapy Effective in Systemic Lupus Erythematosus? Curr Issues Mol Biol 2023; 45:4331-4343. [PMID: 37232744 DOI: 10.3390/cimb45050275] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 05/01/2023] [Accepted: 05/04/2023] [Indexed: 05/27/2023] Open
Abstract
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a broad spectrum of clinical manifestations. The proposed pathophysiological hypotheses of SLE are numerous, involving both innate and adaptive abnormal immune responses. SLE is characterized by the overproduction of different autoantibodies that form immune complexes, which cause damage in different organs. Current therapeutic modalities are anti-inflammatory and immunosuppressive. In the last decade, we have witnessed the development of many biologicals targeting different cytokines and other molecules. One of them is interleukin-17 (IL-17), a central cytokine of a proinflammatory process that is mediated by a group of helper T cells called Th17. Direct inhibitors of IL-17 are used in psoriatic arthritis, spondyloarthritis, and other diseases. Evidence about the therapeutic potential of Th17-targeted therapies in SLE is scarce, and probably the most promising is related to lupus nephritis. As SLE is a complex heterogeneous disease with different cytokines involved in its pathogenesis, it is highly unlikely that inhibition of only one molecule, such as IL-17, will be effective in the treatment of all clinical manifestations. Future studies should identify SLE patients that are eligible for Th17-targeted therapy.
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Affiliation(s)
- Marin Petrić
- Division of Rheumatology and Clinical Immunology, Department of Internal Medicine, University Hospital of Split, Center of Excellence for Systemic Sclerosis Ministry of Health Republic of Croatia, Šoltanska 1, 21000 Split, Croatia
| | - Mislav Radić
- Division of Rheumatology and Clinical Immunology, Department of Internal Medicine, University Hospital of Split, Center of Excellence for Systemic Sclerosis Ministry of Health Republic of Croatia, Šoltanska 1, 21000 Split, Croatia
- Department of Internal Medicine, School of Medicine, University of Split, Šoltanska 2, 21000 Split, Croatia
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Bao S, Huang H, Jin Y, Ding F, Yang Z, Xu X, Liu C, Lu J, Jin Y. Autoantibody-based subgroups and longitudinal seroconversion in juvenile-onset systemic lupus erythematosus. Lupus Sci Med 2023; 10:10/1/e000834. [PMID: 37012058 PMCID: PMC10083868 DOI: 10.1136/lupus-2022-000834] [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: 10/05/2022] [Accepted: 03/16/2023] [Indexed: 04/05/2023]
Abstract
OBJECTIVE To explore the clinical value of autoantibody-based subgroup framework and the trend of autoantibody fluctuation in juvenile-onset SLE (JSLE). METHODS Eighty-seven patients with JSLE were retrospectively collected and divided into subgroups via a two-step cluster based on the status of nine autoantibodies (double-stranded-DNA (dsDNA), nucleosome, histone, ribosomal P protein, Smith (Sm), u1-ribonucleoprotein (RNP), Sjögren's syndrome antigen A (SSA)/Ro52, SSA/Ro60, Sjögren's syndrome antigen B (SSB)/La). The final model selected in this study was based on adequate goodness of fit of the Silhouette coefficient and clinical interpretability. Clinical manifestations, organ involvements and disease activity were compared among the subgroups. Fluctuation in autoantibody status was also collected and analysed. Flare-free survival rates of the patients with positive/negative seroconversion and patients without seroconversion were studied by the Kaplan-Meier method and compared using a log-rank test. RESULTS Two clusters were identified: subgroup 1 (positive anti-Sm/RNP group) and subgroup 2 (negative anti-Sm/RNP group). There were more lupus nephritis (LN) and neuropsychiatric SLE (NPSLE) cases in subgroup 1 than in subgroup 2. Patients in subgroup 1 exhibited higher SLE Disease Activity Index scores compared with those in subgroup 2. Furthermore, anti-ribosomal P protein (61.1%), anti-nucleosome (58.3%) and anti-dsDNA (54%) were most commonly positive autoantibodies. A progressive decrease in the frequency of patients with positive results was demonstrated during the follow-up years. The decrease was notable for anti-dsDNA, anti-nucleosome and anti-ribosomal P protein (remaining 27.27%, 38.89% and 45.00% positive in the fifth year, respectively). While for those negative at baseline diagnosis, the decrease in the frequency of negative results was progressive but modest. Kaplan-Meier curve showed that the flare-free survival of patients with positive seroconversion was significantly lower than those without seroconversion and those with negative seroconversion (p<0.001). CONCLUSIONS In children with SLE, subgroups based on autoantibody profile can be applied to differentiate phenotypes and disease activity. Two important organ involvements, LN and NPSLE, are more common in patients with positive anti-Sm/RNP autoantibodies. Positive seroconversion may provide a valuable perspective for assessing flare, and it is worthwhile to retest the array of autoantibodies during follow-up.
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Affiliation(s)
- Shengfang Bao
- Department of Rheumatology & Immunology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hua Huang
- Department of Rheumatology & Immunology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yingying Jin
- Department of Rheumatology & Immunology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Fei Ding
- Department of Rheumatology & Immunology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zhen Yang
- Department of Rheumatology & Immunology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xuemei Xu
- Department of Rheumatology & Immunology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Chenxi Liu
- Department of Rheumatology & Immunology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jingyi Lu
- Department of Rheumatology & Immunology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yanliang Jin
- Department of Rheumatology & Immunology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Burska A, Rodríguez-Carrio J, Biesen R, Dik WA, Eloranta ML, Cavalli G, Visser M, Boumpas DT, Bertsias G, Wahren-Herlenius M, Rehwinkel J, Frémond ML, Crow MK, Ronnblom L, Conaghan PG, Versnel M, Vital E. Type I interferon pathway assays in studies of rheumatic and musculoskeletal diseases: a systematic literature review informing EULAR points to consider. RMD Open 2023; 9:e002876. [PMID: 36863752 PMCID: PMC9990675 DOI: 10.1136/rmdopen-2022-002876] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 02/08/2023] [Indexed: 03/04/2023] Open
Abstract
OBJECTIVES To systematically review the literature for assay methods that aim to evaluate type I interferon (IFN-I) pathway activation and to harmonise-related terminology. METHODS Three databases were searched for reports of IFN-I and rheumatic musculoskeletal diseases. Information about the performance metrics of assays measuring IFN-I and measures of truth were extracted and summarised. A EULAR task force panel assessed feasibility and developed consensus terminology. RESULTS Of 10 037 abstracts, 276 fulfilled eligibility criteria for data extraction. Some reported more than one technique to measure IFN-I pathway activation. Hence, 276 papers generated data on 412 methods. IFN-I pathway activation was measured using: qPCR (n=121), immunoassays (n=101), microarray (n=69), reporter cell assay (n=38), DNA methylation (n=14), flow cytometry (n=14), cytopathic effect assay (n=11), RNA sequencing (n=9), plaque reduction assay (n=8), Nanostring (n=5), bisulphite sequencing (n=3). Principles of each assay are summarised for content validity. Concurrent validity (correlation with other IFN assays) was presented for n=150/412 assays. Reliability data were variable and provided for 13 assays. Gene expression and immunoassays were considered most feasible. Consensus terminology to define different aspects of IFN-I research and practice was produced. CONCLUSIONS Diverse methods have been reported as IFN-I assays and these differ in what elements or aspects of IFN-I pathway activation they measure and how. No 'gold standard' represents the entirety of the IFN pathway, some may not be specific for IFN-I. Data on reliability or comparing assays were limited, and feasibility is a challenge for many assays. Consensus terminology should improve consistency of reporting.
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Affiliation(s)
- Agata Burska
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds & NIHR Leeds Biomedical Research Centre, Leeds, UK
| | - Javier Rodríguez-Carrio
- University of Oviedo, Area of Immunology, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
| | - Robert Biesen
- Charité University Medicine Berlin, Department of Rheumatology, Berlin, Germany
| | - Willem A Dik
- Erasmus MC, University Medical Center Rotterdam, Laboratory Medical Immunology, Department of Immunology, Rotterdam, Netherlands Immunology, Rotterdam, The Netherlands
| | - Maija-Leena Eloranta
- Uppsala University, Department of Medical Sciences, Rheumatology, Uppsala, Sweden
| | - Giulio Cavalli
- Unit of Immunology, Rheumatology, Allergy and Rare Diseases, Vita-Salute San Raffaele University, Milan, Italy
- EULAR, PARE Patient Research Partners, Amsterdam, Netherlands
| | - Marianne Visser
- University of Crete, Medical School, Department of Internal Medicine, Heraklion, Greece
| | - Dimitrios T Boumpas
- University of Crete, Medical School, Department of Rheumatology-Clinical Immunology, Heraklion, Greece
| | - George Bertsias
- University of Crete, Medical School, Department of Rheumatology-Clinical Immunology, Heraklion, Greece
| | - Marie Wahren-Herlenius
- Karolinska Institutet, Division of Rheumatology, Stockholm, Sweden
- Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Norway
| | - Jan Rehwinkel
- Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, UK
| | - Marie-Louise Frémond
- Université de Paris Cité, Hôpital Necker-Enfants Malades, Immuno-Hématologie et Rhumatologie pédiatriques, Paris, France
| | - Mary K Crow
- Hospital for Special Surgery, Weill Cornell Medical College, Mary Kirkland Center for Lupus Research, New York, USA
| | - Lars Ronnblom
- Uppsala University, Department of Medical Sciences, Rheumatology, Uppsala, Sweden
| | - P G Conaghan
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds & NIHR Leeds Biomedical Research Centre, Leeds, UK
| | - Marjan Versnel
- Erasmus MC, Department of Immunology, Rotterdam, The Netherlands
| | - Ed Vital
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds & NIHR Leeds Biomedical Research Centre, Leeds, UK
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Rodríguez-Carrio J, Burska A, Conaghan PG, Dik WA, Biesen R, Eloranta ML, Cavalli G, Visser M, Boumpas DT, Bertsias G, Wahren-Herlenius M, Rehwinkel J, Frémond ML, Crow MK, Ronnblom L, Vital E, Versnel M. Association between type I interferon pathway activation and clinical outcomes in rheumatic and musculoskeletal diseases: a systematic literature review informing EULAR points to consider. RMD Open 2023; 9:e002864. [PMID: 36882218 PMCID: PMC10008483 DOI: 10.1136/rmdopen-2022-002864] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 02/13/2023] [Indexed: 03/09/2023] Open
Abstract
BACKGROUND Type I interferons (IFN-I) contribute to a broad range of rheumatic and musculoskeletal diseases (RMDs). Compelling evidence suggests that the measurement of IFN-I pathway activation may have clinical value. Although several IFN-I pathway assays have been proposed, the exact clinical applications are unclear. We summarise the evidence on the potential clinical utility of assays measuring IFN-I pathway activation. METHODS A systematic literature review was conducted across three databases to evaluate the use of IFN-I assays in diagnosis and monitor disease activity, prognosis, response to treatment and responsiveness to change in several RMDs. RESULTS Of 366 screened, 276 studies were selected that reported the use of assays reflecting IFN-I pathway activation for disease diagnosis (n=188), assessment of disease activity (n=122), prognosis (n=20), response to treatment (n=23) and assay responsiveness (n=59). Immunoassays, quantitative PCR (qPCR) and microarrays were reported most frequently, while systemic lupus erythematosus (SLE), rheumatoid arthritis, myositis, systemic sclerosis and primary Sjögren's syndrome were the most studied RMDs. The literature demonstrated significant heterogeneity in techniques, analytical conditions, risk of bias and application in diseases. Inadequate study designs and technical heterogeneity were the main limitations. IFN-I pathway activation was associated with disease activity and flare occurrence in SLE, but their incremental value was uncertain. IFN-I pathway activation may predict response to IFN-I targeting therapies and may predict response to different treatments. CONCLUSIONS Evidence indicates potential clinical value of assays measuring IFN-I pathway activation in several RMDs, but assay harmonisation and clinical validation are urged. This review informs the EULAR points to consider for the measurement and reporting of IFN-I pathway assays.
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Affiliation(s)
- Javier Rodríguez-Carrio
- Area of Immunology, University of Oviedo, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Asturias, Spain
| | - Agata Burska
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds & NIHR Leeds Biomedical Research Centre, Leeds, UK
| | - P G Conaghan
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds & NIHR Leeds Biomedical Research Centre, Leeds, UK
| | - Willem A Dik
- Laboratory Medical Immunology, department of Immunology, Erasmus MC University Medical Center Rotterdam, The Netherlands
| | - Robert Biesen
- Department of Rheumatology, Charité University Medicine Berlin, Berlin, Germany
| | - Maija-Leena Eloranta
- Department of Medical Sciences, Rheumatology, Uppsala University, Uppsala, Sweden
| | - Giulio Cavalli
- Unit of Immunology, Rheumatology, Allergy and Rare Diseases, Vita-Salute San Raffaele University, Milan, Italy
| | - Marianne Visser
- EULAR, PARE Patient Research Partners, Amsterdam, The Netherlands
| | - Dimitrios T Boumpas
- Department of Internal Medicine, University of Crete, Medical School, Heraklion, Greece
| | - George Bertsias
- Department of Rheumatology-Clinical Immunology, University of Crete, Medical School, Heraklion, Greece
| | - Marie Wahren-Herlenius
- Karolinska Institutet, Division of Rheumatology, Stockholm, Sweden
- Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Norway
| | - Jan Rehwinkel
- Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, UK
| | - Marie-Louise Frémond
- Université de Paris Cité, Hôpital Necker-Enfants Malades, Immuno-Hématologie et Rhumatologie pédiatriques, Paris, France
| | - Mary K Crow
- Hospital for Special Surgery, Weill Cornell Medical College, Mary Kirkland Center for Lupus Research, New York, USA
| | - Lars Ronnblom
- Department of Medical Sciences, Rheumatology, Uppsala University, Uppsala, Sweden
| | - Ed Vital
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds & NIHR Leeds Biomedical Research Centre, Leeds, UK
| | - Marjan Versnel
- Department of Immunology, Erasmus MC University Medical Center Rotterdam, The Netherlands
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10
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Sardarmelli Z, Sheikh V, Solgi G, Behzad M. Enhanced production of interleukin-29 and related genes are associated with T helper 1 cell parameters in patients with type 2 diabetes mellitus. Hum Immunol 2023; 84:235-240. [PMID: 36635158 DOI: 10.1016/j.humimm.2023.01.002] [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: 11/02/2022] [Revised: 12/27/2022] [Accepted: 01/05/2023] [Indexed: 01/12/2023]
Abstract
OBJECTIVE The production of interleukin (IL)-29 andthe genes related to IL-29 signaling pathway (STAT1, NF-κB, and NFATc1), and T helper (Th) 1 cells (T-bet, IFN-γ, TNF-α, and IL-2) were evaluated in type 2 diabetes mellitus (T2DM). Correlations between IL-29 and diabetes parameters, and between gene expression in IL-29 pathway and Th1 cells were also examined. MATERIALS AND METHODS 41 newly diagnosed patients with T2DM and 41 healthy controls were recruited. CD4+ T cells were purifed and the production of IL-29 in the supernatant of anti- CD3 and anti- CD28 activated Th cells was detected using ELISA. The expression of IL-29- and Th1- related genes was determined with real-time PCR. RESULTS The secretion of IL-29 and the expression levels of NF-κB, NFATc1, IFN-γ, and TNF-α in Th cells were seen to be increased in diabetes persons compared to controls. Positive connections between IL-29 with hemoglobin A1c (HbA1c) and fasting plasma glucose (FPG) were found in diabetes persons. IL-29 was positively correlated with NFATc1 and TNF-α. NFATc1 was positively related to TNF-α. CONCLUSION Abnormal expression levels of IL-29- and Th1- related genes are linked with T2DM pathogenesis. IL-29 may amplify the expression of Th1-specific genes especially TNF-α by upregulating NFATc1 expression.
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Affiliation(s)
- Zahra Sardarmelli
- Department of Immunology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Vida Sheikh
- Department of Internal Medicine, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Ghasem Solgi
- Department of Immunology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Mahdi Behzad
- Department of Immunology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran.
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11
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Hao N, Zhou Z, Zhang F, Li Y, Hu R, Zou J, Zheng R, Wang L, Xu L, Tan W, Li C, Wang F. Interleukin-29 Accelerates Vascular Calcification via JAK2/STAT3/BMP2 Signaling. J Am Heart Assoc 2022; 12:e027222. [PMID: 36537334 PMCID: PMC9973608 DOI: 10.1161/jaha.122.027222] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Background Vascular calcification (VC), associated with enhanced cardiovascular morbidity and mortality, is characterized by the osteogenic transdifferentiation of vascular smooth muscle cells. Inflammation promotes VC initiation and progression. Interleukin (IL)-29, a newly discovered member of type III interferon, has recently been implicated in the pathogenesis of autoimmune diseases. Here we evaluated the role of IL-29 in the VC process and underlying inflammatory mechanisms. Methods and Results The mRNA expression of IL-29 was significantly increased and positively associated with an increase in BMP2 (bone morphogenetic protein 2) mRNA level in calcified carotid arteries from patients with coronary artery disease or chronic kidney disease. IL-29 and BMP2 proteins are colocalized in human calcified arteries. IL-29 binding to its specific receptor IL-28Rα (IL-28 receptor α) (IL-29/IL-28Rα) inhibited the proliferation of rat vascular smooth muscle cells without altering cell apoptosis or migration. IL-29 promoted the calcification of rat vascular smooth muscle cells and their osteogenic transdifferentiation in vitro as well as the rat aortic ring calcification ex vivo, induced by the calcification medium or osteogenic medium. The procalcification effect of IL-29 was reduced by pharmacological inhibition of IL-29/IL-28Rα binding as well as suppression of janus kinase 2/signal transducer and activator of transcription pathway activation, accompanied by decreased BMP2 expression in the cultured rat vascular smooth muscle cells. Conclusions These results suggest an important role of IL-29 in VC development, at least partly, via activating the janus kinase 2/signal transducer and activator of transcription 3 signaling. Inhibition of IL-29 or its specific receptor, IL-28Rα, may provide a novel strategy to reduce VC in patients with vascular diseases.
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Affiliation(s)
- Nannan Hao
- Department of CardiologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu ProvinceChina
| | - Zihao Zhou
- Department of CardiologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu ProvinceChina
| | - Feifei Zhang
- Department of CardiologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu ProvinceChina
| | - Yong Li
- Department of CardiologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu ProvinceChina
| | - Rui Hu
- Department of Vascular SurgeryThe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu ProvinceChina
| | - Junjie Zou
- Department of Vascular SurgeryThe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu ProvinceChina
| | - Rui Zheng
- Department of Cardiovascular SurgeryThe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu ProvinceChina
| | - Lei Wang
- Department of RheumatologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu ProvinceChina
| | - Lingxiao Xu
- Department of RheumatologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu ProvinceChina
| | - Wenfeng Tan
- Department of RheumatologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu ProvinceChina
| | - Chunjian Li
- Department of CardiologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu ProvinceChina
| | - Fang Wang
- Department of CardiologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu ProvinceChina
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12
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Hejazian SS, Hejazian SM, Farnood F, Abedi Azar S. Dysregulation of immunity in COVID-19 and SLE. Inflammopharmacology 2022; 30:1517-1531. [PMID: 36028612 PMCID: PMC9417079 DOI: 10.1007/s10787-022-01047-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Accepted: 07/30/2022] [Indexed: 12/15/2022]
Abstract
The immune response plays a crucial role in preventing diseases, such as infections. There are two types of immune responses, specific and innate immunity, each of which consists of two components: cellular immunity and humoral immunity. Dysfunction in any immune system component increases the risk of developing certain diseases. Systemic lupus erythematosus (SLE), an autoimmune disease in the human body, develops an immune response against its own components. In these patients, due to underlying immune system disorders and receipt of immunosuppressive drugs, the susceptibility to infections is higher than in the general population and is the single largest cause of mortality in this group. COVID-19 infection, which first appeared in late 2019, has caused several concerns in patients with SLE. However, there is no strong proof of additional risk of developing COVID-19 in patients with SLE, and in some cases, studies have shown less severity of the disease in these individuals. This review paper discusses the immune disorders in SLE and COVID-19.
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Affiliation(s)
- Seyyed Sina Hejazian
- Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Farahnoosh Farnood
- Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sima Abedi Azar
- Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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13
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Barnas JL, Albrecht J, Meednu N, Alzamareh DF, Baker C, McDavid A, Looney RJ, Anolik JH. B Cell Activation and Plasma Cell Differentiation Are Promoted by IFN-λ in Systemic Lupus Erythematosus. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2021; 207:2660-2672. [PMID: 34706932 PMCID: PMC8612983 DOI: 10.4049/jimmunol.2100339] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 09/17/2021] [Indexed: 12/24/2022]
Abstract
Type I IFN is essential for viral clearance but also contributes to the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus (SLE), via aberrant nucleic acid-sensing pathways, leading to autoantibody production. Type III IFN (IFN-λ) is now appreciated to have a nonredundant role in viral infection, but few studies have addressed the effects of IFN-λ on immune cells given the more restricted expression of its receptor primarily to the epithelium. In this study, we demonstrate that B cells display a prominent IFN gene expression profile in patients with lupus. Serum levels of IFN-λ are elevated in SLE and positively correlate with B cell subsets associated with autoimmune plasma cell development, including CD11c+T-bet+CD21- B cells. Although B cell subsets express all IFN receptors, IFNLR1 strongly correlates with the CD11c+CD21- B cell expansion, suggesting that IFN-λ may be an unappreciated driver of the SLE IFN signature and B cell abnormalities. We show that IFN-λ potentiates gene transcription in human B cells typically attributed to type I IFN as well as expansion of T-bet-expressing B cells after BCR and TLR7/8 stimulation. Further, IFN-λ promotes TLR7/8-mediated plasmablast differentiation and increased IgM production. CD11c+ B cells demonstrate IFN-λ hyperresponsive signaling compared with other B cell subsets, suggesting that IFN-λ accelerates plasma cell differentiation through this putative extrafollicular pathway. In summary, our data support type III IFN-λ as a cytokine promoting the Ab-secreting cell pool in human viral and autoimmune disease.
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Affiliation(s)
- Jennifer L Barnas
- Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, NY;
| | - Jennifer Albrecht
- Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, NY
| | - Nida Meednu
- Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, NY
| | - Diana F Alzamareh
- Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, NY
| | - Cameron Baker
- University of Rochester Genomics Research Center, University of Rochester Medical Center, Rochester, NY; and
| | - Andrew McDavid
- Department of Biostatistics and Computational Biology, University of Rochester School of Medicine and Dentistry, Rochester, NY
| | - R John Looney
- Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, NY
| | - Jennifer H Anolik
- Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, NY
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14
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Aschman T, Schaffer S, Biniaris Georgallis SI, Triantafyllopoulou A, Staeheli P, Voll RE. Interferon Lambda Regulates Cellular and Humoral Immunity in Pristane-Induced Lupus. Int J Mol Sci 2021; 22:ijms222111747. [PMID: 34769174 PMCID: PMC8584021 DOI: 10.3390/ijms222111747] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 10/21/2021] [Accepted: 10/26/2021] [Indexed: 12/30/2022] Open
Abstract
A pivotal role of type I interferons in systemic lupus erythematosus (SLE) is widely accepted. Type III interferons (IFN-λ) however, the most recently discovered cytokines grouped within the interferon family, have not been extensively studied in lupus disease models yet. Growing evidence suggests a role for IFN-λ in regulating both innate and adaptive immune responses, and increased serum concentrations have been described in multiple autoimmune diseases including SLE. Using the pristane-induced lupus model, we found that mice with defective IFN-λ receptors (Ifnlr1−/−) showed increased survival rates, decreased lipogranuloma formation and reduced anti-dsDNA autoantibody titers in the early phase of autoimmunity development compared to pristane-treated wild-type mice. Moreover, Ifnlr1−/− mice treated with pristane had reduced numbers of inflammatory mononuclear phagocytes and cNK cells in their kidneys, resembling untreated control mice. Systemically, circulating B cells and monocytes (CD115+Ly6C+) were reduced in pristane-treated Ifnlr1−/− mice. The present study supports a significant role for type III interferons in the pathogenesis of pristane-induced murine autoimmunity as well as in systemic and renal inflammation. Although the absence of type III interferon receptors does not completely prevent the development of autoantibodies, type III interferon signaling accelerates the development of autoimmunity and promotes a pro-inflammatory environment in autoimmune-prone hosts.
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Affiliation(s)
- Tom Aschman
- Department of Rheumatology and Clinical Immunology, Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg im Breisgau, Germany; (S.S.); (S.I.B.G.); (A.T.)
- Department of Neuropathology, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 10117 Berlin, Germany
- Innate Immunity in Rheumatic Diseases, Deutsches Rheuma-Forschungszentrum, 10117 Berlin, Germany
- Correspondence: (T.A.); (R.E.V.)
| | - Sandra Schaffer
- Department of Rheumatology and Clinical Immunology, Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg im Breisgau, Germany; (S.S.); (S.I.B.G.); (A.T.)
| | - Stylianos Iason Biniaris Georgallis
- Department of Rheumatology and Clinical Immunology, Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg im Breisgau, Germany; (S.S.); (S.I.B.G.); (A.T.)
- Innate Immunity in Rheumatic Diseases, Deutsches Rheuma-Forschungszentrum, 10117 Berlin, Germany
- Department of Rheumatology and Clinical Immunology, Charité—Universitätsmedizin Berlin, 10117 Berlin, Germany
| | - Antigoni Triantafyllopoulou
- Department of Rheumatology and Clinical Immunology, Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg im Breisgau, Germany; (S.S.); (S.I.B.G.); (A.T.)
- Innate Immunity in Rheumatic Diseases, Deutsches Rheuma-Forschungszentrum, 10117 Berlin, Germany
- Department of Rheumatology and Clinical Immunology, Charité—Universitätsmedizin Berlin, 10117 Berlin, Germany
| | - Peter Staeheli
- Institute of Virology, Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, 79104 Freiburg im Breisgau, Germany;
| | - Reinhard E. Voll
- Department of Rheumatology and Clinical Immunology, Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg im Breisgau, Germany; (S.S.); (S.I.B.G.); (A.T.)
- Center for Chronic Immunodeficiency (CCI), Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg im Breisgau, Germany
- Correspondence: (T.A.); (R.E.V.)
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15
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Idborg H, Oke V. Cytokines as Biomarkers in Systemic Lupus Erythematosus: Value for Diagnosis and Drug Therapy. Int J Mol Sci 2021; 22:ijms222111327. [PMID: 34768756 PMCID: PMC8582965 DOI: 10.3390/ijms222111327] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 10/12/2021] [Accepted: 10/13/2021] [Indexed: 12/21/2022] Open
Abstract
Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease. The disease is characterized by activation and dysregulation of both the innate and the adaptive immune systems. The autoimmune response targets self-molecules including cell nuclei, double stranded DNA and other intra and extracellular structures. Multiple susceptibility genes within the immune system have been identified, as well as disturbances in different immune pathways. SLE may affect different organs and organ systems, and organ involvement is diverse among individuals. A universal understanding of pathophysiological mechanism of the disease, as well as directed therapies, are still missing. Cytokines are immunomodulating molecules produced by cells of the immune system. Interferons (IFNs) are a broad group of cytokines, primarily produced by the innate immune system. The IFN system has been observed to be dysregulated in SLE, and therefore IFNs have been extensively studied with a hope to understand the disease mechanisms and identify novel targeted therapies. In several autoimmune diseases identification and subsequent blockade of specific cytokines has led to successful therapies, for example tumor necrosis factor-alpha (TNF-α) inhibition in rheumatoid arthritis. Authors of this review have sought corresponding developments in SLE. In the current review, we cover the actual knowledge on IFNs and other studied cytokines as biomarkers and treatment targets in SLE.
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Affiliation(s)
- Helena Idborg
- Division of Rheumatology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, 17176 Stockholm, Sweden;
| | - Vilija Oke
- Division of Rheumatology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, 17176 Stockholm, Sweden;
- Center for Rheumatology, Academic Specialist Center, Stockholm Health Care Services, 11365 Stockholm, Sweden
- Correspondence:
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16
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Ding X, Xiang W, Yi R, Huang X, Lin Q, He X. Neutralizing interferon-α blocks inflammation-mediated vascular injury via PI3K and AMPK in systemic lupus erythematosus. Immunology 2021; 164:372-385. [PMID: 34077562 DOI: 10.1111/imm.13379] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 04/12/2021] [Accepted: 05/10/2021] [Indexed: 01/27/2023] Open
Abstract
Plasmacytoid dendritic cells (pDCs) play a key role in the initiation and amplification of systemic lupus erythematosus (SLE)-associated vascular injury. In this study, we found that dsDNA induced dose- and time-dependent increase in IFN-α and Toll-like receptor 7 (TLR7), TLR9 and IRF7 expression in pDCs. Co-cultured circulating endothelial cells (ECs) with activated pDCs significantly decreased proliferation, tube formation and migration in ECs. The elevated level of cellular IFN-α increased cell adhesion, promoted cell apoptosis, induced cell senescence and arrested cells at G0/G1 phase of endothelial progenitor cells (EPCs). Additionally, the co-culture system activated MAPK and inactivated PI3K. Pristane was used to establish a in vivo SLE-like mouse model. Importantly, we showed that INF-α-neutralizing antibody (IFN-α-NA) rescued all the changes induced by IFN-α in vitro and prevented vascular injury in pristane-induced SLE model in vivo. In conclusion, we confirmed that activated pDCs promoted vascular damage and the dysfunction of ECs/EPCs via IFN-α production. IFN-α-neutralizing antibody may be a clinical implication for preventing vascular injury. PI3K signalling and AMPK signalling were associated with SLE-associated vascular functions.
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Affiliation(s)
- Xuewei Ding
- Institute of Pediatrics, The Second Xiangya Hospital, Central South University, Changsha, China.,Laboratory of Pediatrics Nephrology, Institute of Pediatrics, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Wei Xiang
- Hainan Maternal and Children's Medical Center, Haikou, China
| | - Ren Yi
- Institute of Pediatrics, The Second Xiangya Hospital, Central South University, Changsha, China.,Institute of Pediatrics, HaiKou Hospital of the Maternal and Child Health, Haikou, China
| | - Xiaoyan Huang
- Hainan Maternal and Children's Medical Center, Haikou, China
| | - Qiuyu Lin
- Hainan Maternal and Children's Medical Center, Haikou, China
| | - Xiaojie He
- Institute of Pediatrics, The Second Xiangya Hospital, Central South University, Changsha, China.,Laboratory of Pediatrics Nephrology, Institute of Pediatrics, The Second Xiangya Hospital, Central South University, Changsha, China
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17
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Goel RR, Kotenko SV, Kaplan MJ. Interferon lambda in inflammation and autoimmune rheumatic diseases. Nat Rev Rheumatol 2021; 17:349-362. [PMID: 33907323 PMCID: PMC8077192 DOI: 10.1038/s41584-021-00606-1] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/18/2021] [Indexed: 12/23/2022]
Abstract
Interferons are potent antiviral cytokines that modulate immunity in response to infection or other danger signals. In addition to their antiviral functions, type I interferons (IFNα and IFNβ) are important in the pathogenesis of autoimmune diseases. Type III interferons (IFNλs) were initially described as a specialized system that inhibits viral replication at epithelial barrier surfaces while limiting inflammatory damage. However, evidence now suggests that type III interferons have complex effects on both innate and adaptive immune responses and might also be pathogenic in systemic autoimmune diseases. Concentrations of IFNλs are increased in blood and tissues in a number of autoimmune rheumatic diseases, including systemic lupus erythematosus, and are further associated with specific clinical and laboratory parameters. This Review is aimed at providing a critical evaluation of the current literature on IFNλ biology and how type III interferons might contribute to immune dysregulation and tissue damage in autoimmunity. The potential effects of type III interferons on treatment strategies for autoimmune rheumatic diseases, such as interferon blockade, are also considered.
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Affiliation(s)
- Rishi R Goel
- Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
- Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
| | - Sergei V Kotenko
- Department of Microbiology, Biochemistry and Molecular Genetics, Center for Cell Signaling, Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Mariana J Kaplan
- Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
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18
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Type I Interferon as cardiovascular risk factor in systemic and cutaneous lupus erythematosus: A systematic review. Autoimmun Rev 2021; 20:102794. [PMID: 33722754 DOI: 10.1016/j.autrev.2021.102794] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 01/14/2021] [Indexed: 12/22/2022]
Abstract
OBJECTIVE Patients with systemic lupus erythematosus (SLE) have a high burden of cardiovascular disease (CVD) of multifactorial origin. The aim of this systematic review is to analyze the role of the interferon I (IFN-I) signature and fibroblast growth factor-23 (FGF-23) in patients with SLE or cutaneous lupus erythematosus (CLE) herein. MATERIALS AND METHODS We conducted a systematic literature search in PubMed and Scopus using keywords for major adverse cardiovascular events (MACE) and intermediate outcomes (endothelial dysfunction, subclinical atherosclerosis, platelet activation) associated with IFN-I or FGF-23 in patients with SLE and CLE. RESULTS 4745 citations were screened, of which 12 studies were included. IFN-I was associated with MACE in two third of the studies and the association was strongest for cardiac events. An association of IFN-I was found in all studies investigating impaired vascular function, but only in 50% (respectively 40%) of reports examining the relation of IFN-I and platelet activation (respectively subclinical atherosclerosis). Altogether the reports were of variable bias and quality due to high variability of examined IFN-I biomarkers and inconsistent results for different outcome measures. No studies investigating the cardiovascular risk of circulating IFN-I in CLE, nor FGF-23 in SLE or CLE were found. CONCLUSION Clinical studies measuring the association between IFN-I and direct / intermediate measures of CVD are rare and ambiguous in SLE and nonexistent in CLE, hampering a definite conclusion.
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19
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Park J, Jang W, Park HS, Park KH, Kwok SK, Park SH, Oh EJ. Cytokine clusters as potential diagnostic markers of disease activity and renal involvement in systemic lupus erythematosus. J Int Med Res 2021; 48:300060520926882. [PMID: 32489126 PMCID: PMC7271280 DOI: 10.1177/0300060520926882] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
OBJECTIVE To describe interactions among cytokines and to identify subgroups of systemic lupus erythematosus (SLE) patients based on cytokine levels using principal component analysis and cluster analysis. METHODS Levels of 12 cytokines were measured using sensitive multiplex bead assays and associations with SLE features including disease activity and renal involvement were assessed. RESULTS In a group of 203 SLE patients, strong correlations were observed between interleukin (IL)6 and interferon (IFN)γ levels (r = 0.624), IL17 and IFNγ levels (r = 0.768), and macrophage inflammatory protein (MIP)1α and MIP1β levels (r = 0.675). Cluster analysis revealed two distinct patient groups characterized by high levels of IL8, MIP1α, and MIP1β (group 1) or of IL2, IL6, IL10, IL12, IFNγ, and tumor necrosis factor α (group 2). Active disease was more common in group 1 (49/88, 55.7%) than in group 2 (40/115, 34.8%). More patients in group 2 had renal involvement (42/115, 36.5%) than in group 1 (22/88, 25%). CONCLUSIONS Assessment of cytokine profiles can identify distinct SLE patient subgroups and aid in understanding clinical heterogeneity and immunological phenotypes.
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Affiliation(s)
- Joonhong Park
- Department of Laboratory Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Woori Jang
- Department of Laboratory Medicine, Inha University School of Medicine, Incheon, Korea
| | - Hye Sun Park
- Department of Biomedical Science & Health Sciences, Graduate School, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Ki Hyun Park
- Department of Biomedical Science & Health Sciences, Graduate School, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Seung-Ki Kwok
- Division of Rheumatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Sung-Hwan Park
- Division of Rheumatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Eun-Jee Oh
- Department of Laboratory Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
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20
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Schinocca C, Rizzo C, Fasano S, Grasso G, La Barbera L, Ciccia F, Guggino G. Role of the IL-23/IL-17 Pathway in Rheumatic Diseases: An Overview. Front Immunol 2021; 12:637829. [PMID: 33692806 PMCID: PMC7937623 DOI: 10.3389/fimmu.2021.637829] [Citation(s) in RCA: 203] [Impact Index Per Article: 50.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 01/25/2021] [Indexed: 12/14/2022] Open
Abstract
Interleukin-23 (IL-23) is a pro-inflammatory cytokine composed of two subunits, IL-23A (p19) and IL-12/23B (p40), the latter shared with Interleukin-12 (IL-12). IL-23 is mainly produced by macrophages and dendritic cells, in response to exogenous or endogenous signals, and drives the differentiation and activation of T helper 17 (Th17) cells with subsequent production of IL-17A, IL-17F, IL-6, IL-22, and tumor necrosis factor α (TNF-α). Although IL-23 plays a pivotal role in the protective immune response to bacterial and fungal infections, its dysregulation has been shown to exacerbate chronic immune-mediated inflammation. Well-established experimental data support the concept that IL-23/IL-17 axis activation contributes to the development of several inflammatory diseases, such as PsA, Psoriasis, Psoriatic Arthritis; AS, Ankylosing Spondylitis; IBD, Inflammatory Bowel Disease; RA, Rheumatoid Arthritis; SS, Sjogren Syndrome; MS, Multiple Sclerosis. As a result, emerging clinical studies have focused on the blockade of this pathogenic axis as a promising therapeutic target in several autoimmune disorders; nevertheless, a greater understanding of its contribution still requires further investigation. This review aims to elucidate the most recent studies and literature data on the pathogenetic role of IL-23 and Th17 cells in inflammatory rheumatic diseases.
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Affiliation(s)
- Claudia Schinocca
- Rheumatology Section, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University Hospital “P. Giaccone”, Palermo, Italy
| | - Chiara Rizzo
- Rheumatology Section, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University Hospital “P. Giaccone”, Palermo, Italy
| | - Serena Fasano
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Giulia Grasso
- Rheumatology Section, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University Hospital “P. Giaccone”, Palermo, Italy
| | - Lidia La Barbera
- Rheumatology Section, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University Hospital “P. Giaccone”, Palermo, Italy
| | - Francesco Ciccia
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Giuliana Guggino
- Rheumatology Section, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University Hospital “P. Giaccone”, Palermo, Italy
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21
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Xiong ZH, Cao XS, Guan HL, Zheng HL. Immunotherapies application in active stage of systemic lupus erythematosus in pregnancy: A case report and review of literature. World J Clin Cases 2020; 8:6396-6407. [PMID: 33392323 PMCID: PMC7760451 DOI: 10.12998/wjcc.v8.i24.6396] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 09/27/2020] [Accepted: 10/26/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Pregnancy in the setting of systemic lupus erythematosus can worsen the condition from the stable to active stage, with quality of life and fertility desire being particular concerns. Pregnancy in the active stage of systemic lupus erythematosus (ASLE), although rare and complicated to manage, can be treated favorably with immunotherapies ifs used properly. Here we report such a success case.
CASE SUMMARY A 31-year-old primigravida patient, diagnosed with SLE seven years ago, was induced ASLE after a cold at 21 + weeks. The patient’s vital signs on presentation were normal. Her laboratory exam was remarkable for significant proteinuria, liver and renal dysfunction, and low C3 and C4 levels. Infectious work-up was negative. The patient was diagnosed with ASLE. She was given immunosuppressive agents (methylprednisolone, gamma globulin and azathioprine etc.) and plasma adsorption therapy, monitoring blood pressure every 8 h, fetal heart rate twice a day, and liver and renal function at least twice a week. Successful maternal and fetal outcomes are presented here.
CONCLUSION Child-bearing in ASLE has become more promising, even for this difficult case of ASLE with multiple organ damage. Thorough antepartum counseling, cautious maternal-fetal monitoring, and multi-organ function monitoring by multidisciplinary specialties are keys to favorable pregnancy outcomes.
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Affiliation(s)
- Zhi-Hui Xiong
- Department of Obstetrics, Tongde Hospital of Zhejiang Province, Hangzhou 310012, Zhejiang Province, China
| | - Xiao-Song Cao
- Department of Medical Clinic, Lanxi No. 5 Middle School, Lanxi 321100, Zhejiang Province, China
| | - Hai-Lian Guan
- Department of Obstetrics, Tongde Hospital of Zhejiang Province, Hangzhou 310012, Zhejiang Province, China
| | - Hui-Ling Zheng
- Department of Obstetrics, The Second Affiliated Hospital of Zhejiang University of Traditional Chinese Medicine, Hangzhou 310005, Zhejiang Province, China
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22
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Najafi S, Rajaei E, Moallemian R, Nokhostin F. The potential similarities of COVID-19 and autoimmune disease pathogenesis and therapeutic options: new insights approach. Clin Rheumatol 2020; 39:3223-3235. [PMID: 32885345 PMCID: PMC7471540 DOI: 10.1007/s10067-020-05376-x] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 08/23/2020] [Accepted: 08/27/2020] [Indexed: 12/29/2022]
Abstract
Cytokine pathways and their signaling disorders can be the cause of onset and pathogenesis of many diseases such as autoimmune diseases and COVID-19 infection. Autoimmune patients may be at higher risk of developing infection due to the impaired immune responses, the use of immunosuppressive drugs, and damage to various organs. Increased secretion of inflammatory cytokines and intolerance of the patient's immune system to COVID-19 infection are the leading causes of hospitalization of these patients. The content used in this paper has been taken from English language articles (2005-2020) retrieved from the PubMed database and Google Scholar search engine using "COVID-19," "Autoimmune disease," "Therapeutic," "Pathogenesis," and "Pathway" keywords. The emergence of COVID-19 and its association with autoimmune disorders is a major challenge in the management of these diseases. The results showed that the use of corticosteroids in the treatment of autoimmune diseases can make diagnosis and treatment of COVID-19 more challenging by preventing the fever. Due to the common pathogenesis of COVID-19 and autoimmune diseases, the use of autoimmune drugs as a possible treatment option could help control the virus. KEY POINTS: • Inflammatory cytokines play an essential role in the pathogenesis of COVID-19 • ACE2 dysfunctions are related to the with COVID-19 and autoimmune diseases • The use autoimmune diseases drugs can be useful in treating COVID-19.
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Affiliation(s)
- Sahar Najafi
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Elham Rajaei
- Golestan Hospital Clinical Research Development Unit, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Rezvan Moallemian
- State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic & Developmental Sciences, Sheng Yushou Center of Cell Biology and Immunology, School of Life Science and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240 China
| | - Forough Nokhostin
- Internal medicine, Faculty of Medicine, Ahvaz Jundishapur University of Medical Science, Ahvaz, Iran
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23
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Impact of IL-34, IFN-α and IFN-λ1 on activity of systemic lupus erythematosus in Egyptian patients. Reumatologia 2020; 58:221-230. [PMID: 32921829 PMCID: PMC7477477 DOI: 10.5114/reum.2020.98434] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Accepted: 08/01/2020] [Indexed: 01/09/2023] Open
Abstract
Background Systemic lupus erythematosus (SLE) is an autoimmune, multi-system inflammatory disease. Among cytokines involved in SLE pathogenesis, interferons (particularly IFN-α) and interleukin 34 play a pivotal role. Interestingly, the gene signatures of type III (IFN-λ1) and type I IFNs may overlap. Increased levels of IFN-λ also have been reported in SLE. Objectives: The aim of this study was to assess serum levels of IL-34, IFN-λ1, IFN-α and the relationship between these cytokines and clinical and laboratory parameters and response to treatment in a cohort of Egyptian SLE patients. Material and methods The study included 82 newly diagnosed SLE patients: male 17.1% (n = 14), female 82.9% (n = 68), mean age ±SD: 48.6 ±8.2 and 60 healthy subjects matched by age and gender as a control group. Medical history, physical examination and laboratory tests for confirming SLE diagnosis and assessment of disease activity were collected. The assessment of serum levels of studied cytokines were performed using the ELISA method. All studied patients after first cytokine evaluation were treated with a combination of antimalarial drugs, glucocorticosteroids and/or immunosuppressive drugs with follow-up after six months of treatment. Results In the SLE group the mean serum levels of IL-34, IFN-α and IFN-λ1 were 175.9 ±125.9 pg/ml, 109.3 ±32.5 pg/ml and 227.9 ±144.8 pg/ml respectively. These cytokine levels were significantly higher in the SLE group than in healthy controls. 39% of SLE patients (n = 32) had SLAM > 6 and 26.8% (n = 22) had SLEDAI >6. There were 21 SLE patients (25.6%) with lupus nephritis. IL-34 and IFN-λ1 were positively correlated with anti-dsDNA antibodies but negatively correlated with C3 complement component (p ≤ 0.05). IL-34, INF-α and IFN-λ1 were significantly higher in lupus nephritis patients, and correlated with poorest response to treatment. IL-34 and IFN-λ1 were correlated with higher SLAM > 6 and SLEDAI > 6 results; there was no such correlation between IFN-α and disease activity. Accumulation of three or more clinical features during follow-up was significantly associated with high levels of studied cytokines. Triple high positivity was found in 17 patients (20.7%) and correlated with presence of anti-dsDNA antibodies, low levels of C3 component of complement and lupus nephritis. Conclusions SLE patients with high serum levels of IL-34, IFN-α and IFN-λ1 more often had lupus nephritis and poor response to immunosuppressive treatment. The triple cytokine elevation was strongly associated with higher disease activity. These results may indicate the need to distinguish this group of patients with such aggressive phenotype and consider targeted multi-therapy.
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24
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Hjorton K, Hagberg N, Pucholt P, Eloranta ML, Rönnblom L. The regulation and pharmacological modulation of immune complex induced type III IFN production by plasmacytoid dendritic cells. Arthritis Res Ther 2020; 22:130. [PMID: 32503683 PMCID: PMC7275601 DOI: 10.1186/s13075-020-02186-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Accepted: 04/14/2020] [Indexed: 12/21/2022] Open
Abstract
OBJECTIVE Patients with systemic lupus erythematosus (SLE) have an ongoing interferon (IFN) production due to an activation of plasmacytoid dendritic cells (pDCs), which can be triggered to type I IFN synthesis by RNA containing immune complexes (RNA-IC). Considering emerging data suggesting a role of type III IFN in the SLE disease process, we asked if RNA-IC can induce type III IFN production in pDC and how this production can be regulated. METHODS Peripheral blood mononuclear cells (PBMCs) or immune cell subsets were isolated from healthy blood donors or SLE patients and stimulated with IC containing U1 snRNP and SLE-IgG (RNA-IC). Hydroxychloroquine (HCQ) and an interleukin receptor 1-associated kinase 4 inhibitor (IRAK4i) were added to cell cultures. Cytokine mRNA levels were determined with a microarray and protein levels with immunoassays. Single-cell RNA sequencing of pDCs using ddSEQ technology was performed. RESULTS Type III IFN mRNA and protein was induced in RNA-IC-stimulated pDC-NK and pDC-B cell co-cultures. A subset of activated pDCs (3%) expressed both type III and type I IFN mRNA. IFN-λ2, IFN-α2b, interleukin (IL)-3, IL-6, or granulocyte-macrophage colony-stimulating factor (GM-CSF) enhanced IFN-λ1/3 production 2-5-fold. HCQ and an IRAK4i blocked the RNA-IC-triggered IFN-λ1/3 production (p < 0.01). IFN-α2b and GM-CSF increased the proportion of SLE patients producing IFN-λ1/3 in response to RNA-IC from 11 to 33%. CONCLUSIONS Type III IFN production is triggered by RNA-IC in pDCs in a TLR-MyD88-dependent manner, enhanced by NK and B cells as well as several pro-inflammatory cytokines. These results support a contributing role for both type I and type III IFNs in SLE, which needs to be considered when targeting the IFN system in this disease.
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Affiliation(s)
- Karin Hjorton
- Department of Medical Sciences, Rheumatology, Science for Life Laboratory, Uppsala University, Rudbecklaboratoriet, Dag Hammarskjölds v 20, C11, 751 85, Uppsala, Sweden.
| | - Niklas Hagberg
- Department of Medical Sciences, Rheumatology, Science for Life Laboratory, Uppsala University, Rudbecklaboratoriet, Dag Hammarskjölds v 20, C11, 751 85, Uppsala, Sweden
| | - Pascal Pucholt
- Department of Medical Sciences, Rheumatology, Science for Life Laboratory, Uppsala University, Rudbecklaboratoriet, Dag Hammarskjölds v 20, C11, 751 85, Uppsala, Sweden
| | - Maija-Leena Eloranta
- Department of Medical Sciences, Rheumatology, Science for Life Laboratory, Uppsala University, Rudbecklaboratoriet, Dag Hammarskjölds v 20, C11, 751 85, Uppsala, Sweden
| | - Lars Rönnblom
- Department of Medical Sciences, Rheumatology, Science for Life Laboratory, Uppsala University, Rudbecklaboratoriet, Dag Hammarskjölds v 20, C11, 751 85, Uppsala, Sweden
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25
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Barnes BJ, Somerville CC. Modulating Cytokine Production via Select Packaging and Secretion From Extracellular Vesicles. Front Immunol 2020; 11:1040. [PMID: 32547552 PMCID: PMC7272603 DOI: 10.3389/fimmu.2020.01040] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Accepted: 04/29/2020] [Indexed: 12/12/2022] Open
Abstract
Cytokines are soluble factors that play vital roles in systemic function due to their ability to initiate and mediate cell-to-cell communication. Another important mechanism of intercellular communication that has gained significant attention in the past 10 years is the release of extracellular vesicles (EVs). EVs are released by all cells during normal physiology, in states of resting and activation, as well as during disease. Accumulating evidence indicates that cytokines may be packaged into EVs, and the packaging of cytokines into EVs, along with their ultimate secretion, may also be regulated by cytokines. Importantly, the repertoire of biomolecules packaged into EVs is shaped by the biological state of the cell (resting vs. activated and healthy vs. disease) and the EV biogenesis pathway involved, thus providing mechanisms by which EV packaging and secretion may be modulated. Given the critical role of cytokines in driving acute and chronic inflammatory and autoimmune diseases, as well as their role in establishing the tumor immune microenvironment, in this review, we will focus on these disease settings and summarize recent progress and mechanisms by which cytokines may be packaged within and modulated by EVs, as a therapeutic option for regulating innate and adaptive immunity.
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Affiliation(s)
- Betsy J Barnes
- Center for Autoimmune Musculoskeletal and Hematopoietic Diseases, The Feinstein Institutes for Medical Research, Manhasset, NY, United States.,Departments of Molecular Medicine and Pediatrics, Zucker School of Medicine at Hofstra-Northwell, Hempstead, NY, United States
| | - Carter C Somerville
- Center for Autoimmune Musculoskeletal and Hematopoietic Diseases, The Feinstein Institutes for Medical Research, Manhasset, NY, United States
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26
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Parodis I, Åkerström E, Sjöwall C, Sohrabian A, Jönsen A, Gomez A, Frodlund M, Zickert A, Bengtsson AA, Rönnelid J, Gunnarsson I. Autoantibody and Cytokine Profiles during Treatment with Belimumab in Patients with Systemic Lupus Erythematosus. Int J Mol Sci 2020; 21:E3463. [PMID: 32422945 PMCID: PMC7278961 DOI: 10.3390/ijms21103463] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Revised: 05/02/2020] [Accepted: 05/11/2020] [Indexed: 12/30/2022] Open
Abstract
We investigated whether belimumab treatment impacts on levels of autoantibodies and cytokines of interest in systemic lupus erythematosus (SLE). Longitudinally collected serum samples from 78 belimumab-treated Swedish SLE patients were analysed. Serum cytokine levels were determined using Luminex xMAP technology, and nuclear antigen autoantibody specificities using addressable laser bead immunoassay. In patients with detectable levels at baseline, interferon (IFN)-α2 levels were lower at month 6 (median; interquartile range (IQR): 8.9; 1.5-54.9 pg/mL) versus baseline (28.4; 20.9-100.3 pg/mL; p = 0.043). Interleukin (IL)-6 (baseline: 7.1; 2.9-16.1 pg/mL) decreased from month 6 (0.5; 0.5-6.3 pg/mL; p = 0.018) and throughout a 24 month follow-up. IL-10 (baseline: 12.6; 2.8-29.7 pg/mL) showed more rapid decreases from month 3 (1.8; 0.6-9.1 pg/mL; p = 0.003). Levels of anti-dsDNA (p < 0.001), anti-Smith antigen (Sm) (p = 0.002), anti-U1 small nuclear ribonucleoprotein (U1RNP) (p < 0.001), anti-Sm-U1RNP complex (p = 0.028), and anti-ribosomal P (p = 0.012) antibodies decreased from month 3 and remained decreased. Anti-Sm positivity at baseline was associated with higher probability and/or shorter time to achieve sustained SLE responder index-4 response (hazard ratio (HR): 2.52; 95% CI: 1.20-5.29; p = 0.015), independently of other factors. Decline of IL-6 levels through month 3 was greater in responders. In summary, belimumab treatment lowered IFN-α2, IL-6, and IL-10 levels, as well as levels of multiple autoantibodies, however after different time spans. Notably, anti-Sm positivity and early decline in IL-6 levels were associated with favorable treatment outcome.
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Affiliation(s)
- Ioannis Parodis
- Division of Rheumatology, Department of Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden; (E.A.); (A.G.); (A.Z.); (I.G.)
- Rheumatology, Karolinska University Hospital, SE-171 76 Stockholm, Sweden
| | - Emil Åkerström
- Division of Rheumatology, Department of Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden; (E.A.); (A.G.); (A.Z.); (I.G.)
- Rheumatology, Karolinska University Hospital, SE-171 76 Stockholm, Sweden
| | - Christopher Sjöwall
- Rheumatology/Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Linköping University, SE-581 85 Linköping, Sweden; (C.S.); (M.F.)
| | - Azita Sohrabian
- Department of Immunology, Genetics and Pathology, Uppsala University, SE-751 85 Uppsala, Sweden; (A.S.); (J.R.)
| | - Andreas Jönsen
- Rheumatology, Department of Clinical Sciences Lund, Lund University, Skåne University Hospital, SE-222 42 Lund, Sweden; (A.J.); (A.A.B.)
| | - Alvaro Gomez
- Division of Rheumatology, Department of Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden; (E.A.); (A.G.); (A.Z.); (I.G.)
- Rheumatology, Karolinska University Hospital, SE-171 76 Stockholm, Sweden
| | - Martina Frodlund
- Rheumatology/Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Linköping University, SE-581 85 Linköping, Sweden; (C.S.); (M.F.)
| | - Agneta Zickert
- Division of Rheumatology, Department of Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden; (E.A.); (A.G.); (A.Z.); (I.G.)
- Rheumatology, Karolinska University Hospital, SE-171 76 Stockholm, Sweden
| | - Anders A Bengtsson
- Rheumatology, Department of Clinical Sciences Lund, Lund University, Skåne University Hospital, SE-222 42 Lund, Sweden; (A.J.); (A.A.B.)
| | - Johan Rönnelid
- Department of Immunology, Genetics and Pathology, Uppsala University, SE-751 85 Uppsala, Sweden; (A.S.); (J.R.)
| | - Iva Gunnarsson
- Division of Rheumatology, Department of Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden; (E.A.); (A.G.); (A.Z.); (I.G.)
- Rheumatology, Karolinska University Hospital, SE-171 76 Stockholm, Sweden
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27
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Liu TT, Zeng XP, Gu ML, Deng AM. Increased CD200 levels in peripheral blood mononuclear cells of patients with primary Sjögren's syndrome. Int J Rheum Dis 2020; 23:654-660. [PMID: 32180363 DOI: 10.1111/1756-185x.13810] [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: 09/30/2019] [Revised: 01/15/2020] [Accepted: 02/03/2020] [Indexed: 11/30/2022]
Abstract
OBJECTIVES Primary Sjögren's syndrome (pSS) is a chronic autoimmune disease with an unknown etiology. CD200 is associated with many autoimmune diseases, but little is known about its role in pSS. This study aims to correlate the expression of CD200 with pSS and evaluate its significance. METHODS Plasma CD200, CD200R, and interleukin (IL)-17 levels were measured and analyzed by enzyme-linked immunosorbent assay. Messenger RNA levels of CD200 and CD200R in peripheral blood mononuclear cells (PBMCs) were quantified by quantitative real-time polymerase chain reaction (RT-qPCR). Following pretreatment of CD200-Fc, the protein levels of IL-17A were measured in PBMCs from patients and healthy controls. RESULTS Results showed that, compared to CD200 in healthy controls, the relative levels in PBMCs from pSS were greater than 2-fold. In addition, CD200 levels in plasma positively correlated with IL-17 levels, as well as between plasma CD200 and pSS activity indexes (including immunoglobulin G and European League Against Rheumatism SS Disease Activity Index). While CD200R levels were significantly decreased in pSS patients, no correlation could be found. Furthermore, the protein level of IL-17 decreased after pretreatment of CD200-Fc in PBMCs from pSS patients. CONCLUSION Our results suggested that the CD200/CD200R pathway is involved in pSS pathogenesis. It is hypothesized that regulation of IL-17 expression affects Th17 differentiation. This newly discovered pathway could give rise to a novel targeted therapy for pSS.
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Affiliation(s)
- Ting-Ting Liu
- Department of Laboratory Medicine, Changhai Hospital, The Second Military Medical University, Shanghai, China
| | - Xiang-Peng Zeng
- Department of Digestive Diseases, 900TH Hospital of Joint Logistics Support Force (Fuzhou General Hospital of Fujian Medical University, Eastern Hospital Affiliated to Xiamen University), Fuzhou, China
| | - Ming-Li Gu
- Department of Laboratory Medicine, Changhai Hospital, The Second Military Medical University, Shanghai, China
| | - An-Mei Deng
- Department of Laboratory Medicine, Changhai Hospital, The Second Military Medical University, Shanghai, China
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28
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Zhan Y, Kong I, Chopin M, Macri C, Zhang JG, Xie J, Nutt SL, O'Keeffe M, Hawkins ED, Morand EF, Lew AM. Plasmacytoid dendritic cells from parent strains of the NZB/W F1 lupus mouse contribute different characteristics to autoimmune propensity. Immunol Cell Biol 2020; 98:203-214. [PMID: 31916630 DOI: 10.1111/imcb.12313] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 01/06/2020] [Accepted: 01/07/2020] [Indexed: 11/30/2022]
Abstract
The NZB/W F1 (F1) mice develop severe disease that is similar to human systemic lupus erythematosus. By contrast, each parent strain, NZB or NZW, has limited autoimmunity, suggesting traits of both strains contribute to pathogenesis. Although many of the contributing genes have been identified, the contributing cellular abnormality associated with each parent strain remains unresolved. Given that plasmacytoid dendritic cells (pDCs) are key to the pathogenesis of lupus, we investigated the properties of pDCs from NZB and NZW mice. We found that NZB mouse had higher numbers of pDCs, with much of the increase being contributed by a more abundant CD8+ pDC subset. This was associated with prolonged survival and stronger proliferation of CD4+ T cells. By contrast, NZW pDCs had heightened capacity to produce interferon-α (IFNα) and IFNλ, and promoted stronger B-cell proliferation upon CpG stimulation. Thus, our data reveal the different functional and numerical characteristics of pDCs from NZW and NZB mouse.
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Affiliation(s)
- Yifan Zhan
- The Walter & Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.,Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| | - Isabella Kong
- The Walter & Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.,Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| | - Michael Chopin
- The Walter & Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.,Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| | - Christophe Macri
- Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
| | - Jian-Guo Zhang
- The Walter & Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.,Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| | - Jiaying Xie
- College of Life Sciences, Nankai University, Tianjin, China
| | - Stephen L Nutt
- The Walter & Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.,Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| | - Meredith O'Keeffe
- Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
| | - Edwin D Hawkins
- The Walter & Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.,Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| | - Eric F Morand
- Centre for Inflammatory Diseases, Monash University, Melbourne, VIC, Australia
| | - Andrew M Lew
- The Walter & Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.,Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.,Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, VIC, Australia
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29
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Mora-Arias T, Amezcua-Guerra LM. Type III Interferons (Lambda Interferons) in Rheumatic Autoimmune Diseases. Arch Immunol Ther Exp (Warsz) 2020; 68:1. [PMID: 31915933 DOI: 10.1007/s00005-019-00564-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Accepted: 12/10/2019] [Indexed: 12/12/2022]
Abstract
The last 2 decades have witnessed the discovery and characterization of a new family of cytokines with immunological characteristics similar to those described for type I interferons, type III or lambda interferons. Unraveling the molecular mechanisms underlying each type of interferon has allowed us to understand how some autoimmune diseases can be considered as interferonopathies. Under normal conditions, type III interferons play a key role in the defense against viruses by modulating the functioning of several types of innate and adaptive immune cells. These effects include upregulation of major histocompatibility complex molecules by myeloid dendritic cells, increased functioning of pattern recognition receptors by plasmacytoid dendritic cells, decreased activity of regulatory T cells, enhanced production of antibodies by plasmatic cells and increased expression of chemokines and adhesion molecules by leukocytes and endothelial cells. Notably, all these mechanisms have been described to boost autoimmunity, and type III interferons pathway activation has been related to the pathogenesis of autoimmune conditions such as systemic lupus erythematosus, systemic sclerosis and Sjögren's syndrome. This review provides an overview of the current evidence on the contribution of type III interferons in the pathogenesis of rheumatic autoimmune diseases in humans.
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Affiliation(s)
- Tania Mora-Arias
- Department of Immunology, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano 1, Sección XVI, Tlalpan, 14080, Mexico City, Mexico
| | - Luis M Amezcua-Guerra
- Department of Immunology, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano 1, Sección XVI, Tlalpan, 14080, Mexico City, Mexico.
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30
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Mathian A, Mouries-Martin S, Dorgham K, Devilliers H, Yssel H, Garrido Castillo L, Cohen-Aubart F, Haroche J, Hié M, Pineton de Chambrun M, Miyara M, Pha M, Rozenberg F, Gorochov G, Amoura Z. Ultrasensitive serum interferon-α quantification during SLE remission identifies patients at risk for relapse. Ann Rheum Dis 2019; 78:1669-1676. [PMID: 31570366 DOI: 10.1136/annrheumdis-2019-215571] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Revised: 09/03/2019] [Accepted: 09/04/2019] [Indexed: 11/04/2022]
Abstract
OBJECTIVES Maintenance of remission has become central in the management of systemic lupus erythematosus (SLE). The importance of interferon-alpha (IFN-α) in the pathogenesis of SLE notwithstanding, its expression in remission has been poorly studied as yet. To study its expression in remission and its prognostic value in the prediction of a disease relapse, serum IFN-α levels were determined using an ultrasensitive single-molecule array digital immunoassay which enables the measurement of cytokines at physiological concentrations. METHODS A total of 254 SLE patients in remission, according to the Definition of Remission in SLE classification, were included in the study. Serum IFN-α concentrations were determined at baseline and patients were followed up for 1 year. Lupus flares were defined according to the Safety of Estrogens in Lupus Erythematosus: National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index Flare Index, whereas the Kaplan-Meier analysis and Cox regression analysis were used to estimate the time to relapse and to identify baseline factors associated with time to relapse, respectively. RESULTS Of all patients in remission, 26% displayed abnormally high IFN-α serum levels that were associated with the presence of antibodies specific for ribonucleoprotein (RNP), double stranded (ds)DNA and Ro/SSA60, as well as young age. Importantly, elevated-baseline IFN-α serum levels and remission duration were associated in an independent fashion, with shorter time to relapse, while low serum levels of complement component 3 and anti-dsDNA Abs were not. CONCLUSION Direct serum IFN-α assessment with highly sensitive digital immunoassay permits clinicians to identify a subgroup of SLE patients, clinically in remission, but at higher risk of relapse.
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Affiliation(s)
- Alexis Mathian
- Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Groupement Hospitalier Pitié-Salpêtrière, French National Referral Center for Systemic Lupus Erythematosus, Antiphospholipid Antibody Syndrome and Other Autoimmune Disorders, Service de Médecine Interne 2, Institut E3M, Inserm UMRS, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France
| | - Suzanne Mouries-Martin
- Centre Hospitalier Universitaire de Dijon, Hôpital François-Mitterrand, service de médecine interne et maladies systémiques (médecine interne 2), Dijon, France
| | - Karim Dorgham
- Sorbonne Université, Inserm UMRS, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Assistance Publique-Hôpitaux de Paris, Groupement Hospitalier Pitié-Salpêtrière, Département d'Immunologie, Paris, France
| | - Hervé Devilliers
- Centre Hospitalier Universitaire de Dijon, Hôpital François-Mitterrand, service de médecine interne et maladies systémiques (médecine interne 2) et Centre d'Investigation Clinique, Inserm CIC 1432, Dijon, France
| | - Hans Yssel
- Sorbonne Université, Inserm UMRS, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Assistance Publique-Hôpitaux de Paris, Groupement Hospitalier Pitié-Salpêtrière, Département d'Immunologie, Paris, France
| | - Laura Garrido Castillo
- Sorbonne Université, Inserm UMRS, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Assistance Publique-Hôpitaux de Paris, Groupement Hospitalier Pitié-Salpêtrière, Département d'Immunologie, Paris, France
| | - Fleur Cohen-Aubart
- Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Groupement Hospitalier Pitié-Salpêtrière, French National Referral Center for Systemic Lupus Erythematosus, Antiphospholipid Antibody Syndrome and Other Autoimmune Disorders, Service de Médecine Interne 2, Institut E3M, Inserm UMRS, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France
| | - Julien Haroche
- Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Groupement Hospitalier Pitié-Salpêtrière, French National Referral Center for Systemic Lupus Erythematosus, Antiphospholipid Antibody Syndrome and Other Autoimmune Disorders, Service de Médecine Interne 2, Institut E3M, Inserm UMRS, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France
| | - Miguel Hié
- Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Groupement Hospitalier Pitié-Salpêtrière, French National Referral Center for Systemic Lupus Erythematosus, Antiphospholipid Antibody Syndrome and Other Autoimmune Disorders, Service de Médecine Interne 2, Institut E3M, Inserm UMRS, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France
| | - Marc Pineton de Chambrun
- Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Groupement Hospitalier Pitié-Salpêtrière, French National Referral Center for Systemic Lupus Erythematosus, Antiphospholipid Antibody Syndrome and Other Autoimmune Disorders, Service de Médecine Interne 2, Institut E3M, Inserm UMRS, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France
| | - Makoto Miyara
- Sorbonne Université, Inserm UMRS, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Assistance Publique-Hôpitaux de Paris, Groupement Hospitalier Pitié-Salpêtrière, Département d'Immunologie, Paris, France
| | - Micheline Pha
- Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Groupement Hospitalier Pitié-Salpêtrière, French National Referral Center for Systemic Lupus Erythematosus, Antiphospholipid Antibody Syndrome and Other Autoimmune Disorders, Service de Médecine Interne 2, Institut E3M, Inserm UMRS, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France
| | - Flore Rozenberg
- Université de Paris, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Service de Virologie, Paris, France
| | - Guy Gorochov
- Sorbonne Université, Inserm UMRS, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Assistance Publique-Hôpitaux de Paris, Groupement Hospitalier Pitié-Salpêtrière, Département d'Immunologie, Paris, France
| | - Zahir Amoura
- Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Groupement Hospitalier Pitié-Salpêtrière, French National Referral Center for Systemic Lupus Erythematosus, Antiphospholipid Antibody Syndrome and Other Autoimmune Disorders, Service de Médecine Interne 2, Institut E3M, Inserm UMRS, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France
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Vlachiotis S, Andreakos E. Lambda interferons in immunity and autoimmunity. J Autoimmun 2019; 104:102319. [DOI: 10.1016/j.jaut.2019.102319] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Accepted: 08/09/2019] [Indexed: 01/23/2023]
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Puapatanakul P, Chansritrakul S, Susantitaphong P, Ueaphongsukkit T, Eiam-Ong S, Praditpornsilpa K, Kittanamongkolchai W, Avihingsanon Y. Interferon-Inducible Protein 10 and Disease Activity in Systemic Lupus Erythematosus and Lupus Nephritis: A Systematic Review and Meta-Analysis. Int J Mol Sci 2019; 20:ijms20194954. [PMID: 31597273 PMCID: PMC6801540 DOI: 10.3390/ijms20194954] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 09/30/2019] [Accepted: 10/01/2019] [Indexed: 12/15/2022] Open
Abstract
There is increasing evidence of a correlation between interferon-inducible protein 10 (IP-10) and disease activity of systemic lupus erythematosus (SLE) and lupus nephritis (LN). We conducted a comprehensive search on IP-10 using MEDLINE, Scopus, and Cochrane electronic databases from the beginning to the end of December 2017. All studies that compared serum and/or urine IP-10 between active SLE/LN patients and any control groups were identified and included in this systematic review and meta-analysis. The mean difference (MD) of IP-10 level among active SLE and LN patients, as well as the correlation of IP-10 with disease activity, were meta-analyzed using a random-effects model. From 23 eligible studies, 15 provided adequate data for meta-analysis. Serum IP-10 was significantly elevated in patients with active SLE compared to non-active SLE patients (MD 356.5 pg/mL, 95% CI 59.6 to 653.4, p = 0.019). On the other hand, the levels of serum IP-10 was not different between active LN and non-active LN. However, serum IP-10 was positively correlated with disease activity like SLE disease activity index (SLEDAI) (pooled r = 0.29, 95% CI 0.22 to 0.35, p < 0.001). Furthermore, urine IP-10 tended to be higher in patients with active LN compared to non-active LN patients but this did not reach statistical significance (MD 3.47 pg/mgCr × 100, 95% CI -0.18 to 7.12, p = 0.06). Nevertheless, urine IP-10 was positively correlated with renal SLEDAI (pooled r = 0.29, 95% CI 0.05 to 0.50, p = 0.019). In conclusion, serum and urine IP-10 levels may be useful in monitoring the disease activity of SLE and LN. Serum IP-10 was correlated with systemic disease whereas urine IP-10 was a useful biomarker for detecting active LN.
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Affiliation(s)
- Pongpratch Puapatanakul
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand.
| | | | - Paweena Susantitaphong
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand.
| | | | - Somchai Eiam-Ong
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand.
| | - Kearkiat Praditpornsilpa
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand.
| | - Wonngarm Kittanamongkolchai
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand.
- Renal Immunology and Transplantation Research Unit, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand.
| | - Yingyos Avihingsanon
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand.
- Renal Immunology and Transplantation Research Unit, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand.
- Center of Excellence in Immunology and Immune-mediated Diseases, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand.
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Abstract
Fibrosis is a highly conserved and coordinated wound healing response to injury. In the liver, injury is promoted by immune effector mechanisms that are common across various disease etiologies and even between organs such as lungs, kidneys, heart, and other organs. Thus, the liver represents a useful model to study inflammation and repair, particularly as it is frequently biopsied in clinical contexts. Currently, strong evidence implicates IFNL3/4 polymorphisms and interferon (IFN)-λ3 levels as determinants of the extent of hepatic inflammation and fibrosis in viral and nonviral liver diseases, as well as in governing the severity of nonhepatotropic viral diseases. Interestingly, IFNL3/4 polymorphisms and IFN-λ3 levels correlate with fibrosis extent in other organs such as the lung and kidney. In this review, we discuss the association between IFN-λ and tissue inflammation and fibrosis in human disease and the potential clinical utility of the findings.
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Affiliation(s)
- Mohammed Eslam
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Westmead, Australia
| | - Golo Ahlenstiel
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Westmead, Australia
- Blacktown Medical School, Western Sydney University, Blacktown, Australia
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Westmead, Australia
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Zhang R, Li Y, Pan B, Li Y, Liu A, Li X. Increased expression of hub gene CXCL10 in peripheral blood mononuclear cells of patients with systemic lupus erythematosus. Exp Ther Med 2019; 18:4067-4075. [PMID: 31616519 PMCID: PMC6781829 DOI: 10.3892/etm.2019.8013] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Accepted: 08/23/2019] [Indexed: 12/11/2022] Open
Abstract
Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease, characterized by overactive inflammation and aberrant activation of lymphocytes. Chemokine C-X-C motif ligand 10 (CXCL10) has an important role in the initiation and deterioration of SLE. However, the expression levels of CXCL10 mRNA in T-helper (Th) cells and B lymphocytes from SLE patients have remained elusive. In the present study, a Bioinformatics analysis of differentially expressed gene (DEG) profiles obtained from RNA sequencing data for three matched samples was performed to explore the hub genes, mainly through Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes and protein-protein interaction analysis. Furthermore, the expression of CXCL10 in peripheral blood mononuclear cells (PBMCs), CD4+ Th cells and CD19+ B cells of 108 subjects, including 66 SLE patients and 42 healthy controls, was confirmed by reverse transcription-quantitative PCR. In addition, 4 single-nucleotide polymorphism (SNP) loci in the 3'-untranslated region of CXCL10 were assessed using the Snapshot SNP genotyping assay. A total of 152 clustered DEGs mainly accumulated in immune-associated GO terms and interferon-associated pathways were identified. The expression of CXCL10, one of the central genes in the interaction network cluster (the degree of interaction, MCODE score=28.414), was 6.27-fold higher in SLE patients compared with control patients. Furthermore, CXCL10 mRNA was confirmed to be elevated in PBMCs and CD19+ B cells of patients with SLE (P<0.001 for the two cell types). However, no significant difference in CD4+ T lymphocytes was present (P=0.881). In addition, no polymorphism was identified in four selected loci from the samples. Taken together, the present results demonstrated that CXCL10, one of the hub genes in the pathogenesis of SLE, is upregulated in PBMCs and B lymphocytes of patients with SLE, although none of the SNPs selected for analysis in the present study were identified to have any potential associations with SLE.
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Affiliation(s)
- Ruixian Zhang
- Department of Dermatology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, P.R. China.,Institute of Environmental Hygiene, Yunnan Center for Disease Control and Prevention, Kunming, Yunnan 650022, P.R. China
| | - Ya Li
- Department of Clinical Laboratory, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650031, P.R. China
| | - Bangpin Pan
- Department of Dermatology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, P.R. China
| | - Yi Li
- Department of Dermatology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, P.R. China
| | - Aimin Liu
- Basic Nursing Teaching Department of Kunming Medical University, Kunming, Yunnan 650500, P.R. China
| | - Xiaolan Li
- Department of Dermatology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, P.R. China
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35
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Chyuan IT, Tzeng HT, Chen JY. Signaling Pathways of Type I and Type III Interferons and Targeted Therapies in Systemic Lupus Erythematosus. Cells 2019; 8:cells8090963. [PMID: 31450787 PMCID: PMC6769759 DOI: 10.3390/cells8090963] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 08/17/2019] [Accepted: 08/20/2019] [Indexed: 02/06/2023] Open
Abstract
Type I and type III interferons (IFNs) share several properties in common, including the induction of signaling pathways, the activation of gene transcripts, and immune responses, against viral infection. Recent advances in the understanding of the molecular basis of innate and adaptive immunity have led to the re-examination of the role of these IFNs in autoimmune diseases. To date, a variety of IFN-regulated genes, termed IFN signature genes, have been identified. The expressions of these genes significantly increase in systemic lupus erythematosus (SLE), highlighting the role of type I and type III IFNs in the pathogenesis of SLE. In this review, we first discussed the signaling pathways and the immunoregulatory roles of type I and type III IFNs. Next, we discussed the roles of these IFNs in the pathogenesis of autoimmune diseases, including SLE. In SLE, IFN-stimulated genes induced by IFN signaling contribute to a positive feedback loop of autoimmunity, resulting in perpetual autoimmune inflammation. Based on this, we discussed the use of several specific IFN blocking strategies using anti-IFN-α antibodies, anti-IFN-α receptor antibodies, and IFN-α-kinoid or downstream small molecules, which intervene in Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathways, in clinical trials for SLE patients. Hopefully, the development of novel regimens targeting IFN signaling pathways will shed light on promising future therapeutic applications for SLE patients.
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Affiliation(s)
- I-Tsu Chyuan
- Department of Internal Medicine, Cathay General Hospital, Taipei 10630, Taiwan
- Department of Medical Research, Cathay General Hospital, Taipei 10630, Taiwan
- School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City 24205, Taiwan
| | - Hong-Tai Tzeng
- Institute for translational research in biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
| | - Ji-Yih Chen
- Department of Medicine, Division of Allergy, Immunology and Rheumatology, Chang Gung Memorial Hospital, Taoyuan 33375, Taiwan.
- College of Medicine, Chang Gung University, Taoyuan 33375, Taiwan.
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Burke JR, Cheng L, Gillooly KM, Strnad J, Zupa-Fernandez A, Catlett IM, Zhang Y, Heimrich EM, McIntyre KW, Cunningham MD, Carman JA, Zhou X, Banas D, Chaudhry C, Li S, D’Arienzo C, Chimalakonda A, Yang X, Xie JH, Pang J, Zhao Q, Rose SM, Huang J, Moslin RM, Wrobleski ST, Weinstein DS, Salter-Cid LM. Autoimmune pathways in mice and humans are blocked by pharmacological stabilization of the TYK2 pseudokinase domain. Sci Transl Med 2019; 11:11/502/eaaw1736. [DOI: 10.1126/scitranslmed.aaw1736] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2018] [Revised: 02/24/2019] [Accepted: 07/03/2019] [Indexed: 12/30/2022]
Abstract
TYK2 is a nonreceptor tyrosine kinase involved in adaptive and innate immune responses. A deactivating coding variant has previously been shown to prevent receptor-stimulated activation of this kinase and provides high protection from several common autoimmune diseases but without immunodeficiency. An agent that recapitulates the phenotype of this deactivating coding variant may therefore represent an important advancement in the treatment of autoimmunity. BMS-986165 is a potent oral agent that similarly blocks receptor-stimulated activation of TYK2 allosterically and with high selectivity and potency afforded through optimized binding to a regulatory domain of the protein. Signaling and functional responses in human TH17, TH1, B cells, and myeloid cells integral to autoimmunity were blocked by BMS-986165, both in vitro and in vivo in a phase 1 clinical trial. BMS-986165 demonstrated robust efficacy, consistent with blockade of multiple autoimmune pathways, in murine models of lupus nephritis and inflammatory bowel disease, supporting its therapeutic potential for multiple immune-mediated diseases.
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Idborg H, Zandian A, Ossipova E, Wigren E, Preger C, Mobarrez F, Checa A, Sohrabian A, Pucholt P, Sandling JK, Fernandes-Cerqueira C, Rönnelid J, Oke V, Grosso G, Kvarnström M, Larsson A, Wheelock CE, Syvänen AC, Rönnblom L, Kultima K, Persson H, Gräslund S, Gunnarsson I, Nilsson P, Svenungsson E, Jakobsson PJ. Circulating Levels of Interferon Regulatory Factor-5 Associates With Subgroups of Systemic Lupus Erythematosus Patients. Front Immunol 2019; 10:1029. [PMID: 31156624 PMCID: PMC6533644 DOI: 10.3389/fimmu.2019.01029] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Accepted: 04/23/2019] [Indexed: 12/14/2022] Open
Abstract
Systemic Lupus Erythematosus (SLE) is a heterogeneous autoimmune disease, which currently lacks specific diagnostic biomarkers. The diversity within the patients obstructs clinical trials but may also reflect differences in underlying pathogenesis. Our objective was to obtain protein profiles to identify potential general biomarkers of SLE and to determine molecular subgroups within SLE for patient stratification. Plasma samples from a cross-sectional study of well-characterized SLE patients (n = 379) and matched population controls (n = 316) were analyzed by antibody suspension bead array targeting 281 proteins. To investigate the differences between SLE and controls, Mann–Whitney U-test with Bonferroni correction, generalized linear modeling and receiver operating characteristics (ROC) analysis were performed. K-means clustering was used to identify molecular SLE subgroups. We identified Interferon regulating factor 5 (IRF5), solute carrier family 22 member 2 (SLC22A2) and S100 calcium binding protein A12 (S100A12) as the three proteins with the largest fold change between SLE patients and controls (SLE/Control = 1.4, 1.4, and 1.2 respectively). The lowest p-values comparing SLE patients and controls were obtained for S100A12, Matrix metalloproteinase-1 (MMP1) and SLC22A2 (padjusted = 3 × 10−9, 3 × 10−6, and 5 × 10−6 respectively). In a set of 15 potential biomarkers differentiating SLE patients and controls, two of the proteins were transcription factors, i.e., IRF5 and SAM pointed domain containing ETS transcription factor (SPDEF). IRF5 was up-regulated while SPDEF was found to be down-regulated in SLE patients. Unsupervised clustering of all investigated proteins identified three molecular subgroups among SLE patients, characterized by (1) high levels of rheumatoid factor-IgM, (2) low IRF5, and (3) high IRF5. IRF5 expressing microparticles were analyzed by flow cytometry in a subset of patients to confirm the presence of IRF5 in plasma and detection of extracellular IRF5 was further confirmed by immunoprecipitation-mass spectrometry (IP-MS). Interestingly IRF5, a known genetic risk factor for SLE, was detected extracellularly and suggested by unsupervised clustering analysis to differentiate between SLE subgroups. Our results imply a set of circulating molecules as markers of possible pathogenic importance in SLE. We believe that these findings could be of relevance for understanding the pathogenesis and diversity of SLE, as well as for selection of patients in clinical trials.
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Affiliation(s)
- Helena Idborg
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Arash Zandian
- SciLifeLab, Division of Affinity Proteomics, Department of Protein Science, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Elena Ossipova
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Edvard Wigren
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Charlotta Preger
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Fariborz Mobarrez
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.,Department of Medical Sciences, Akademiska Hospital, Uppsala University, Uppsala, Sweden
| | - Antonio Checa
- Division of Physiological Chemistry 2, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Azita Sohrabian
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Pascal Pucholt
- Department of Medical Sciences, Rheumatology, Uppsala University, Uppsala, Sweden
| | - Johanna K Sandling
- Department of Medical Sciences, Rheumatology, Uppsala University, Uppsala, Sweden
| | - Cátia Fernandes-Cerqueira
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Johan Rönnelid
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Vilija Oke
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Giorgia Grosso
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Marika Kvarnström
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Anders Larsson
- Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, Sweden
| | - Craig E Wheelock
- Division of Physiological Chemistry 2, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Ann-Christine Syvänen
- Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Lars Rönnblom
- Department of Medical Sciences, Rheumatology, Uppsala University, Uppsala, Sweden
| | - Kim Kultima
- Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, Sweden
| | - Helena Persson
- Science for Life Laboratory, Drug Discovery and Development & School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Susanne Gräslund
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Iva Gunnarsson
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Peter Nilsson
- SciLifeLab, Division of Affinity Proteomics, Department of Protein Science, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Elisabet Svenungsson
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Per-Johan Jakobsson
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
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Oke V, Gunnarsson I, Dorschner J, Eketjäll S, Zickert A, Niewold TB, Svenungsson E. High levels of circulating interferons type I, type II and type III associate with distinct clinical features of active systemic lupus erythematosus. Arthritis Res Ther 2019; 21:107. [PMID: 31036046 PMCID: PMC6489203 DOI: 10.1186/s13075-019-1878-y] [Citation(s) in RCA: 131] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 03/26/2019] [Indexed: 01/07/2023] Open
Abstract
Background and aim Interferons (IFNs) are considered to be key molecules in the pathogenesis of systemic lupus erythematosus (SLE). We measured levels of type I, II and III IFNs in a large cohort of patients with systemic lupus erythematosus (SLE) and controls and explored associations among high levels of different IFN types and distinct SLE features. Methods Four hundred ninety-seven well-characterized SLE patients and 322 population controls were included. Disease activity was assessed by SLE Disease Activity Index (SLEDAI) and Systemic Lupus Activity Measure (SLAM). Functional type I IFN activity was estimated by a WISH reporter cell assay. Levels of IFN-γ were estimated by MSD 30-plex assay. IFN-α and IFN-λ1 were measured by ELISA. Values above the third quartile of patients’ measurements were defined as high. Associations among high IFN results and SLE features were investigated by nominal regression analysis. Results All IFN measurements were higher in SLE patients than in controls. High type I IFN activity correlated with levels of IFN-γ and IFN-α and associated with active SLE in most domains: weight loss, fatigue, fever, rash, lymphadenopathy, arthritis, nephritis and haematological manifestations. Specific SLE subsets were linked to the upregulation of different subtypes of circulating IFNs: high IFN-γ to arthritis, nephritis and anti-Ro60 antibodies and high IFN-α to mucocutaneous engagement and anti-Ro52 and anti-La antibodies. Isolated high IFN-λ1 was coupled to anti-nucleosome antibodies and less severe SLE. Conclusions High functional type I IFN activity captures active SLE in most domains, but more distinct patterns of organ involvement are associated with profiles of circulating IFNs. High IFN-γ as well as high functional type I IFN activity is a characteristic of severe SLE with nephritis and arthritis, while elevated levels of IFN-α associate with active mucocutaneous inflammation and a more benign cardiovascular profile. IFN-λ1 in isolation is associated with milder disease. Our findings suggest that IFNs contribute to the heterogeneity of clinical manifestations in SLE, and measuring circulating IFNs could assist in designing clinical trials with therapies targeting IFN pathways. Electronic supplementary material The online version of this article (10.1186/s13075-019-1878-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Vilija Oke
- Rheumatology Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, SE-171 76, Stockholm, Sweden.
| | - Iva Gunnarsson
- Rheumatology Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, SE-171 76, Stockholm, Sweden
| | - Jessica Dorschner
- Division of Rheumatology and Department of Immunology, Mayo Clinic, Rochester, MN, USA
| | - Susanna Eketjäll
- Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca, Integrated Cardio Metabolic Centre, Karolinska Institutet, Huddinge, Sweden
| | - Agneta Zickert
- Rheumatology Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, SE-171 76, Stockholm, Sweden
| | - Timothy B Niewold
- Division of Rheumatology and Department of Immunology, Mayo Clinic, Rochester, MN, USA.,Colton Center for Autoimmunity, New York University School of Medicine, New York, NY, USA
| | - Elisabet Svenungsson
- Rheumatology Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, SE-171 76, Stockholm, Sweden
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Li Y, Yu X, Ma Y, Hua S. IL-23 and dendritic cells: What are the roles of their mutual attachment in immune response and immunotherapy? Cytokine 2019; 120:78-84. [PMID: 31029042 DOI: 10.1016/j.cyto.2019.02.018] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 02/21/2019] [Accepted: 02/22/2019] [Indexed: 12/12/2022]
Abstract
Interleukin-23 (IL-23) is a cytokine that is composed of the subunits p19 and p40, while its receptor (IL-23R) consists of two subunits, that is, IL-23Rα and IL-12Rβ1. The interaction between IL-23 and IL-23R is necessary for exerting cardinal biological effects upon certain cell types, including promotion of memory T cell proliferation and Th17 cell-mediated IL-17 secretion. Accordingly, dendritic cells (DCs) are one of the main sources for IL-23 secretion. Interestingly, IL-23R is also present on the DC plasma membrane, suggesting that IL-23 potentially acts on DCs via an autocrine manner. In this review, we have summarized a variety of IL-23-mediated effects on the intracellular signaling pathways such as Janus kinase 2, tyrosine kinase 2, signal transducer and activator of transcription (STAT), mitogen-activated protein kinase signaling, and so forth, which may underlie numerous processes such as DC maturation, antigen presentation, T cell proliferation/activation, and cytokine secretion, which may be implicated in many immune-related diseases through IL-23/DC interactions. Accordingly, these signaling pathways are extensively involved in the pathogenesis and progression of numerous diseases, including autoimmune disease (e.g., atopic dermatitis, asthma, and multiple sclerosis) and infection (e.g., bacterial, fungal, and viral infections). Taken together, they are potentially applicable to novel but promising strategies for treating numerous diseases associated with the mutual attachment of IL-23 and DCs.
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Affiliation(s)
- Yanchun Li
- Department of Respiratory Medicine, The First Hospital of Jilin University, Changchun, 130 021 Jinlin, China
| | - Xiuhua Yu
- Department of Respiratory Medicine, The First Hospital of Jilin University, Changchun, 130 021 Jinlin, China
| | - Yucong Ma
- Department of Respiratory Medicine, The First Hospital of Jilin University, Changchun, 130 021 Jinlin, China
| | - Shucheng Hua
- Department of Respiratory Medicine, The First Hospital of Jilin University, Changchun, 130 021 Jinlin, China.
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Lazear HM, Schoggins JW, Diamond MS. Shared and Distinct Functions of Type I and Type III Interferons. Immunity 2019; 50:907-923. [PMID: 30995506 PMCID: PMC6839410 DOI: 10.1016/j.immuni.2019.03.025] [Citation(s) in RCA: 764] [Impact Index Per Article: 127.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2019] [Revised: 03/18/2019] [Accepted: 03/25/2019] [Indexed: 12/12/2022]
Abstract
Type I interferons (IFNs) (IFN-α, IFN-β) and type III IFNs (IFN-λ) share many properties, including induction by viral infection, activation of shared signaling pathways, and transcriptional programs. However, recent discoveries have revealed context-specific functional differences. Here, we provide a comprehensive review of type I and type III IFN activities, highlighting shared and distinct features from molecular mechanisms through physiological responses. Beyond discussing canonical antiviral functions, we consider the adaptive immune priming, anti-tumor, and autoimmune functions of IFNs. We discuss a model wherein type III IFNs serve as a front-line defense that controls infection at epithelial barriers while minimizing damaging inflammatory responses, reserving the more potent type I IFN response for when local responses are insufficient. In this context, we discuss current therapeutic applications targeting these cytokine pathways and highlight gaps in understanding of the biology of type I and type III IFNs in health and disease.
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Affiliation(s)
- Helen M Lazear
- Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
| | - John W Schoggins
- Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Michael S Diamond
- Departments of Medicine, Pathology & Immunology, and Molecular Microbiology, and The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, Saint Louis, MO 63110, USA.
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Álvarez-Rodríguez L, Martínez-Taboada V, Calvo-Alén J, Beares I, Villa I, López-Hoyos M. Altered Th17/Treg Ratio in Peripheral Blood of Systemic Lupus Erythematosus but Not Primary Antiphospholipid Syndrome. Front Immunol 2019; 10:391. [PMID: 30894863 PMCID: PMC6414457 DOI: 10.3389/fimmu.2019.00391] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Accepted: 02/14/2019] [Indexed: 12/14/2022] Open
Abstract
Introduction: The role of the immune response in the pathogenesis of antiphospholipid syndrome (APS) remains elusive. It is possible that differences in the frequencies of Th17 cells and/or defects in the immunoregulatory mechanisms are involved in the pathogenesis of APS. Our aim was to determine the peripheral blood Th cells phenotype and the circulating cytokine profile in patients with primary APS (pAPS) and compare it with systemic lupus erythemathosus (SLE) as disease control group. Methods: The frequencies of circulating regulatory T cells (Tregs) were determined in PBMCs from 36 patients with pAPS by flow cytometry. As control groups we included 21 age- and gender-matched healthy controls (HC) and 11 patients with SLE. The suppressive capacity of Tregs was evaluated in vitro by coculture assay. On the other hand, intracellular cytokine production was assessed in Th1, Th2, and Th17 cells and circulating IL-6, IL-10, and IL-35 were measured by Cytometric Bead Array and ELISA. The quantification of Th master gene expression levels was performed by real time quantitative PCR. Results: pAPS patients and SLE patients did not show differences in the percentage or number of Tregs compared to HC. The suppressive capacity of Tregs was also similar in the three study group. Instead, we found higher FoxP3·mRNA expression levels in pAPS patients and HC than SLE patients. Regarding the Th17 response, patients with pAPS and HC showed a significantly lower frequency of circulating Th17 cells than SLE. However, no differences were observed in the Th1 response between patients and controls. Thus, increased Th17/Th1 and Th17/Treg ratios were found in SLE patients but not in pAPS patients. pAPS and SLE patients had higher serum IL-6 levels than HC but there was not difference between both disease groups. Besides, a significant increase in the immunosuppressive cytokine levels was observed only in pAPS as compared to HC. Conclusions: Our data demonstrate an increased inflammatory profile of peripheral blood CD4+ T cells from SLE as compared with pAPS mostly due to an increased Th17 response. In conclusion, there seems not to be a direct pathogenic role for Th cells in pAPS but in SLE.
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Affiliation(s)
- Lorena Álvarez-Rodríguez
- Transplantation and Autoimmunity Laboratory, Rheumatology Department, University Hospital Marqués de Valdecilla-IDIVAL, Santander, Spain
| | - Víctor Martínez-Taboada
- Faculty of Medicine, Rheumatology Department, University Hospital Marqués de Valdecilla-IDIVAL, Cantabria University, Santander, Spain
| | - Jaime Calvo-Alén
- Rheumatology Department, University Hospital Araba, Vitoria-Gasteiz, Spain
| | - Iñaki Beares
- Transplantation and Autoimmunity Laboratory, Rheumatology Department, University Hospital Marqués de Valdecilla-IDIVAL, Santander, Spain
| | - Ignacio Villa
- Rheumatology Department, Hospital Sierrallana, Torrelavega, Spain
| | - Marcos López-Hoyos
- Immunology Department, University Hospital Marqués de Valdecilla-IDIVAL, Cantabria University, Santander, Spain
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Idborg H, Zandian A, Sandberg AS, Nilsson B, Elvin K, Truedsson L, Sohrabian A, Rönnelid J, Mo J, Grosso G, Kvarnström M, Gunnarsson I, Lehtiö J, Nilsson P, Svenungsson E, Jakobsson PJ. Two subgroups in systemic lupus erythematosus with features of antiphospholipid or Sjögren's syndrome differ in molecular signatures and treatment perspectives. Arthritis Res Ther 2019; 21:62. [PMID: 30777133 PMCID: PMC6378708 DOI: 10.1186/s13075-019-1836-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Accepted: 01/24/2019] [Indexed: 01/31/2023] Open
Abstract
Background Previous studies and own clinical observations of patients with systemic lupus erythematosus (SLE) suggest that SLE harbors distinct immunophenotypes. This heterogeneity might result in differences in response to treatment in different subgroups and obstruct clinical trials. Our aim was to understand how SLE subgroups may differ regarding underlying pathophysiology and characteristic biomarkers. Methods In a cross-sectional study, including 378 well-characterized SLE patients and 316 individually matched population controls, we defined subgroups based on the patients’ autoantibody profile at inclusion. We selected a core of an antiphospholipid syndrome-like SLE (aPL+ group; positive in the lupus anticoagulant (LA) test and negative for all three of SSA (Ro52 and Ro60) and SSB antibodies) and a Sjögren’s syndrome-like SLE (SSA/SSB+ group; positive for all three of SSA (Ro52 and Ro60) and SSB antibodies but negative in the LA test). We applied affinity-based proteomics, targeting 281 proteins, together with well-established clinical biomarkers and complementary immunoassays to explore the difference between the two predefined SLE subgroups. Results The aPL+ group comprised 66 and the SSA/SSB+ group 63 patients. The protein with the highest prediction power (receiver operating characteristic (ROC) area under the curve = 0.89) for separating the aPL+ and SSA/SSB+ SLE subgroups was integrin beta-1 (ITGB1), with higher levels present in the SSA/SSB+ subgroup. Proteins with the lowest p values comparing the two SLE subgroups were ITGB1, SLC13A3, and CERS5. These three proteins, rheumatoid factor, and immunoglobulin G (IgG) were all increased in the SSA/SSB+ subgroup. This subgroup was also characterized by a possible activation of the interferon system as measured by high KRT7, TYK2, and ETV7 in plasma. In the aPL+ subgroup, complement activation was more pronounced together with several biomarkers associated with systemic inflammation (fibrinogen, α-1 antitrypsin, neutrophils, and triglycerides). Conclusions Our observations indicate underlying pathogenic differences between the SSA/SSB+ and the aPL+ SLE subgroups, suggesting that the SSA/SSB+ subgroup may benefit from IFN-blocking therapies while the aPL+ subgroup is more likely to have an effect from drugs targeting the complement system. Stratifying SLE patients based on an autoantibody profile could be a way forward to understand underlying pathophysiology and to improve selection of patients for clinical trials of targeted treatments. Electronic supplementary material The online version of this article (10.1186/s13075-019-1836-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Helena Idborg
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, 171 76, Stockholm, Sweden
| | - Arash Zandian
- Division of Affinity Proteomics, SciLifeLab, Department of Protein Science, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Ann-Sofi Sandberg
- Clinical Proteomics Mass Spectrometry, Department of Oncology-Pathology, Science for Life Laboratory and Karolinska Institutet, Stockholm, Sweden
| | - Bo Nilsson
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Kerstin Elvin
- Unit of Clinical Immunology, Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Karolinska Institutet, Solna, Stockholm, Sweden
| | - Lennart Truedsson
- Section of Microbiology, Immunology and Glycobiology, Department of Laboratory Medicine, Lund University, Lund, Sweden
| | - Azita Sohrabian
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Johan Rönnelid
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - John Mo
- Patient Safety Respiratory, Inflammation, Autoimmunity, Infection and Vaccines, AstraZeneca R&D, Gothenburg, Sweden
| | - Giorgia Grosso
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, 171 76, Stockholm, Sweden
| | - Marika Kvarnström
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, 171 76, Stockholm, Sweden
| | - Iva Gunnarsson
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, 171 76, Stockholm, Sweden
| | - Janne Lehtiö
- Clinical Proteomics Mass Spectrometry, Department of Oncology-Pathology, Science for Life Laboratory and Karolinska Institutet, Stockholm, Sweden
| | - Peter Nilsson
- Division of Affinity Proteomics, SciLifeLab, Department of Protein Science, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Elisabet Svenungsson
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, 171 76, Stockholm, Sweden.
| | - Per-Johan Jakobsson
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, 171 76, Stockholm, Sweden.
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Sandholm K, Persson B, Skattum L, Eggertsen G, Nyman D, Gunnarsson I, Svenungson E, Nilsson B, Ekdahl KN. Evaluation of a Novel Immunoassay for Quantification of C1q for Clinical Diagnostic Use. Front Immunol 2019; 10:7. [PMID: 30740097 PMCID: PMC6357986 DOI: 10.3389/fimmu.2019.00007] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Accepted: 01/03/2019] [Indexed: 01/28/2023] Open
Abstract
Objectives: C1q is a valuable biomarker of disease activity in systemic lupus erythematosus (SLE). The “gold standard” assay, rocket immunoelectrophoresis (RIE), is time-consuming, and thus a shift to soluble immune precipitation techniques such as nephelometry has occurred. However, quantification of C1q with these techniques has been questioned as a result of the antibody binding properties of C1q. In the present work, we have compared results using various techniques (RIE, nephelometry, and ELISA) and have developed and validated a new magnetic bead-based sandwich immunoassay (MBSI). Methods: C1q was quantified by nephelometry and the new sandwich immunoassay in 45 serum samples analyzed using RIE. C1q was also assessed in plasma using RIE and sandwich immunoassay in samples from SLE patients with nephritis (n = 69), SLE patients without nephritis (n = 310) as classified by BILAG score, and matched controls (n = 322). In addition, cerebrospinal fluid (CSF) samples from 31 patients, previously analyzed with ELISA, were also analyzed with the MBSI to test the behavior of this new assay in the lower detection range. Results: We found a strong correlation between the new MBSI, RIE, and ELISA, but not with nephelometry. The MBSI demonstrated lower levels of C1q in SLE patients than in matched controls (p < 0.0001), and patients with nephritis had lower levels than patients without nephritis (p < 0.01). Similarily, RIE showed significant differences between the patient groups (p < 0.0001). An association was also found between the levels of C1q and the SLE disease activity index (SLEDAI). Furthermore, there was good correlation between the values obtained by MBSI and ELISA, in both serum (r = 0.960) and CSF (r = 0.786), underscoring the ability of both techniques to measure low concentrations of C1q with high accuracy. Conclusion: The sandwich immunoassay correlated well with RIE, but soluble immune precipitation techniques, such as nephelometry, did not appear suitable alternatives, since C1q itself, and possibly anti-C1q antibodies, interfered with the measurements. The new sandwich immunoassay is therefore a good replacement for RIE in monitoring SLE disease activity.
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Affiliation(s)
- Kerstin Sandholm
- Linnaeus Center of Biomaterials Chemistry, Linnaeus University, Kalmar, Sweden
| | - Barbro Persson
- Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Lillemor Skattum
- Section of Microbiology, Department of Laboratory Medicine, Immunology and Glycobiology, Lund University, and Clinical Immunology and Transfusion Medicine, Lund, Sweden
| | - Gösta Eggertsen
- Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.,Karolinska University Laboratory, Clinical Chemistry, Stockholm, Sweden
| | - Dag Nyman
- Åland Borrelia Group, Åland Central Hospital, Mariehamn, Finland
| | - Iva Gunnarsson
- Rheumatology Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Elisabet Svenungson
- Rheumatology Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Bo Nilsson
- Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Kristina N Ekdahl
- Linnaeus Center of Biomaterials Chemistry, Linnaeus University, Kalmar, Sweden.,Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
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Larosa M, Zen M, Gatto M, Jesus D, Zanatta E, Iaccarino L, Inês L, Doria A. IL-12 and IL-23/Th17 axis in systemic lupus erythematosus. Exp Biol Med (Maywood) 2019; 244:42-51. [PMID: 30664357 DOI: 10.1177/1535370218824547] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
IMPACT STATEMENT Our article is focused on emerging pathogenetic pathways in systemic lupus erythematosus (SLE). Notably, IL-12 and IL-23 have been described as emerging cytokines in SLE pathogenesis. We know that IL-23 stimulates Th17 cells to produce IL-17. We try to point out the importance of IL-23/Th17 axis in SLE and to focus on the interaction between this axis and IL-12. Ustekinumab, a fully human IgG1κ monoclonal antibody directed towards the p40 shared subunit of IL-12 and IL-23, has been recently investigated in SLE, suggesting a potential novel therapeutic strategy in SLE. To our knowledge, there are no reviews which simultaneously focus on IL-12 an IL-23/Th17 axis in SLE. Thus, we believe our work will be of interest to the readers.
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Affiliation(s)
- Maddalena Larosa
- 1 Department of Medicine-DIMED, Division of Rheumatology, University of Padova, 35128 Padova, Italy
| | - Margherita Zen
- 1 Department of Medicine-DIMED, Division of Rheumatology, University of Padova, 35128 Padova, Italy
| | - Mariele Gatto
- 1 Department of Medicine-DIMED, Division of Rheumatology, University of Padova, 35128 Padova, Italy
| | - Diogo Jesus
- 2 Rheumatology Department, Centro Hospitalar e Universitário de Coimbra, 3000-075 Coimbra, Portugal
| | - Elisabetta Zanatta
- 1 Department of Medicine-DIMED, Division of Rheumatology, University of Padova, 35128 Padova, Italy
| | - Luca Iaccarino
- 1 Department of Medicine-DIMED, Division of Rheumatology, University of Padova, 35128 Padova, Italy
| | - Luis Inês
- 2 Rheumatology Department, Centro Hospitalar e Universitário de Coimbra, 3000-075 Coimbra, Portugal.,3 Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal.,4 Faculty of Health Sciences, University of Beira Interior, 6201-001 Covilhã, Portugal
| | - Andrea Doria
- 1 Department of Medicine-DIMED, Division of Rheumatology, University of Padova, 35128 Padova, Italy
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Lehman JS, Dasari S, Damodaran SS, El-Azhary RA, Gibson LE, Hashmi SK, Hogan WJ, Kenderian SJ, Patnaik MS, Litzow MR, Lazarus HM, Meves A. Differential expression of interferon-induced genes and other tissue-based biomarkers in acute graft-versus-host disease vs. lupus erythematosus in skin. Clin Exp Dermatol 2018; 44:e81-e88. [PMID: 30280423 DOI: 10.1111/ced.13759] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/21/2018] [Indexed: 01/26/2023]
Abstract
BACKGROUND In both acute graft-versus-host disease (GVHD) and lupus erythematosus (LE), the patient's own tissues are subjected to immunological assault via complex mechanisms influenced by interferon (IFN) and other cytokines. Although not typically confused clinically, these entities have overlapping histopathological findings in the skin. AIM To assess whether GVHD can be differentiated from LE using molecular methods on skin specimens. METHODS We developed a quantitative reverse transcription PCR assay based on previously identified tissue-based biomarkers of cutaneous GVHD, and compared gene expression in GVHD with that in LE. RESULTS Both entities showed robust expression of IFN-induced genes and of genes encoding proteins involved in antigen presentation, cell signalling and tissue repair. Levels of gene expression differed significantly in GVHD compared with LE, particularly those of IFN-induced genes such as MX1, OAS3, TAP1 and STAT3 (P < 0.01). Three logistic regression models could differentiate the two entities with a high degree of certainty (receiver operating characteristic area under the curve of 1.0). CONCLUSION The study demonstrates the feasibility of distinguishing between microscopically similar inflammatory dermatoses using tissue-based molecular techniques.
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Affiliation(s)
- J S Lehman
- Department of Dermatology, Mayo Clinic, Rochester, MN, USA.,Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - S Dasari
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - S S Damodaran
- Department of Dermatology, Mayo Clinic, Rochester, MN, USA
| | - R A El-Azhary
- Department of Dermatology, Mayo Clinic, Rochester, MN, USA
| | - L E Gibson
- Department of Dermatology, Mayo Clinic, Rochester, MN, USA.,Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - S K Hashmi
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | - W J Hogan
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | - S J Kenderian
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | - M S Patnaik
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | - M R Litzow
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | - H M Lazarus
- Adult Hematologic Malignancies and Stem Cell Transplant Section, Seidman Cancer Center, University Hospitals Case Medical Center, Cleveland, OH, USA
| | - A Meves
- Department of Dermatology, Mayo Clinic, Rochester, MN, USA
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Nalakonda G, Islam M, Chukwu VE, Soliman A, Munim R, Abukraa I. Psycho-rheumatic Integration in Systemic Lupus Erythematosus: An Insight into Antibodies Causing Neuropsychiatric Changes. Cureus 2018; 10:e3091. [PMID: 30324045 PMCID: PMC6171782 DOI: 10.7759/cureus.3091] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The main purpose of this paper is to bring together all the antibodies and markers related to neurological and psychiatric manifestations in systemic lupus erythematosus and also the pharmacology that could help treat these symptoms. Existing research data regarding specific antibodies involved in the disease process and drugs that were being studied was collected and analyzed. After reviewing the studies published by various authors, symptoms were shown to be mainly caused by antibodies against N-methyl-D-aspartate receptor (NMDAR) antibodies, anti-endothelial, anti-ribosomal P, antiphospholipid antibodies, cytokines like interferons and chemokines. The monoclonal antibody rituximab has shown to be beneficial in some of the cases. Based on all the articles reviewed, the antibodies and cytokines showed the most effective evidence in causing the different manifestations of neuropsychiatric systemic lupus erythematosus (NPSLE), but studies regarding the drugs being effective against all the symptoms are inconclusive as there are very few studies. Further research to support the drug’s effectiveness in managing the symptoms is needed. More studies are needed regarding early diagnosis of NPSLE using the antibodies as biomarkers as it could help in preventing these manifestations.
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Affiliation(s)
- Gouthami Nalakonda
- Medical Student, Chalmeda Anandrao Institute of Medical Sciences, Karimnagar, IND
| | - Mimsa Islam
- Internal Medicine, Sir Salimullah Medical College, Dhaka, USA
| | | | | | - Rujina Munim
- Miscellaneous, Sylhet Mag Osmani Medical College and Hospital, Sylhet, BGD
| | - Inas Abukraa
- Faculty of Medicine, Tripoli University, Tripoli, LBY
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Idborg H, Eketjäll S, Pettersson S, Gustafsson JT, Zickert A, Kvarnström M, Oke V, Jakobsson PJ, Gunnarsson I, Svenungsson E. TNF-α and plasma albumin as biomarkers of disease activity in systemic lupus erythematosus. Lupus Sci Med 2018; 5:e000260. [PMID: 29955370 PMCID: PMC6018889 DOI: 10.1136/lupus-2018-000260] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2018] [Revised: 04/20/2018] [Accepted: 05/04/2018] [Indexed: 12/22/2022]
Abstract
OBJECTIVES Composite criteria/indices are presently used to diagnose and monitor patients with systemic lupus erythematosus (SLE). Biomarkers for these purposes would be helpful in clinical practice. We therefore evaluated a large panel of cytokines and basic laboratory tests and investigated their performance as discriminators versus controls and as biomarkers of disease activity (DA). METHODS We examined 437 patients with SLE, fulfilling American College of Rheumatology-82 criteria, and 322 matched controls. DA was assessed according to both SLE DA Index 2000 (SLEDAI-2K) and SLE Activity Measure (SLAM). British Isles Lupus Activity Group (BILAG) was used to assess renal DA. Additionally, 132 patients self-assessed their Global Disease Activity (PtGDA). Mesoscale Discovery 30-plex cytokine assay and routine blood chemistry was performed on fasting EDTA-plasma. RESULTS Of 26 tested biomarkers, we identified TNF-α as the superior discriminator between patients with SLE and controls (median=4.5 pg/mL, IQR=3.1-6.2 vs median=2.3 pg/mL, IQR=2.0-2.8). The strongest correlations to SLEDAI-2K and SLAM were obtained with TNF-α (Spearman rho (ρ)=0.32 and ρ=0.34, respectively), partly driven by the nephritis subgroup, and with p-albumin (ρ=-0.33 and ρ=-0.31, respectively). P-albumin was decreased and TNF-α was increased in patients with kidney involvement (renal BILAG A/B vs C/D/E, p=4×10-16 and p=6×10-9 respectively). IP-10 was increased in patients with joint involvement (SLAM item 24≥2 vs ≤1, p=0.0005) but did not differ when comparing patients with active/inactive kidney involvement. The most powerful correlations to PtGDA was observed with p-albumin (ρ=-0.42), IL-6 (ρ=0.30) and TNF-α (ρ=0.29). CONCLUSION TNF-α and p-albumin both performed well as discriminators between patients with SLE and controls and as proxies for DA according to both rheumatologists' and patients' assessments. In particular, renal DA was well reflected by TNF-α. We propose that the TNF-α and p-albumin merit further investigations as clinically useful biomarkers in SLE. We also observed that the pattern of activated cytokines varies with organ involvement.
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Affiliation(s)
- Helena Idborg
- Rheumatology Unit, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Susanna Eketjäll
- Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Integrated Cardio Metabolic Centre (ICMC), Karolinska Institutet, Huddinge, Sweden
- Science for Life Laboratory, Department of Clinical Neuroscience, Karolinska Institutet, Solna, Sweden
| | - Susanne Pettersson
- Theme Inflammation and Infection, Karolinska University Hospital, Stockholm, Sweden
- Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
| | - Johanna T Gustafsson
- Rheumatology Unit, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Agneta Zickert
- Rheumatology Unit, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Marika Kvarnström
- Rheumatology Unit, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Vilija Oke
- Rheumatology Unit, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Per-Johan Jakobsson
- Rheumatology Unit, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Iva Gunnarsson
- Rheumatology Unit, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Elisabet Svenungsson
- Rheumatology Unit, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
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Ciechomska M, Skalska U. Targeting interferons as a strategy for systemic sclerosis treatment. Immunol Lett 2017; 195:45-54. [PMID: 29106987 DOI: 10.1016/j.imlet.2017.10.011] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Revised: 10/24/2017] [Accepted: 10/24/2017] [Indexed: 12/13/2022]
Abstract
Systemic Sclerosis (SSc) is an autoimmune disease characterised by vasculopathy, uncontrolled inflammation and enhanced fibrosis which can subsequently lead to the loss of organ function or even premature death. Interferons (IFNs) are pleiotropic cytokines that are critical not only in mounting an effective immune response against viral and bacterial infections but also strongly contribute to the pathogenesis of SSc. Furthermore, elevated levels of IFNs are found in SSc patients and correlate with skin thickness and disease activity suggesting potential role of IFNs as biomarkers. In this review, we summarise existing knowledge regarding all types of IFNs and IFN-inducible genes in the pathogenesis of SSc. We then argue why IFN-blocking strategies are promising therapeutic targets in SSc and other autoimmune diseases.
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Affiliation(s)
- Marzena Ciechomska
- National Institute of Geriatrics Rheumatology and Rehabilitation, Warsaw, Poland
| | - Urszula Skalska
- National Institute of Geriatrics Rheumatology and Rehabilitation, Warsaw, Poland
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