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Kharouf F, Gladman DD. Treatment controversies in spondyloarthritis and psoriatic arthritis: focus on biologics and targeted therapies. Expert Rev Clin Immunol 2024; 20:1381-1400. [PMID: 39072530 DOI: 10.1080/1744666x.2024.2384705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Accepted: 07/22/2024] [Indexed: 07/30/2024]
Abstract
INTRODUCTION There are several treatment controversies that have emerged in spondyloarthritis and psoriatic arthritis. These are related to the nature of the conditions as well as to the use of medications. AREAS COVERED This review, which included a search of PubMed database as well as the references within the articles provides an overview of the nature of spondyloarthritis, controversy over the inclusion of psoriatic arthritis (PsA) as a peripheral spondyloarthritis, and a summary of current treatments for both PsA and axial spondyloarthritis (axSpA), with special emphasis on targeted therapy. The review highlights the differences in response to certain medications, particularly biologic therapy and summarizes the randomized controlled trials in psoriatic arthritis and axial spondyloarthritis providing data about the responses in table format. EXPERT OPINION There is a need for better outcome measures in axSpA. Currently, the measures are subjective. Imaging may be more appropriate but there is a need for research into the reliability and responsiveness of imaging techniques. In PsA, there may also be better response measures and research into the reliability and responsiveness of available measures is underway. There is also a need for novel therapies as well as biomarkers for response in both diseases.
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Affiliation(s)
- Fadi Kharouf
- Division of Rheumatology, University Health Network, University of Toronto, Toronto, Ontario, Canada
- Gladman-Krembil Psoriatic Disease Program, Schroeder Arthritis Institute, Krembil Research Institute, Toronto Western Hospital, Toronto, Ontario, Canada
| | - Dafna D Gladman
- Division of Rheumatology, University Health Network, University of Toronto, Toronto, Ontario, Canada
- Gladman-Krembil Psoriatic Disease Program, Schroeder Arthritis Institute, Krembil Research Institute, Toronto Western Hospital, Toronto, Ontario, Canada
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2
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Nagit RE, Rezus E, Cianga P. Exploring the Pathogenesis of Spondylarthritis beyond HLA-B27: A Descriptive Review. Int J Mol Sci 2024; 25:6081. [PMID: 38892265 PMCID: PMC11172491 DOI: 10.3390/ijms25116081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 05/15/2024] [Accepted: 05/29/2024] [Indexed: 06/21/2024] Open
Abstract
Spondylarthritis (SpA) is a chronic inflammatory condition that encompasses damage to the axial or peripheral skeleton, accompanied by specific extra-articular symptoms. Within this group, Ankylosing Spondylitis stands out as the hallmark member. Although the heritability of Ankylosing Spondylitis is estimated to be over 95%, only a portion of the heritability has been explained, with HLA-B27 accounting for 20.1% of it; therefore, ongoing research endeavors are currently concentrated on investigating the potential participation of different entities in the development of the disease. Genome-wide association studies have led to significant advances in our understanding of the genetics of SpA. In this descriptive review, we delve into the pathogenesis of Spondylarthritis beyond HLA-B27. We summarize the latest research on the potential participation of various entities in the development of the disease, including other genetic loci, immune dysregulation, microbiota, and environmental factors. The multifactorial nature of SpA and the complex interplay of genetic, immunological, and environmental factors are being increasingly recognized; therefore, it is of paramount importance to consider a holistic approach to comprehend the pathogenesis of SpA in order to identify novel therapeutic targets.
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Affiliation(s)
- Ruxandra-Elena Nagit
- Immunology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania;
| | - Elena Rezus
- Rheumatology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania;
- Clinical Rehabilitation Hospital, 700661 Iași, Romania
| | - Petru Cianga
- Immunology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania;
- Immunology Laboratory, “St. Spiridon” Clinical Hospital, 700111 Iași, Romania
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3
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Gonzalez Diaz I, Gutierrez Riart M, Martin-Arranz MD, Plasencia Rodriguez C, Suarez Ferrer C. Incidence and Course of Joint Inflammation Associated with Inflammatory Bowel Disease in Patients Undergoing Treatment with Vedolizumab/Ustekinumab: The VEDUSTAR Study. J Clin Med 2024; 13:1076. [PMID: 38398390 PMCID: PMC10889195 DOI: 10.3390/jcm13041076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 02/10/2024] [Accepted: 02/11/2024] [Indexed: 02/25/2024] Open
Abstract
BACKGROUND The role of ustekinumab (UST) and vedolizumab (VDZ) in the extraintestinal joint manifestations of inflammatory bowel disease (IBD) remain unclear, and most existing studies are retrospective. The aim of this prospective study was to analyze the incidence of new-onset joint disease or the worsening of pre-existing IBD-associated joint disease in patients treated with UST and VDZ. METHODS The study population comprised IBD patients with previous spondyloarthritis (SpA) or new-onset arthropathy undergoing treatment with VDZ or UST. RESULTS Eighty patients were referred to rheumatology because of previous SpA or onset of symptoms. Most patients (90%) were anti-TNF experienced. Two patients with previous SpA (2/22; 9%) experienced a flare-up (one with UST and one with VDZ), and two patients with VDZ developed SpA during follow-up (2/58; 3%). Only one of these four patients did not have gastrointestinal symptoms, and VDZ was discontinued because of joint symptoms. The other three patients had concomitant intestinal activity, and treatment was not discontinued. CONCLUSION Our experience shows that treatment with UST and VDZ did not worsen joint disease in patients with SpA. Most remained stable or improved. In addition, poor control of IBD in patients with joint flare-ups could be the main cause of worsening SpA.
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Affiliation(s)
- Irene Gonzalez Diaz
- Gastroenterology Department, La Paz University Hospital, 28046 Madrid, Spain;
| | - Mariana Gutierrez Riart
- Rheumatology Department, La Paz University Hospital, 28046 Madrid, Spain; (M.G.R.); (C.P.R.)
| | - Maria Dolores Martin-Arranz
- Gastroenterology Department, La Paz University Hospital, 28046 Madrid, Spain;
- Hospital La Paz Institute for Health Research, La Paz University Hospital, 28046 Madrid, Spain
- Faculty of Medicine, Universidad Autónoma, 28046 Madrid, Spain
| | | | - Cristina Suarez Ferrer
- Gastroenterology Department, La Paz University Hospital, 28046 Madrid, Spain;
- Hospital La Paz Institute for Health Research, La Paz University Hospital, 28046 Madrid, Spain
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Mezghiche I, Yahia-Cherbal H, Rogge L, Bianchi E. Interleukin 23 receptor: Expression and regulation in immune cells. Eur J Immunol 2024; 54:e2250348. [PMID: 37837262 DOI: 10.1002/eji.202250348] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 10/11/2023] [Accepted: 10/12/2023] [Indexed: 10/15/2023]
Abstract
The importance of IL-23 and its specific receptor, IL-23R, in the pathogenesis of several chronic inflammatory diseases has been established, but the underlying pathological mechanisms are not fully understood. This review focuses on IL-23R expression and regulation in immune cells.
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Affiliation(s)
| | | | - Lars Rogge
- Institut Pasteur, Université Paris Cité, Paris, France
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Mease PJ, Gladman DD, Poddubnyy D, Chakravarty SD, Shawi M, Kollmeier AP, Xu XL, Xu S, Deodhar A, Baraliakos X. Efficacy of Guselkumab on Axial-Related Symptoms Through up to 2 Years in Adults with Active Psoriatic Arthritis in the Phase 3, Randomized, Placebo-Controlled DISCOVER-2 Study. Rheumatol Ther 2023; 10:1637-1653. [PMID: 37819505 PMCID: PMC10654317 DOI: 10.1007/s40744-023-00592-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Accepted: 08/03/2023] [Indexed: 10/13/2023] Open
Abstract
INTRODUCTION Guselkumab previously showed greater improvements versus placebo in axial symptoms in patients with psoriatic arthritis (PsA) (assessed by Bath Ankylosing Spondylitis Disease Activity Index [BASDAI] and Ankylosing Spondylitis Disease Activity Score [ASDAS]), in post hoc analyses of the phase 3, placebo-controlled, randomized DISCOVER-1 and DISCOVER-2 studies. We now evaluate durability of response in axial-related outcomes through 2 years of DISCOVER-2. METHODS DISCOVER-2 biologic-naive adults with active PsA (≥ 5 tender/ ≥ 5 swollen joints, C-reactive protein ≥ 0.6 mg/dl) were randomized to guselkumab 100 mg every 4 weeks (Q4W) or at week 0, week 4, then Q8W, or placebo → guselkumab Q4W at week 24. Among patients with imaging-confirmed sacroiliitis (investigator-identified), axial symptoms were assessed through 2 years utilizing BASDAI, BASDAI Question #2 (spinal pain), modified BASDAI (mBASDAI; excludes Question #3 [peripheral joint pain]), and ASDAS. Mean changes in scores and proportions of patients achieving ≥ 50% improvement in BASDAI (BASDAI 50) and ASDAS responses, including major improvement (decrease ≥ 2.0), were determined through week 100. Treatment failure rules (through week 24) and nonresponder imputation of missing data (post-week 24) were utilized. Mean BASDAI component scores were assessed through week 100 (observed data). Exploratory analyses evaluated efficacy by sex and HLA-B*27 status. RESULTS Among 246 patients with PsA and imaging-confirmed sacroiliitis, guselkumab-treated patients had greater mean improvements in BASDAI, mBASDAI, spinal pain, and ASDAS scores, lower mean BASDAI component scores, and greater response rates in achieving BASDAI 50 and ASDAS major improvement vs. placebo at week 24. Differences from placebo were observed for guselkumab-treated patients in selected endpoints regardless of sex or HLA-B*27 status. At week 100, mean improvements were ~ 3 points for all BASDAI scores and 1.6-1.7 for ASDAS; 49-54% achieved BASDAI 50 and 39% achieved ASDAS major improvement at week 100. CONCLUSIONS Guselkumab treatment provided durable and meaningful improvements in axial symptoms and disease activity in substantial proportions of patients with active PsA and imaging-confirmed sacroiliitis. TRIAL REGISTRATION Clinicaltrials.gov NCT03158285.
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Affiliation(s)
- Philip J Mease
- Department of Rheumatology, Swedish Medical Center/Providence St. Joseph Health and University of Washington, Rheumatology Research, 601 Broadway, Ste 600, Seattle, WA, 98122, USA.
| | - Dafna D Gladman
- Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Hospital, Toronto, ON, Canada
| | | | - Soumya D Chakravarty
- Janssen Scientific Affairs, LLC, Horsham, PA, USA
- Drexel University College of Medicine, Philadelphia, PA, USA
| | - May Shawi
- Janssen Research & Development, LLC, Titusville, NJ, USA
| | | | - Xie L Xu
- Janssen Research & Development, LLC, San Diego, CA, USA
| | - Stephen Xu
- Janssen Research & Development, LLC, Spring House, PA, USA
| | - Atul Deodhar
- Oregon Health & Science University, Portland, OR, USA
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Kim SH, Lee SH. Updates on ankylosing spondylitis: pathogenesis and therapeutic agents. JOURNAL OF RHEUMATIC DISEASES 2023; 30:220-233. [PMID: 37736590 PMCID: PMC10509639 DOI: 10.4078/jrd.2023.0041] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 08/07/2023] [Accepted: 08/08/2023] [Indexed: 09/23/2023]
Abstract
Ankylosing spondylitis (AS) is an autoinflammatory disease that manifests with the unique feature of enthesitis. Gut microbiota, HLA-B*27, and biomechanical stress mutually influence and interact resulting in setting off a flame of inflammation. In the HLA-B*27 positive group, dysbiosis in the gut environment disrupts the barrier to exogenous bacteria or viruses. Additionally, biomechanical stress induces inflammation through enthesial resident or gut-origin immune cells. On this basis, innate and adaptive immunity can propagate inflammation and lead to chronic disease. Finally, bone homeostasis is regulated by cytokines, by which the inflamed region is substituted into new bone. Agents that block cytokines are constantly being developed to provide diverse therapeutic options for preventing the progression of inflammation. In addition, some antibodies have been shown to distinguish disease selectively, which support the involvement of autoimmune immunity in AS. In this review, we critically analyze the complexity and uniqueness of the pathogenesis with updates on the findings of immunity and provide new information about biologics and biomarkers.
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Affiliation(s)
- Se Hee Kim
- Division of Rheumatology, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, College of Medicine, Kyung Hee University, Seoul, Korea
| | - Sang-Hoon Lee
- Division of Rheumatology, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, College of Medicine, Kyung Hee University, Seoul, Korea
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Ding Y, Yang Y, Xue L. Immune cells and their related genes provide a new perspective on the common pathogenesis of ankylosing spondylitis and inflammatory bowel diseases. Front Immunol 2023; 14:1137523. [PMID: 37063924 PMCID: PMC10101339 DOI: 10.3389/fimmu.2023.1137523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Accepted: 03/21/2023] [Indexed: 04/03/2023] Open
Abstract
BackgroundThe close relationship between ankylosing spondylitis (AS) and inflammatory bowel diseases (IBD) has been supported by many aspects, including but not limited to clinical manifestations, epidemiology and pathogenesis. Some evidence suggests that immune cells actively participated in the pathogenesis of both diseases. However, information on which cells are primarily involved in this process and how these cells mobilize, migrate and interact is still limited.MethodsDatasets were downloaded from Gene Expression Omnibus (GEO) database. Common differentially expressed genes (coDEGs) were identified by package “limma”. The protein-protein interaction (PPI) network and Weighted Gene Co-Expression Network Analysis (WGCNA) were used to analyze the interactions between coDEGs. KEGG pathway enrichment analysis and inverse cumulative distribution function were applied to identify common differential pathways, while Gene Set Enrichment Analysis (GSEA) was used to confirm the significance. Correlation analysis between coDEGs and immune cells led to the identification of critical immune-cell-related coDEGs. The diagnostic models were established based on least absolute shrinkage and selection operator (LASSO) regression, while receiver operating characteristic (ROC) analysis was used to identify the ability of the model. Validation datasets were imported to demonstrate the significant association of coDEGs with specific immune cells and the capabilities of the diagnostic model.ResultsIn total, 67 genes were up-regulated and 185 genes were down-regulated in both diseases. Four down-regulated pathways and four up-regulated pathways were considered important. Up-regulated coDEGs were firmly associated with neutrophils, while down-regulated genes were significantly associated with CD8+ T−cells and CD4+ T−cells in both AS and IBD datasets. Five up-regulated and six down-regulated key immue-cell-related coDEGs were identified. Diagnostic models based on key immue-cell-related coDEGs were established and tested. Validation datasets confirmed the significance of the correlation between coDEGs and specific immune cells.ConclusionThis study provides fresh insights into the co-pathogenesis of AS and IBD. It is proposed that neutrophils and T cells may be actively involved in this process, however, in opposite ways. The immue-cell-related coDEGs, revealed in this study, may be relevant to their regulation, although relevant research is still lacking.
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Tam HKJ, Robinson PC, Nash P. Inhibiting IL-17A and IL-17F in Rheumatic Disease: Therapeutics Help to Elucidate Disease Mechanisms. Curr Rheumatol Rep 2022; 24:310-320. [PMID: 35861937 PMCID: PMC9470681 DOI: 10.1007/s11926-022-01084-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/29/2022] [Indexed: 11/20/2022]
Abstract
PURPOSE OF REVIEW Psoriatic arthritis and ankylosing spondylitis belong to a family of rheumatological diseases that lead to painful joint inflammation that impacts on patient function and quality of life. Recent studies have shown that the pro-inflammatory cytokine IL-17 is involved in the inflammatory joint changes in spondyloarthritides. We will review the pathophysiology of IL-17 and review the biological therapies targeting IL-17. RECENT FINDINGS IL-17 is produced and released from T cells and is dependent on multiple upstream cytokines, which include IL-23. There are six members of the IL-17 family that are secreted from multiple populations of T cells. The initial biologic medications have been developed against IL-17A, which is the best-studied member of this family. These medications appear to be effective in controlling joint inflammation, improving patient quality of life, and are generally well tolerated. More recently, medications have been developed that target both IL-17A and IL-17F. In addition, brodalumab, an antibody targeting the IL-17 receptor, has had a resurgence after initial concerns for an increased risk of suicide. IL-17 is an inflammatory cytokine that is critical in the pathobiology of axial spondyloarthritides. Recent biological therapies targeting IL-17A are effective and well tolerated in patients with axial spondyloarthritis. Specific targeting of the Il-17A/F heterodimer is also effective and provides another viable option in the clinician's armamentarium.
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Affiliation(s)
| | - Philip C. Robinson
- The University of Queensland, Herston, QLD 4006 Australia
- Department of Rheumatology, Royal Brisbane & Women’s Hospital, Herston, QLD Australia
| | - Peter Nash
- School of Medicine and Dentistry, Griffith University, Gold Coast, QLD Australia
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Zhang T, Yu L, Shao M, Wu Y, Wang J, Deng Y, Ni M, Sun X, Chen Y, Xu S, Ma Y, Shuai Z, Pan F. Associations between IL-23R gene polymorphism (rs10889677 A/C) and ankylosing spondylitis and rheumatoid arthritis susceptibility: A meta-analysis with trial sequential analysis. Autoimmunity 2022; 55:388-397. [PMID: 35583389 DOI: 10.1080/08916934.2022.2076837] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Autoimmune diseases are a kind of chronic diseases for which the immune system loses tolerance to autoantigens. This meta-analysis' purpose is to determine whether there exists a correlation between IL-23R polymorphism and common autoimmune diseases like ankylosing spondylitis (AS) and rheumatoid arthritis (RA). METHODS We searched the relevant literatures up to September 2021 and used different effect models for meta-analysis. 95% confidence interval (95% CI) and odds ratio (OR) were used to determine the relationship between rs10889677 (A/C) polymorphism and AS as well as RA. Finally, to promote the reliability of results, the trial sequential analysis (TSA) has also been applied and we searched the data related to autoimmune diseases (AS, RA) on genome-wide association studies (GWAS). RESULTS Generally, 31 studies were included. Rs10889677 (A/C) was significantly correlated with the susceptibility to AS and RA among the general individuals (p < .05). Moreover, there existed a relevance between allele A and AS as well as RA in Caucasians (p < .05). AA genotype increased the risk of autoimmune diseases in Mongolians. As a result, the robustness of meta-analysis has further been proved by TSA. CONCLUSION IL-23R (rs10889677 A/C) A allele was a risk gene for AS and RA in the general population, especially in Caucasians. AA genotype increased the risk of AS and RA in Mongolians.
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Affiliation(s)
- Tao Zhang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China.,The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, China
| | - Lingxiang Yu
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China.,The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, China
| | - Ming Shao
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China.,The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, China
| | - Ye Wu
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China.,Department of Hospital Management Research, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Jinian Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China.,Department of Hospital Management Research, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yujie Deng
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China.,Department of Hospital Management Research, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Man Ni
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China.,Department of Hospital Management Research, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Xiaoya Sun
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China.,Department of Hospital Management Research, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yuting Chen
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China.,The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, China
| | - Shanshan Xu
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China.,The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, China
| | - Yubo Ma
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China.,The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, China
| | - Zongwen Shuai
- Department of Hospital Management Research, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Faming Pan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China.,The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, China
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Shetty A, Tripathi SK, Junttila S, Buchacher T, Biradar R, Bhosale S, Envall T, Laiho A, Moulder R, Rasool O, Galande S, Elo L, Lahesmaa R. A systematic comparison of FOSL1, FOSL2 and BATF-mediated transcriptional regulation during early human Th17 differentiation. Nucleic Acids Res 2022; 50:4938-4958. [PMID: 35511484 PMCID: PMC9122603 DOI: 10.1093/nar/gkac256] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 03/30/2022] [Accepted: 04/19/2022] [Indexed: 12/21/2022] Open
Abstract
Th17 cells are essential for protection against extracellular pathogens, but their aberrant activity can cause autoimmunity. Molecular mechanisms that dictate Th17 cell-differentiation have been extensively studied using mouse models. However, species-specific differences underscore the need to validate these findings in human. Here, we characterized the human-specific roles of three AP-1 transcription factors, FOSL1, FOSL2 and BATF, during early stages of Th17 differentiation. Our results demonstrate that FOSL1 and FOSL2 co-repress Th17 fate-specification, whereas BATF promotes the Th17 lineage. Strikingly, FOSL1 was found to play different roles in human and mouse. Genome-wide binding analysis indicated that FOSL1, FOSL2 and BATF share occupancy over regulatory regions of genes involved in Th17 lineage commitment. These AP-1 factors also share their protein interacting partners, which suggests mechanisms for their functional interplay. Our study further reveals that the genomic binding sites of FOSL1, FOSL2 and BATF harbour hundreds of autoimmune disease-linked SNPs. We show that many of these SNPs alter the ability of these transcription factors to bind DNA. Our findings thus provide critical insights into AP-1-mediated regulation of human Th17-fate and associated pathologies.
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Affiliation(s)
| | | | | | | | - Rahul Biradar
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku 20520, Finland
- InFLAMES Research Flagship Center, University of Turku, Turku 20520, Finland
| | - Santosh D Bhosale
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku 20520, Finland
- Department of Biochemistry and Molecular Biology, Protein Research Group, University of Southern Denmark, Campusvej 55, Odense M, DK 5230, Denmark
| | - Tapio Envall
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku 20520, Finland
| | - Asta Laiho
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku 20520, Finland
- InFLAMES Research Flagship Center, University of Turku, Turku 20520, Finland
| | - Robert Moulder
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku 20520, Finland
- InFLAMES Research Flagship Center, University of Turku, Turku 20520, Finland
| | - Omid Rasool
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku 20520, Finland
- InFLAMES Research Flagship Center, University of Turku, Turku 20520, Finland
| | - Sanjeev Galande
- Centre of Excellence in Epigenetics, Department of Biology, Indian Institute of Science Education and Research (IISER), Pune 411008, India
- Department of Life Sciences, Shiv Nadar University, Delhi-NCR
| | - Laura L Elo
- Correspondence may also be addressed to Laura Elo. Tel: +358 29 450 2090;
| | - Riitta Lahesmaa
- To whom correspondence should be addressed. Tel: +358 29 450 2415;
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Rezaiemanesh A, Mahmoudi M, Amirzargar AA, Vojdanian M, Babaie F, Mahdavi J, Rajabinejad M, Jamshidi AR, Nicknam MH. Upregulation of Unfolded Protein Response and ER Stress-Related IL-23 Production in M1 Macrophages from Ankylosing Spondylitis Patients. Inflammation 2022; 45:665-676. [PMID: 35112266 DOI: 10.1007/s10753-021-01575-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Revised: 09/19/2021] [Accepted: 09/29/2021] [Indexed: 12/20/2022]
Abstract
The inflammatory interleukin (IL)-23/IL-17 axis plays an important role in the pathogenesis of ankylosing spondylitis (AS), but with an unknown regulatory mechanism. This study aimed to investigate the role of endoplasmic reticulum (ER) stress and autophagy pathway in the expression of IL-23 in peripheral blood-derived macrophages in AS patients. Peripheral blood samples were obtained from 15 AS and 15 healthy control subjects. MACS was used to isolate monocytes from PBMCs. Then, M-CSF was used to differentiate monocytes to M2 macrophages. IFN-γ and/or LPS were used to activate macrophages and M2 polarization towards M1 macrophages. Thapsigargin was used to induce ER stress and 3-MA to inhibit autophagy. The purity of extracted monocytes and macrophage markers was evaluated by flow cytometry. mRNA expression of HLA-B and-B27, ER stress-related genes, autophagy-related genes, and IL-23p19 was performed using RT-qPCR. Soluble levels of IL-23p19 were measured using ELISA. Significant increase in mRNA expression of HLA-B, HLA-B27, BiP, XBP1, CHOP, and PERK mRNAs was observed in macrophages of AS patients before and after stimulation with IFN-γ and LPS. No significant change in autophagy gene expression was detected. mRNA and soluble levels of IL-23p19 demonstrated a significant increase in macrophages of AS patients compared to healthy subjects. ER stress induction led to a significant increase in IL-23p19 in macrophages. Inhibition of autophagy did not affect IL-23 expression. ER stress, unlike autophagy, is associated with increased IL-23 levels in macrophages of AS patients.Key Messages ER stress in macrophages from AS patients plays a role in the increased production of IL-23. The autophagy pathway is not involved in the modulation of IL-23 production by AS macrophages.
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Affiliation(s)
- Alireza Rezaiemanesh
- Department of Immunology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mahdi Mahmoudi
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Akbar Amirzargar
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Molecular Immunology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahdi Vojdanian
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Farhad Babaie
- Department of Immunology and Genetic, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Jila Mahdavi
- Department of Biology, Payame Noor University, Tehran, Iran
| | - Misagh Rajabinejad
- Student Research Committee, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.,Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Ahmad Reza Jamshidi
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Hossein Nicknam
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. .,Molecular Immunology Research Center, Tehran University of Medical Sciences, Tehran, Iran.
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12
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Ankylosing spondylitis: an autoimmune or autoinflammatory disease? Nat Rev Rheumatol 2021; 17:387-404. [PMID: 34113018 DOI: 10.1038/s41584-021-00625-y] [Citation(s) in RCA: 173] [Impact Index Per Article: 43.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/23/2021] [Indexed: 12/20/2022]
Abstract
Ankylosing spondylitis (AS) is a chronic inflammatory disorder of unknown aetiology. Unlike other systemic autoimmune diseases, in AS, the innate immune system has a dominant role characterized by aberrant activity of innate and innate-like immune cells, including γδ T cells, group 3 innate lymphoid cells, neutrophils, mucosal-associated invariant T cells and mast cells, at sites predisposed to the disease. The intestine is involved in disease manifestations, as it is at the forefront of the interaction between the mucosal-associated immune cells and the intestinal microbiota. Similarly, biomechanical factors, such as entheseal micro-trauma, might also be involved in the pathogenesis of the articular manifestation of AS, and sentinel immune cells located in the entheses could provide links between local damage, genetic predisposition and the development of chronic inflammation. Although these elements might support the autoinflammatory nature of AS, studies demonstrating the presence of autoantibodies (such as anti-CD74, anti-sclerostin and anti-noggin antibodies) and evidence of activation and clonal expansion of T cell populations support an autoimmune component to the disease. This Review presents the evidence for autoinflammation and the evidence for autoimmunity in AS and, by discussing the pathophysiological factors associated with each, aims to reconcile the two hypotheses.
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Xue X, De Leon-Tabaldo A, Luna-Roman R, Castro G, Albers M, Schoetens F, DePrimo S, Devineni D, Wilde T, Goldberg S, Hoffmann T, Fourie AM, Thurmond RL. Preclinical and clinical characterization of the RORγt inhibitor JNJ-61803534. Sci Rep 2021; 11:11066. [PMID: 34040108 PMCID: PMC8155022 DOI: 10.1038/s41598-021-90497-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Accepted: 05/11/2021] [Indexed: 12/14/2022] Open
Abstract
The nuclear receptor retinoid-related orphan receptor gamma t (RORγt) plays a critical role in driving Th17 cell differentiation and expansion, as well as IL-17 production in innate and adaptive immune cells. The IL-23/IL-17 axis is implicated in several autoimmune and inflammatory diseases, and biologics targeting IL-23 and IL-17 have shown significant clinical efficacy in treating psoriasis and psoriatic arthritis. JNJ-61803534 is a potent RORγt inverse agonist, selectively inhibiting RORγt-driven transcription versus closely-related family members, RORα and RORβ. JNJ-61803534 inhibited IL-17A production in human CD4+ T cells under Th17 differentiation conditions, but did not inhibit IFNγ production under Th1 differentiation conditions, and had no impact on in vitro differentiation of regulatory T cells (Treg), nor on the suppressive activity of natural Tregs. In the mouse collagen-induced arthritis model, JNJ-61803534 dose-dependently attenuated inflammation, achieving ~ 90% maximum inhibition of clinical score. JNJ-61803534 significantly inhibited disease score in the imiquimod-induced mouse skin inflammation model, and dose-dependently inhibited the expression of RORγt-regulated genes, including IL-17A, IL-17F, IL-22 and IL-23R. Preclinical 1-month toxicity studies in rats and dogs identified doses that were well tolerated supporting progression into first-in-human studies. An oral formulation of JNJ-61803534 was studied in a phase 1 randomized double-blind study in healthy human volunteers to assess safety, pharmacokinetics, and pharmacodynamics. The compound was well tolerated in single ascending doses (SAD) up to 200 mg, and exhibited dose-dependent increases in exposure upon oral dosing, with a plasma half-life of 164 to 170 h. In addition, dose-dependent inhibition of ex vivo stimulated IL-17A production in whole blood was observed, demonstrating in vivo target engagement. In conclusion, JNJ-61803534 is a potent and selective RORγt inhibitor that exhibited acceptable preclinical safety and efficacy, as well as an acceptable safety profile in a healthy volunteer SAD study, with clear evidence of a pharmacodynamic effect in humans.
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Affiliation(s)
- Xiaohua Xue
- Janssen Research & Development, LLC, La Jolla, CA, USA.
| | | | | | - Glenda Castro
- Janssen Research & Development, LLC, Spring House, PA, USA
| | - Michael Albers
- Department of Research, Phenex Pharmaceuticals AG, Heidelberg, Germany
| | | | | | | | - Thomas Wilde
- Janssen Research & Development, LLC, Spring House, PA, USA
| | | | - Thomas Hoffmann
- Department of Research, Phenex Pharmaceuticals AG, Heidelberg, Germany
| | - Anne M Fourie
- Janssen Research & Development, LLC, La Jolla, CA, USA
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14
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Ashrafi M, Kuhn KA, Weisman MH. The arthritis connection to inflammatory bowel disease (IBD): why has it taken so long to understand it? RMD Open 2021; 7:e001558. [PMID: 33863841 PMCID: PMC8055104 DOI: 10.1136/rmdopen-2020-001558] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 03/16/2021] [Accepted: 03/18/2021] [Indexed: 12/14/2022] Open
Abstract
Inflammatory bowel disease (IBD) associated arthritis is a subgroup of spondyloarthritis (SpA) that has suffered from lack of recognition in rheumatology clinical and research circles for over 100 years. Although clinically distinguishable from rheumatoid arthritis and ankylosing spondylitis, it took advances in detection systems in the middle of the last century (rheumatoid factor, HLA-B27) to convincingly make the final separations. We now know that significant numbers of patients with SpA have associated clinical IBD and almost half of them show subclinical gut inflammation, yet the connection between the gut and the musculoskeletal system has remained a vexing problem. Two publications from Nathan Zvaifler (one in 1960, the other in 1975) presciently described the relationship between the gut and the spine/peripheral joints heralding much of the work present today in laboratories around the world trying to examine basic mechanisms for the connections (there are likely to be many) between the gut, the environment (presumably our intestinal flora) and the downstream effect on the musculoskeletal system. The role of dysregulated microbiome along with microbiome-driven T helper 17 cell expansion and immune cell migration to the joints has been recognised, all of which occur in the appropriate context of genetic background inside and outside of the human leucocyte antigen system. Moreover, different adhesion molecules that mediate immune cells homing to the gut and joints have been noted. In this review, we studied the origins and evolution of IBD-arthritis, proposed pathogenic mechanisms and the current gaps that need to be filled for a complete understanding of IBD-arthritis.
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Affiliation(s)
- Maedeh Ashrafi
- Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran (the Islamic Republic of)
| | - Kristine A Kuhn
- Internal Medicine, University of Colorado - Anschutz Medical Campus, Aurora, Colorado, USA
| | - Michael H Weisman
- Internal Medicine, Stanford University School of Medicine, Stanford, California, USA
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15
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Bollow M. [Typical arthritis of the hands : Psoriatic arthritis]. Radiologe 2021; 61:448-457. [PMID: 33783565 DOI: 10.1007/s00117-021-00841-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/18/2021] [Indexed: 11/29/2022]
Abstract
BACKGROUND Psoriatic arthritis (PsA) is considered the prototype of peripheral spondyloarthritides (SpA) and is associated as skin-bone disease (SkiBo) with typical skin changes and with typical arthritides of the joints, especially of the hands and feet. OBJECTIVE Systematic review of imaging manual findings patterns in PsA with its typical enthesitic arthritides in context with clinical findings. MATERIALS AND METHODS A review based on the current literature on the subject from a radiological and rheumatological point of view is provided. RESULTS In PsA, inflammatory manifestations in the hands and feet are the most frequently affected regions of the body. Image morphological variability between early and late stages is evident. The projection radiographic characteristic of PsA is the simultaneous coexistence of osteodestructive-rarefactive changes with typical osteoproliferative-proliferative changes, which are part of the Classification of Psoriatic Arthritis (CASPAR) criteria. With the help of magnetic resonance imaging (MRI), the image-morphological spondyloarthritis inflammatory patterns of enthesitis, dactylitis and osteitis can be detected in the hands even in the early stages. CONCLUSIONS The basic knowledge of the image morphological changes of this complex autoimmunological skin-bone disease will be imparted in order to gain the necessary confidence in the systematic diagnostic evaluation of hand arthritis patterns typical for PsA in images both at the initial diagnosis and over the course of the disease and in the classification of early and late stages, which serve as a guide for rheumatologists regarding "step-up" treatments.
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Affiliation(s)
- Matthias Bollow
- Ruhr-Universität Bochum, Bochum, Deutschland. .,Klinik für diagnostische und interventionelle Radiologie, Augusta-Kranken-Anstalt Bochum, Bergstraße 26, 44791, Bochum, Deutschland.
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16
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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: 188] [Impact Index Per Article: 47.0] [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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Abstract
Axial spondyloarthritis (axSpA) is an inflammatory disease of the axial skeleton associated with significant pain and disability. Previously, the diagnosis of ankylosing spondylitis required advanced changes on plain radiographs of the sacroiliac joints. Classification criteria released in 2009, however, identified a subset of patients, under the age of 45, with back pain for more than three months in the absence of radiographic sacroiliitis who were classified as axSpA based on a positive magnetic resonance imaging or HLAB27 positivity and specific clinical features. This subgroup was labeled non-radiographic (nr)-axSpA. These patients, compared with those identified by the older New York criteria, contained a larger percentage of women and demonstrated less structural damage. However, their clinical manifestations and response to biologics were similar to radiographic axSpA. The discovery of the interleukin (IL) IL-23/IL-17 pathway revealed key molecules involved in the pathophysiology of axSpA. This discovery propelled the generation of antibodies directed toward IL-17A, which are highly effective and demonstrate treatment responses in axSpA that are similar to those observed with anti-TNF agents. The finding that agents that block IL-23 were not effective in axSpA came as a surprise and the potential underlying mechanisms underlying this lack of response are discussed. New agents with dual inhibition of the IL-17A and F isoforms and some oral small molecule agents that target the Jak-STAT pathway, have also shown efficacy in axSpA.
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Affiliation(s)
- Christopher Ritchlin
- Allergy, Immunology & Rheumatology Division, University of Rochester Medical Center, Rochester, New York, USA
| | - Iannis E Adamopoulos
- Rheumatology, Allergy & Clinical Immunology Division, University of California, Davis, Shriners Hospital, Sacramento, California, USA
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18
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Li L, Wu Z, Wu M, Qiu X, Wu Y, Kuang Z, Wang L, Sun T, Liu Y, Yi S, Jing H, Zhou S, Chen B, Wu D, Wu W, Liu J. IBI112, a selective anti-IL23p19 monoclonal antibody, displays high efficacy in IL-23-induced psoriasiform dermatitis. Int Immunopharmacol 2020; 89:107008. [PMID: 33069927 DOI: 10.1016/j.intimp.2020.107008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 09/06/2020] [Accepted: 09/11/2020] [Indexed: 11/16/2022]
Abstract
Psoriasis is a highly prevalent inflammatory skin disease. Plaque psoriasis is the most common type of psoriasis, and the interleukin (IL)-23/IL-17 axis plays a key role in disease progression. In this article, we describe IBI112, a highly potent anti-IL-23 monoclonal antibody under clinical development, which efficiently neutralizes IL23p19, a subunit of IL-23, to abrogate IL-23 binding to its receptor and block downstream signal transducer and activator of transcription 3 (STAT3) phosphorylation. Specifically, IBI112 blocked IL-23 induced downstream IL-17 production from splenocytes. In addition, IBI112 administration reduced skin thickness in a psoriasis-like epidermal hyperplasia mouse model challenged by continuous hIL-23 injection. IBI112 showed synergism with an anti-IL-1R antibody in controlling disease progression in an imiquimod (IMQ) -induced psoriasis model. Moreover, with mutations in Fc fragment of IBI112, extended half-life was observed when compared to the wild-type IgG1 version in both human-FcRn-knock-in mice and cynomolgus monkeys. IBI112 was well tolerated after high dose administration in cynomolgus monkeys. In summary, we have developed an extended half-life, anti-IL-23p19 monoclonal antibody, IBI112, which efficiently neutralized IL-23, blocked IL-23-induced IL-17 production, and alleviated disease symptoms in two mouse models of psoriasis.
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Affiliation(s)
- Li Li
- Innovent Biologics (Suzhou) Co., Ltd, 168 Dongping Street, Suzhou Industrial Park, Suzhou 215123, Jiangsu, China
| | - Zhihai Wu
- Innovent Biologics (Suzhou) Co., Ltd, 168 Dongping Street, Suzhou Industrial Park, Suzhou 215123, Jiangsu, China
| | - Min Wu
- Innovent Biologics (Suzhou) Co., Ltd, 168 Dongping Street, Suzhou Industrial Park, Suzhou 215123, Jiangsu, China
| | - Xuan Qiu
- Innovent Biologics (Suzhou) Co., Ltd, 168 Dongping Street, Suzhou Industrial Park, Suzhou 215123, Jiangsu, China
| | - Yue Wu
- Innovent Biologics (Suzhou) Co., Ltd, 168 Dongping Street, Suzhou Industrial Park, Suzhou 215123, Jiangsu, China
| | - Zhihui Kuang
- Innovent Biologics (Suzhou) Co., Ltd, 168 Dongping Street, Suzhou Industrial Park, Suzhou 215123, Jiangsu, China
| | - Li Wang
- Innovent Biologics (Suzhou) Co., Ltd, 168 Dongping Street, Suzhou Industrial Park, Suzhou 215123, Jiangsu, China
| | - Ta Sun
- Innovent Biologics (Suzhou) Co., Ltd, 168 Dongping Street, Suzhou Industrial Park, Suzhou 215123, Jiangsu, China
| | - Yang Liu
- Innovent Biologics (Suzhou) Co., Ltd, 168 Dongping Street, Suzhou Industrial Park, Suzhou 215123, Jiangsu, China
| | - Shuai Yi
- Innovent Biologics (Suzhou) Co., Ltd, 168 Dongping Street, Suzhou Industrial Park, Suzhou 215123, Jiangsu, China
| | - Hua Jing
- Innovent Biologics (Suzhou) Co., Ltd, 168 Dongping Street, Suzhou Industrial Park, Suzhou 215123, Jiangsu, China
| | - Shuaixiang Zhou
- Innovent Biologics (Suzhou) Co., Ltd, 168 Dongping Street, Suzhou Industrial Park, Suzhou 215123, Jiangsu, China
| | - Bingliang Chen
- Innovent Biologics (Suzhou) Co., Ltd, 168 Dongping Street, Suzhou Industrial Park, Suzhou 215123, Jiangsu, China
| | - Dongdong Wu
- Innovent Biologics (Suzhou) Co., Ltd, 168 Dongping Street, Suzhou Industrial Park, Suzhou 215123, Jiangsu, China
| | - Weiwei Wu
- Innovent Biologics (Suzhou) Co., Ltd, 168 Dongping Street, Suzhou Industrial Park, Suzhou 215123, Jiangsu, China.
| | - Junjian Liu
- Innovent Biologics (Suzhou) Co., Ltd, 168 Dongping Street, Suzhou Industrial Park, Suzhou 215123, Jiangsu, China.
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19
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Finucci A, Ditto MC, Parisi S, Borrelli R, Priora M, Realmuto C, Fusaro E. Rheumatic manifestations in inflammatory bowel disease. Minerva Gastroenterol (Torino) 2020; 67:79-90. [PMID: 32623869 DOI: 10.23736/s2724-5985.20.02726-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Rheumatic manifestations are the most frequent extra-intestinal manifestations (EIMs) in inflammatory bowel disease (IBD) patients, and they are responsible for a relevant reduction of quality of life. IBD is associated with a variety of musculoskeletal manifestations such as arthritis and non-inflammatory pain as well as with metabolic diseases, such as osteoporosis. Different imaging techniques (primarily ultrasound, magnetic resonance imaging and X-rays) can help the clinician to correctly identify the nature of manifestations and to treat the patient accordingly. Nowadays, in the setting of IBD-related arthritides, different drugs are available and can be effective on both articular and intestinal involvement. Therefore, a multi-disciplinary approach provides an early diagnosis and a better clinical outcome that can only be given from the recognition and consideration of the different EIMs. As for rheumatic manifestations, namely IBD-related arthritis, an early intervention allows to control disease activity and to prevent structural damage.
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Affiliation(s)
- Annacarla Finucci
- Unit of Rheumatology, Città della Salute e della Scienza, Turin, Italy -
| | | | - Simone Parisi
- Unit of Rheumatology, Città della Salute e della Scienza, Turin, Italy
| | - Richard Borrelli
- Unit of Rheumatology, Città della Salute e della Scienza, Turin, Italy
| | - Marta Priora
- Unit of Rheumatology, Città della Salute e della Scienza, Turin, Italy
| | - Cristina Realmuto
- Unit of Rheumatology, Città della Salute e della Scienza, Turin, Italy
| | - Enrico Fusaro
- Unit of Rheumatology, Città della Salute e della Scienza, Turin, Italy
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20
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Abstract
Axial involvement in psoriatic arthritis is a well-recognized manifestation with a prevalence between 12.5% and 78%. This huge heterogeneity is due to the different criteria used by authors to define psoriatic arthritis with axial involvement combining clinical features with radiographic evidence of disease. Specific genetic and clinical attributes of axial psoriatic arthritis might differentiate it from axial spondyloarthritis with concurrent skin psoriasis. Few studies address the specific management. The purpose of this review is to acknowledge the current understanding of axial involvement in psoriatic arthritis and highlight the need for a definition to facilitate research and clinical recognition.
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21
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Cuthbert RJ, Watad A, Fragkakis EM, Dunsmuir R, Loughenbury P, Khan A, Millner PA, Davison A, Marzo-Ortega H, Newton D, Bridgewood C, McGonagle DG. Evidence that tissue resident human enthesis γδT-cells can produce IL-17A independently of IL-23R transcript expression. Ann Rheum Dis 2019; 78:1559-1565. [PMID: 31530557 PMCID: PMC6837256 DOI: 10.1136/annrheumdis-2019-215210] [Citation(s) in RCA: 104] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2019] [Revised: 08/11/2019] [Accepted: 08/12/2019] [Indexed: 12/15/2022]
Abstract
OBJECTIVES Murine models of interleukin (IL)-23-driven spondyloarthritis (SpA) have demonstrated entheseal accumulation of γδT-cells which were responsible for the majority of local IL-17A production. However, IL-23 blockers are ineffective in axial inflammation in man. This study investigated γδT-cell subsets in the normal human enthesis to explore the biology of the IL-23/17 axis. METHODS Human spinous processes entheseal soft tissue (EST) and peri-entheseal bone (PEB) were harvested during elective orthopaedic procedures. Entheseal γδT-cells were evaluated using immunohistochemistry and isolated and characterised using flow cytometry. RNA was isolated from γδT-cell subsets and analysed by qPCR. Entheseal γδT-cells were stimulated with phorbol 12-myristate 13-acetate (PMA) and ionomycin, anti-CD3/28 or IL-23 and IL-17A production was measured by high-sensitivity ELISA and qPCR. RESULTS Entheseal γδT-cells were confirmed immunohistochemically with Vδ1 and Vδ2 subsets that are cytometrically defined. Transcript profiles of both cell populations suggested tissue residency and immunomodulatory status. Entheseal Vδ2 cells expressed high relative abundance of IL-23/17-associated transcripts including IL-23R, RORC and CCR6, whereas the Vδ1 subset almost completely lacked detectable IL-23R transcript. Following PMA stimulation IL-17A was detectable in both Vδ1 and Vδ2 subsets, and following CD3/CD28 stimulation both subsets showed IL-17A and IL-17F transcripts with neither transcript being detectable in the Vδ1 subset following IL-23 stimulation. CONCLUSION Spinal entheseal Vδ1 and Vδ2 subsets are tissue resident cells with inducible IL-17A production with evidence that the Vδ1 subset does so independently of IL-23R expression.
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Affiliation(s)
- Richard James Cuthbert
- Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds, UK
| | - Abdulla Watad
- Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds, UK
- Department of Medicine 'B' and Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel Aviv, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | | | | | | | - Almas Khan
- Leeds Teaching Hospitals NHS Trust, Leeds, UK
| | | | - Adam Davison
- Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds, UK
| | - Helena Marzo-Ortega
- Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds, UK
- National Institute for Health Research (NIHR) Leeds Biomedical Research Centre (BRC), Leeds Teaching Hospitals, Leeds, UK
| | - Darren Newton
- Section of Experimental Hematology, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK
| | - Charlie Bridgewood
- Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds, UK
| | - Dennis G McGonagle
- Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds, UK
- National Institute for Health Research (NIHR) Leeds Biomedical Research Centre (BRC), Leeds Teaching Hospitals, Leeds, UK
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22
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Associations between interleukin-23R polymorphisms and ankylosing spondylitis susceptibility: an updated meta-analysis. Z Rheumatol 2019; 78:272-280. [PMID: 29691688 DOI: 10.1007/s00393-018-0472-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
OBJECTIVE The aim of this study was to determine whether interleukin-23R (IL-23R) polymorphisms are associated with susceptibility to ankylosing spondylitis (AS). METHODS Meta-analyses were conducted to determine the associations between IL-23R polymorphisms and AS susceptibility in Europeans, Asians, and all subjects combined. RESULTS A total of 17 studies (21 separate comparisons) were included in this meta-analysis. The meta-analysis revealed a significant association between AS and the two alleles of the rs11209032 polymorphism in all study subjects (odds ratio [OR] = 1.160, 95% confidence interval [CI] = 1.091-1.204, P < 0.001). Stratification by ethnicity identified a significant association between this polymorphism and AS in Europeans (OR = 1.234, 95% CI = 1.159-1.313, P < 0.001), but not in Asians (OR = 1.003, 95% CI = 0.920-1.219, P = 0.942). Meta-analyses of the rs1004819, rs10489629, rs1343151, rs1495965, rs7517847, and rs11465804 polymorphisms showed the same pattern as shown for rs11209032. The meta-analysis also revealed a significant association between the two alleles of the rs2201841 and rs11209026 polymorphisms and the risk of developing AS in Europeans, but not in Asians. Interestingly, the rs10889677 polymorphism was not found to be associated with AS susceptibility in either Europeans or Asians. CONCLUSIONS This meta-analysis showed that several IL-23R polymorphisms are associated with the development of AS in Europeans.
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Rodriguez-Nicolas A, Jiménez P, Carmona FD, Martín J, Matas Cobos AM, Ruiz-Cabello F, Redondo-Cerezo E. Association between Genetic Polymorphisms of Inflammatory Response Genes and Acute Pancreatitis. Immunol Invest 2019; 48:585-596. [PMID: 31044631 DOI: 10.1080/08820139.2019.1576729] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Inflammation plays a central role in the pathophysiology of acute pancreatitis (AP). We hypothesized that changes in the function of key components of the inflammatory cascade, caused by genetic polymorphisms, could determine the development and/or severity of AP. We studied the following polymorphisms in 269 patients: IL23R rs11209026, TNF rs1800629, RIPK2 rs42490, NOD2 rs9302752, MCP1 rs1024611 and NFKB1 rs28362491. The rs11209026 A allele was related to the presence of AP (p = 0.007261; OR = 1 .523). Epistasis analysis revealed that AP susceptibility was increased by interaction between IL23R rs11209026 and TNF rs1800629 (p = 1.205 × 10-5; ORinteraction = 4.031). The rs42490-G allele was associated with an increased risk of severe pancreatitis (p = 0.01583; OR = 2.736), severe or moderately severe pancreatitis (p = 0.04206; OR = 1.609), and death (p = 0.03226; OR = 3.010). In conclusion, these results point to a plausible role for genetic polymorphisms in IL23R and RIPK2 in the development and severity of AP.
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Affiliation(s)
- Antonio Rodriguez-Nicolas
- a Servicio de Análisis Clínicos e Inmunología, UGC de Laboratorio Clínico , Hospital Universitario Virgen de las Nieves , Granada , Spain
- b Programa de doctorado en Biomedicina , Universidad de Granada , Granada , Spain
| | - Pilar Jiménez
- a Servicio de Análisis Clínicos e Inmunología, UGC de Laboratorio Clínico , Hospital Universitario Virgen de las Nieves , Granada , Spain
| | - F David Carmona
- c Departamento de Genética e Instituto de Biotecnología , Universidad de Granada , Granada , Spain
| | - Javier Martín
- d Instituto de Parasitología y Biomedicina López Neyra , CSIC , Granada , Spain
| | - Ana M Matas Cobos
- e Servicio de Aparato Digestivo , Hospital Universitario Virgen de las Nieves , Granada , Spain
| | - Francisco Ruiz-Cabello
- a Servicio de Análisis Clínicos e Inmunología, UGC de Laboratorio Clínico , Hospital Universitario Virgen de las Nieves , Granada , Spain
- f Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA) , Granada , Spain
| | - Eduardo Redondo-Cerezo
- e Servicio de Aparato Digestivo , Hospital Universitario Virgen de las Nieves , Granada , Spain
- f Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA) , Granada , Spain
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24
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Sayed MI, Hashad DI, Soliman EA, Talaaba MM. Association of IL-23R gene single nucleotide polymorphism; rs 11209026 with incidence and severity of ankylosing spondylitis in a cohort of Egyptian patients. ALEXANDRIA JOURNAL OF MEDICINE 2019. [DOI: 10.1016/j.ajme.2017.08.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
Affiliation(s)
- Mohamed I. Sayed
- Clinical Pathology Department, Faculty of Medicine-Alexandria University, Egypt
| | - Doaa I. Hashad
- Clinical Pathology Department, Faculty of Medicine-Alexandria University, Egypt
| | - Eman A. Soliman
- Internal Medicine Department, Faculty of Medicine-Alexandria University, Egypt
| | - Maha M. Talaaba
- Clinical Pathology Department, Faculty of Medicine-Alexandria University, Egypt
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Fragoulis GE, Liava C, Daoussis D, Akriviadis E, Garyfallos A, Dimitroulas T. Inflammatory bowel diseases and spondyloarthropathies: From pathogenesis to treatment. World J Gastroenterol 2019; 25:2162-2176. [PMID: 31143068 PMCID: PMC6526158 DOI: 10.3748/wjg.v25.i18.2162] [Citation(s) in RCA: 127] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Revised: 04/11/2019] [Accepted: 04/19/2019] [Indexed: 02/06/2023] Open
Abstract
Spondyloarthropathies (SpA) include many different forms of inflammatory arthritis and can affect the spine (axial SpA) and/or peripheral joints (peripheral SpA) with Ankylosing spondylitis (AS) being the prototype of the former. Extra-articular manifestations, like uveitis, psoriasis and inflammatory bowel disease (IBD) are frequently observed in the setting of SpA and are, in fact, part of the SpA classification criteria. Bowel involvement seems to be the most common of these manifestations. Clinically evident IBD is observed in 6%-14% of AS patients, which is significantly more frequent compared to the general population. Besides, it seems that silent microscopic gut inflammation, is evident in around 60% in AS patients. Interestingly, occurrence of IBD has been associated with AS disease activity. For peripheral SpA, two different forms have been proposed with diverse characteristics. Of note, SpA (axial or peripheral) is more commonly observed in Crohn's disease than in ulcerative colitis. The common pathogenetic mechanisms that explain the link between IBD and SpA are still ill-defined. The role of dysregulated microbiome along with migration of T lymphocytes and other cells from gut to the joint ("gut-joint" axis) has been recognized, in the context of a genetic background including associations with alleles inside or outside the human leukocyte antigen system. Various therapeutic modalities are available with monoclonal antibodies against tumour necrosis factor, interleukin-23 and interleukin-17, being the most effective. Both gastroenterologists and rheumatologists should be alert to identify the co-existence of these conditions and ideally follow-up these patients in combined clinics.
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Affiliation(s)
- George E Fragoulis
- First Department of Propaedeutic Internal Medicine, National and Kapodistrian University of Athens, “Laiko” General Hospital, Athens 11527, Greece
- Institute of Infection, Immunity & Inflammation, University of Glasgow, Glasgow G128TA, United Kingdom
| | - Christina Liava
- 4th Department of Internal Medicine, Hippokration Hospital, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Dimitrios Daoussis
- Department of Internal Medicine, Division of Rheumatology, Patras University Hospital, Patras 26504, Greece
| | - Euangelos Akriviadis
- 4th Department of Internal Medicine, Hippokration Hospital, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Alexandros Garyfallos
- 4th Department of Internal Medicine, Hippokration Hospital, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Theodoros Dimitroulas
- 4th Department of Internal Medicine, Hippokration Hospital, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
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26
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Hemmatzadeh M, Babaie F, Ezzatifar F, Mohammadi FS, Ebrazeh M, Golabi Aghdam S, Hajaliloo M, Azizi G, Gowhari Shabgah A, Shekari N, Sehati N, Hosseinzadeh R, Mohammadi H, Babaloo Z. Susceptibility to ERAP1 gene single nucleotide polymorphism modulates the inflammatory cytokine setting in ankylosing spondylitis. Int J Rheum Dis 2019; 22:715-724. [PMID: 30740926 DOI: 10.1111/1756-185x.13494] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Revised: 12/26/2018] [Accepted: 01/04/2019] [Indexed: 11/28/2022]
Abstract
AIM To evaluate the association of ERAP1 gene single nucleotide polymorphisms (SNPs) with the risk of ankylosing spondylitis (AS) and their role in modulation of the inflammatory interleukin (IL)-17/IL-23 axis in the disease. METHODS For genotyping, 190 AS cases and 190 healthy controls were enrolled. After DNA extraction, all the subjects were genotyped for rs17482078, rs469876, and rs27038 polymorphisms using single specific primer polymerase chain reaction (PCR) assay. After isolation of peripheral blood mononuclear cells, RNA extraction and complementary DNA synthesis, real-time PCR using SYBR Green master mix was employed to determine messenger RNA (mRNA) expression of IL-17A and IL-23 in PBMCs. Using enzyme-linked immunosorbent assay, the concentration of these cytokines was determined in serum samples. RESULTS It was observed that the A allele of rs27038 polymorphism significantly increased AS risk (odds ratio [OR] = 1.53, 95% CI =1.11-2.12; P = 0.0096). Moreover, AA and AG genotypes of this SNP were associated with increased (OR = 2.89, 95% CI = 1.42-5.85; P = 0.0031) and decreased (OR = 0.57, 95% CI = 0.36-0.92; P = 0.021), respectively, risk of the disease. The rs27038 SNP was associated with C-reactive protein level. There were significantly increased mRNA and serum concentrations of both IL-17A and IL-23 in AS patients compared with controls. Furthermore, AS patients with the AA in comparison to other genotypes for rs27038 SNP indicated significantly increased mRNA and serum concentration levels for both cytokines. CONCLUSIONS This study demonstrated the association of ERAP1 gene rs27038 polymorphism with the risk of AS in an Iranian population. Additionally, it seems that rs27038 is involved in the modulation of the inflammatory IL-17/IL-23 axis in AS.
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Affiliation(s)
- Maryam Hemmatzadeh
- Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farhad Babaie
- Cellular and Molecular Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Fatemeh Ezzatifar
- Molecular and Cell Biology Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.,Student Research Committee, Mazandaran University of Medical Sciences, Sari, Iran
| | - Fatemeh S Mohammadi
- Immunology Research Center, Inflammation and Inflammatory Diseases Division, Medical School, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mehrdad Ebrazeh
- Department of Biology, Bonab Branch, Islamic Azad University, Bonab, Iran
| | - Shirin Golabi Aghdam
- Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehrzad Hajaliloo
- Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Gholamreza Azizi
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran.,Department of Immunology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran
| | | | - Najibeh Shekari
- Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nasrin Sehati
- Department of Genetic, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran
| | - Ramin Hosseinzadeh
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hamed Mohammadi
- Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zohreh Babaloo
- Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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27
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de Winter JJ, Paramarta JE, de Jong HM, van de Sande MG, Baeten DL. Peripheral disease contributes significantly to the level of disease activity in axial spondyloarthritis. RMD Open 2019; 5:e000802. [PMID: 30713720 PMCID: PMC6340525 DOI: 10.1136/rmdopen-2018-000802] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2018] [Revised: 10/02/2018] [Accepted: 10/24/2018] [Indexed: 01/21/2023] Open
Abstract
Objective Spondyloarthritis (SpA) can encompass axial, peripheral and extra-articular disease manifestations. Patients are classified as axial or peripheral SpA depending on the presence or absence of current back pain, independently of the other disease manifestations. Therefore, we aimed to assess the percentage of patients with axial SpA with peripheral disease and how this peripheral disease contributes to the overall disease activity. Methods Prevalence and disease activity of peripheral disease manifestations were assessed in a real-life observational cohort of 314 patients with the clinical diagnosis of SpA and fulfilling the Assessment of SpondyloArthritis international Society (ASAS) criteria. Results Of the 314 patients fulfilling the ASAS criteria, 230 fulfilled the axial and 84 the peripheral SpA criteria. Of the 230 patients with axial SpA, 49% had purely axial disease without peripheral disease manifestations whereas 51% had combined axial (back pain) and peripheral (arthritis, enthesitis and/or dactylitis) disease. The latter group had the highest disease activity in comparison with pure axial SpA as well as with peripheral SpA. Conclusion Half of the patients classified as axial SpA according to the ASAS criteria also have peripheral disease manifestations such as arthritis, enthesitis and/or dactylitis. These peripheral disease manifestations contribute significantly to overall disease activity.
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Affiliation(s)
- Janneke J de Winter
- Amsterdam Rheumatology and Immunology Center, Department of Clinical Immunology and Rheumatology, Amsterdam UMC University of Amsterdam, Amsterdam, The Netherlands
| | - Jacqueline E Paramarta
- Amsterdam Rheumatology and Immunology Center, Department of Clinical Immunology and Rheumatology, Amsterdam UMC University of Amsterdam, Amsterdam, The Netherlands
| | - Henriëtte M de Jong
- Amsterdam Rheumatology and Immunology Center, Department of Clinical Immunology and Rheumatology, Amsterdam UMC University of Amsterdam, Amsterdam, The Netherlands
| | - Marleen G van de Sande
- Amsterdam Rheumatology and Immunology Center, Department of Clinical Immunology and Rheumatology, Amsterdam UMC University of Amsterdam, Amsterdam, The Netherlands
| | - Dominique L Baeten
- Amsterdam Rheumatology and Immunology Center, Department of Clinical Immunology and Rheumatology, Amsterdam UMC University of Amsterdam, Amsterdam, The Netherlands
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28
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Sode J, Bank S, Vogel U, Andersen PS, Sørensen SB, Bojesen AB, Andersen MR, Brandslund I, Dessau RB, Hoffmann HJ, Glintborg B, Hetland ML, Locht H, Heegaard NH, Andersen V. Genetically determined high activities of the TNF-alpha, IL23/IL17, and NFkB pathways were associated with increased risk of ankylosing spondylitis. BMC MEDICAL GENETICS 2018; 19:165. [PMID: 30208882 PMCID: PMC6136164 DOI: 10.1186/s12881-018-0680-z] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Accepted: 09/03/2018] [Indexed: 02/07/2023]
Abstract
Background Ankylosing spondylitis (AS) results from the combined effects of susceptibility genes and environmental factors. Polymorphisms in genes regulating inflammation may explain part of the heritability of AS. Methods Using a candidate gene approach in this case-control study, 51 mainly functional single nucleotide polymorphisms (SNPs) in genes regulating inflammation were assessed in 709 patients with AS and 795 controls. Data on the patients with AS were obtained from the DANBIO registry where patients from all of Denmark are monitored in routine care during treatment with conventional and biologic disease modifying anti-rheumatic drugs (bDMARDs). The results were analyzed using logistic regression (adjusted for age and sex). Results Nine polymorphisms were associated with risk of AS (p < 0.05). The polymorphisms were in genes regulating a: the TNF-α pathway (TNF -308 G > A (rs1800629), and − 238 G > A (rs361525); TNFRSF1A -609 G > T (rs4149570), and PTPN22 1858 G > A (rs2476601)), b: the IL23/IL17 pathway (IL23R G > A (rs11209026), and IL18–137 G > C (rs187238)), or c: the NFkB pathway (TLR1 743 T > C (rs4833095), TLR4 T > C (rs1554973), and LY96–1625 C > G (rs11465996)). After Bonferroni correction the homozygous variant genotype of TLR1 743 T > C (rs4833095) (odds ratios (OR): 2.59, 95% confidence interval (CI): 1.48–4.51, p = 0.04), and TNFRSF1A -609 G > T (rs4149570) (OR: 1.79, 95% CI: 1.31–2.41, p = 0.01) were associated with increased risk of AS and the combined homozygous and heterozygous variant genotypes of TNF -308 G > A (rs1800629) (OR: 0.56, 95% CI: 0.44–0.72, p = 0.0002) were associated with reduced risk of AS. Conclusion We replicated associations between AS and the polymorphisms in TNF (rs1800629), TNFRSF1A (rs4149570), and IL23R (rs11209026). Furthermore, we identified novel risk loci in TNF (rs361525), IL18 (rs187238), TLR1 (rs4833095), TLR4 (rs1554973), and LY96 (rs11465996) that need validation in independent cohorts. The results suggest that genetically determined high activity of the TNF-α, IL23/IL17, and NFkB pathways increase risk of AS.
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Affiliation(s)
- Jacob Sode
- Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark.,Department of Autoimmunology and Biomarkers, Statens Serum Institut, Copenhagen, Denmark.,Department of Rheumatology, Frederiksberg Hospital, Frederiksberg, Denmark.,Department of Rheumatology, Skåne University Hospital, Lund, Sweden
| | - Steffen Bank
- Focused Research Unit for Molecular Diagnostic and Clinical Research, Hospital of Southern Jutland, Aabenraa, Denmark. .,Medical Department, Viborg Regional Hospital, Viborg, Denmark.
| | - Ulla Vogel
- National Research Centre for the Working Environment, Copenhagen, Denmark
| | - Paal Skytt Andersen
- Microbiology and Infection Control, Statens Serum Institut, Copenhagen, Denmark.,Veterinary Disease Biology, University of Copenhagen, Copenhagen, Denmark
| | - Signe Bek Sørensen
- Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark.,Focused Research Unit for Molecular Diagnostic and Clinical Research, Hospital of Southern Jutland, Aabenraa, Denmark.,Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Anders Bo Bojesen
- Focused Research Unit for Molecular Diagnostic and Clinical Research, Hospital of Southern Jutland, Aabenraa, Denmark
| | - Malene Rohr Andersen
- Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Hellerup, Denmark
| | - Ivan Brandslund
- Department of Biochemistry, Hospital of Lillebaelt, Vejle, Denmark
| | - Ram Benny Dessau
- Department of Clinical Microbiology, Slagelse Hospital, Slagelse, Denmark
| | - Hans Jürgen Hoffmann
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.,Department of Respiratory Diseases B, Aarhus University Hospital, Aarhus, Denmark
| | - Bente Glintborg
- Department of Rheumatology, Gentofte and Herlev Hospital, Hellerup, Denmark.,The DANBIO Registry, Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Rigshospitalet, Glostrup, Denmark
| | - Merete Lund Hetland
- The DANBIO Registry, Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Rigshospitalet, Glostrup, Denmark.,Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Henning Locht
- Department of Rheumatology, Frederiksberg Hospital, Frederiksberg, Denmark
| | - Niels Henrik Heegaard
- Department of Autoimmunology and Biomarkers, Statens Serum Institut, Copenhagen, Denmark.,Clinical Biochemistry, Clinical Institute, University of Southern Denmark, Odense, Denmark
| | - Vibeke Andersen
- Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark.,Focused Research Unit for Molecular Diagnostic and Clinical Research, Hospital of Southern Jutland, Aabenraa, Denmark.,Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.,OPEN Odense Patient Data Explorative Network, Odense University Hospital, Odense, Denmark
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29
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Xia Y, Liang Y, Guo S, Yu JG, Tang MS, Xu PH, Qin FD, Wang GP. Association between cytokine gene polymorphisms and ankylosing spondylitis susceptibility: a systematic review and meta-analysis. Postgrad Med J 2018; 94:508-516. [PMID: 30322951 DOI: 10.1136/postgradmedj-2018-135665] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2018] [Revised: 09/11/2018] [Accepted: 09/15/2018] [Indexed: 01/05/2023]
Abstract
PURPOSE OF THE STUDY The aim of this study was to perform a meta-analysis to derive precise estimation of the association of interleukin-23 receptor (IL-23R), IL-1 receptor 2 (IL-1R2), IL-12 beta (IL-12B), IL-10 and tumour necrosis factor (TNF)-α polymorphisms with ankylosing spondylitis (AS) susceptibility. STUDY DESIGN A systematic literature search was conducted to identify the relevant studies. Pooled OR with 95% CI was calculated to assess the strength of the association in a fixed or random-effects model. RESULTS A total of 13 917 cases and 19 849 controls in 43 eligible studies were included in the meta-analysis. Seventeen single-nucleotide polymorphisms (SNPs) in the abovementioned five cytokine genes were evaluated. The results indicate that the nine SNPs (rs11209026, rs1004819, rs10489629, rs11465804, rs1343151, rs11209032, rs1495965, rs7517847, rs2201841) of IL-23R are associated with AS susceptibility in all study subjects in the allelic model. Moreover, stratification by ethnicity identified a significant association between seven SNPs of IL-23R and AS susceptibility in Europeans and Americans, but not in Asians. In addition, the IL-10-819 C/T and TNF-α-857 C/T polymorphisms also confer susceptibility to AS, especially in Asian population. CONCLUSION The results suggested that the genetic susceptibility for AS is associated with the nine SNPs of IL-23R in overall population. In the subgroup analysis, significant associations were shown in European and American population, but not in Asian population. Our results also suggest that IL-10-819 C/T and TNF-α-857 C/T polymorphism might be associated with AS risk, especially in Asian population.
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Affiliation(s)
- Yi Xia
- Department of Humanities and management, Wannan Medical College, Wuhu, China
| | - Yan Liang
- Department of Nephrology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Shi Guo
- Department of Humanities and management, Wannan Medical College, Wuhu, China
| | - Jie-Gen Yu
- School of Basic Medicine, Wannan Medical College, Wuhu, China
| | - Meng-Sha Tang
- Department of Humanities and management, Wannan Medical College, Wuhu, China
| | - Peng-Hui Xu
- Department of Humanities and management, Wannan Medical College, Wuhu, China
| | - Fen-Dui Qin
- Department of Humanities and management, Wannan Medical College, Wuhu, China
| | - Guo-Pin Wang
- Department of Humanities and management, Wannan Medical College, Wuhu, China
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30
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Zhong L, Wang W, Song H. Complex role of IL-23R polymorphisms on ankylosing spondylitis: a meta-analysis. Expert Rev Clin Immunol 2018; 14:635-643. [PMID: 29944013 DOI: 10.1080/1744666x.2018.1491308] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- Linqing Zhong
- Department of Pediatrics, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wei Wang
- Department of Pediatrics, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hongmei Song
- Department of Pediatrics, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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31
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Gooderham MJ, Papp KA, Lynde CW. Shifting the focus - the primary role of IL-23 in psoriasis and other inflammatory disorders. J Eur Acad Dermatol Venereol 2018; 32:1111-1119. [PMID: 29438576 PMCID: PMC6033004 DOI: 10.1111/jdv.14868] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Accepted: 01/29/2018] [Indexed: 12/12/2022]
Abstract
Insights into the pathophysiology of autoimmune inflammatory diseases including psoriasis have advanced considerably in recent years, and in parallel, so too have the available treatment options. Current clinical paradigms for the treatment of psoriasis have evolved to include targeted biologic therapies, starting with tumour necrosis factor‐alpha (TNF‐α) inhibitors and later, agents targeting interleukin (IL)‐12/23 and IL‐17. The most recent evidence suggests that IL‐23 might be an even more potent target for the effective treatment of psoriasis and other autoimmune inflammatory disorders. This review will describe recent developments leading to the current understanding of the key role of IL‐23 as a ‘master regulator’ of autoimmune inflammation and the clinical evidence for agents that specifically target this modulator in the context of treating psoriasis, spondyloarthropathy and inflammatory bowel disease.
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Affiliation(s)
- M J Gooderham
- SKiN Centre for Dermatology, Probity Medical Research, Queen's University, Peterborough, ON, Canada
| | - K A Papp
- K Papp Clinical Research and Probity Medical Research, Waterloo, ON, Canada
| | - C W Lynde
- Lynde Dermatology, Probity Medical Research, Markham, ON, Canada.,Department of Medicine, University of Toronto, Toronto, ON, Canada
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32
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Rademacher J, Poddubnyy D. Emerging drugs for the treatment of axial spondyloarthritis. Expert Opin Emerg Drugs 2018; 23:83-96. [DOI: 10.1080/14728214.2018.1445719] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Judith Rademacher
- Department of Gastroenterology, Infectiology and Rheumatology, Charité - Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health, Berlin, Germany
| | - Denis Poddubnyy
- Department of Gastroenterology, Infectiology and Rheumatology, Charité - Universitätsmedizin Berlin, Berlin, Germany
- German Rheumatism Research Centre, Berlin, Germany
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Role of Interleukin- (IL-) 17 in the Pathogenesis and Targeted Therapies in Spondyloarthropathies. Mediators Inflamm 2018; 2018:2403935. [PMID: 29670461 PMCID: PMC5833467 DOI: 10.1155/2018/2403935] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2017] [Revised: 12/18/2017] [Accepted: 12/31/2017] [Indexed: 12/11/2022] Open
Abstract
Spondyloarthropathy (SpA) is a unique type of joint inflammation characterized by coexisting erosive bone damage and pathological new bone formation. Previous genetic association studies have demonstrated that several cytokine pathways play a critical role in the pathogenesis of ankylosing spondylitis (AS), psoriatic arthritis (PsA), and other types of SpA. In addition to several well-known proinflammatory cytokines, recent studies suggest that IL-17 plays a pivotal role in the pathogenesis of SpA. Further evidence from human and animal studies have defined that IL-17 and IL-17-producing cells contribute to tissue inflammation, autoimmunity, and host defense, leading to the following pathologic events associated with SpA. Recently, several clinical trials targeting IL-17 pathways demonstrated the positive response of IL-17 blockade in treating AS, indicating a great potential of IL-17-targeting therapy in SpA. In this review article, we have discussed the contributing role of IL-17 and different IL-17-producing cells in the pathogenesis of SpA and provided an outline of therapeutic application of the IL-17 blockade in the treatment of SpA. Other targeted cytokines associated with IL-17 axis in SpA will also be included.
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34
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Rios Rodriguez V, Llop M, Poddubnyy D. Hematopoietic and mesenchymal stem cells: a promising new therapy for spondyloarthritis? Immunotherapy 2018; 9:899-911. [PMID: 29338611 DOI: 10.2217/imt-2017-0034] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
In the last years, a considerable progress has been made in the treatment of spondyloarthritides. Nonetheless, there remain a considerable number of patients who are unresponsive to all current therapies. Since the late 1990s, numerous trials have investigated the use of stem cell transplantation as a new approach for the treatment of autoimmune disease, particularly with hematopoietic stem cell transplantation. More recently, the research has focused on mesenchymal stem cell application due to their low immunogenicity and immunomodulatory properties. In this article, we summarize available data on hematopoietic stem cell and mesenchymal stem cell use for the treatment of spondyloarthritides and discuss the data gaps and possible research agenda in this area.
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Affiliation(s)
- Valeria Rios Rodriguez
- Department of Gastroenterology, Infectiology & Rheumatology, Campus Benjamin Franklin, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Maria Llop
- Department of Rheumatology, Hospital Ramón y Cajal, Madrid, Spain
| | - Denis Poddubnyy
- Department of Gastroenterology, Infectiology & Rheumatology, Campus Benjamin Franklin, Charité Universitätsmedizin Berlin, Berlin, Germany
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35
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Han R, Xia Q, Xu S, Fan D, Pan F. Interleukin-23 receptor polymorphism (rs10889677 A/C) in ankylosing spondylitis: Meta-analysis in Caucasian and Asian populations. Clin Chim Acta 2017; 477:53-59. [PMID: 29198991 DOI: 10.1016/j.cca.2017.11.038] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Revised: 11/28/2017] [Accepted: 11/29/2017] [Indexed: 11/24/2022]
Abstract
BACKGROUND The association between interleukin-23 receptor (IL23R) gene rs10889677 polymorphism and ankylosing spondylitis (AS) susceptibility was inconsistent in the recent literatures. A systematic review and meta-analysis was therefore performed. METHODS Online electronic databases were searched for relevant studies published up to November 2017. Meta-analyses were performed for the comparisons of allele (A versus C) and multiple genetic models, including dominant, recessive, heterozygous, and homozygous models using fixed or random effects models. Odds ratios (OR) with 95% confidence intervals (95%CI) were utilized to assess the potential relationship. RESULTS Sixteen studies containing 19 separate comparisons, totaling 6450 cases and 8009 controls were included. A significant association between rs10889677 A allele and AS susceptibility was detected (OR=1.136, 95%CI=1.043-1.236, P=0.003). Stratified analysis by ethnicity indicated that rs10889677 A allele was significantly associated with AS in Europeans (OR=1.192, 95%CI=1.080-1.315, P<0.001), but not Asians (OR=1.045, 95%CI=0.913-1.197, P=0.523). In addition, there were no significant associations between rs10889677 polymorphism and AS susceptibility in any of dominant, recessive, homozygous and heterozygous models. CONCLUSION This meta-analysis demonstrates that IL23R gene rs10889677 A allele confers increased risk of AS in Europeans, but its role in Asian populations needs further exploration.
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Affiliation(s)
- Renfang Han
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui 230032, China
| | - Qing Xia
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui 230032, China
| | - Shengqian Xu
- Department of Rheumatism and Immunity, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
| | - Dazhi Fan
- Department of Obstetrics, South Medical University Affiliated Maternal & Child Health Hospital of Foshan, 11 Renmin Road, Foshan 528000, Guangdong, China
| | - Faming Pan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui 230032, China.
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Rahman MA, Thomas R. The SKG model of spondyloarthritis. Best Pract Res Clin Rheumatol 2017; 31:895-909. [DOI: 10.1016/j.berh.2018.07.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Accepted: 07/06/2018] [Indexed: 12/21/2022]
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37
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Urolithiasis as an extraarticular manifestation of ankylosing spondylitis. Rheumatol Int 2017; 37:1949-1956. [DOI: 10.1007/s00296-017-3788-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Accepted: 08/07/2017] [Indexed: 12/17/2022]
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38
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El-Zayadi AA, Jones EA, Churchman SM, Baboolal TG, Cuthbert RJ, El-Jawhari JJ, Badawy AM, Alase AA, El-Sherbiny YM, McGonagle D. Interleukin-22 drives the proliferation, migration and osteogenic differentiation of mesenchymal stem cells: a novel cytokine that could contribute to new bone formation in spondyloarthropathies. Rheumatology (Oxford) 2017; 56:488-493. [PMID: 27940584 DOI: 10.1093/rheumatology/kew384] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVES. The SpAs are genetically and therapeutically linked to IL-23, which in turn regulates IL-22, a cytokine that has been implicated in the regulation of new bone formation in experimental models. We hypothesize that IL-22, a master regulator of stem cells in other niches, might also regulate human mesenchymal stem cell (MSC) osteogenesis. METHODS. The effects of IL-22 on in vitro MSC proliferation, migration and osteogenic differentiation were evaluated in the presence or absence of IFN-γ and TNF (to ascertain IL-22 activity in pro-inflammatory environments). Colorimetric XTT assay, trans-well migration assays, quantitative real-time PCR (qRT-PCR) for MSC lineage markers and osteogenesis assays were used. RESULTS. Combined treatment of MSC with IL-22, IFN-γ and TNF resulted in increased MSC proliferation ( P = 0.008) and migration ( P = 0.04), an effect that was not seen in cells treated with IL-22 alone and untreated cells. Osteogenic and adipogenic, but not chondrogenic, transcription factors were upregulated by IL-22 alone ( P < 0.05). MSC osteogenesis was enhanced following IL-22 exposure ( P = 0.03, measured by calcium production). The combination of IFN-γ and TNF with or without IL-22 suppressed MSC osteogenesis ( P = 0.03). CONCLUSION. This work shows that IL-22 is involved in human MSC proliferation/migration in inflammatory environments, with MSC osteogenesis occurring only in the absence of IFN-γ/TNF. These effects of IL-22 on MSC function is a novel pathway for exploring pathological, post-inflammation osteogenesis in human SpA.
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Affiliation(s)
- Ahmed A El-Zayadi
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK
- Department of Obstetrics and Gynaecology, Mansoura University Hospitals, Mansoura University, Mansoura, Egypt
| | - Elena A Jones
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK
- NIHR-Leeds Musculoskeletal and Biomedical Research Unit, Chapel Allerton, Leeds Teaching Hospital Trust, Leeds, West Yorkshire, UK
| | - Sarah M Churchman
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK
- NIHR-Leeds Musculoskeletal and Biomedical Research Unit, Chapel Allerton, Leeds Teaching Hospital Trust, Leeds, West Yorkshire, UK
| | - Thomas G Baboolal
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK
| | - Richard J Cuthbert
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK
| | - Jehan J El-Jawhari
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK
- Clinical Pathology Department, Mansoura University Hospitals, Mansoura University, Mansoura, Egypt
| | - Ahmed M Badawy
- Department of Obstetrics and Gynaecology, Mansoura University Hospitals, Mansoura University, Mansoura, Egypt
| | - Adewonuola A Alase
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK
| | - Yasser M El-Sherbiny
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK
- Clinical Pathology Department, Mansoura University Hospitals, Mansoura University, Mansoura, Egypt
| | - Dennis McGonagle
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK
- NIHR-Leeds Musculoskeletal and Biomedical Research Unit, Chapel Allerton, Leeds Teaching Hospital Trust, Leeds, West Yorkshire, UK
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Speca S, Dubuquoy L. Chronic bowel inflammation and inflammatory joint disease: Pathophysiology. Joint Bone Spine 2017; 84:417-420. [PMID: 28062378 DOI: 10.1016/j.jbspin.2016.12.016] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/27/2016] [Indexed: 12/19/2022]
Abstract
Bowel inflammation is closely linked to chronic joint inflammation. Research reported in the 1980s demonstrated bowel inflammation with gross and microscopic pathological features identical to those of Crohn's disease in over 60% of patients with spondyloarthritis (SpA). Numerous prospective studies have evidenced joint involvement in patients with chronic inflammatory bowel disease (IBD) and bowel inflammation in patients with SpA. Nevertheless, the interactions of joint disease and chronic bowel inflammation remain incompletely elucidated. Two main hypotheses have been suggested to explain potential links between inflammation of the mucosal immune system and peripheral arthritis: one identifies gut bacteria as potentially implicated in the development of joint inflammation and the other involves the recruitment of gut lymphocytes or activated macrophages to the joints. Pathophysiological investigations have established that HLA-B27 is a pivotal pathogenic factor. Here, we review current data on links between chronic bowel inflammation and inflammatory joint disease.
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Affiliation(s)
- Silvia Speca
- Lille Inflammation Research International Center (LIRIC), U995, University Lille, Inserm, CHU Lille, 59000 Lille, France
| | - Laurent Dubuquoy
- Lille Inflammation Research International Center (LIRIC), U995, University Lille, Inserm, CHU Lille, 59000 Lille, France.
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Rezaiemanesh A, Mahmoudi M, Amirzargar AA, Vojdanian M, Jamshidi AR, Nicknam MH. Ankylosing spondylitis M-CSF-derived macrophages are undergoing unfolded protein response (UPR) and express higher levels of interleukin-23. Mod Rheumatol 2016; 27:862-867. [DOI: 10.1080/14397595.2016.1259716] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Affiliation(s)
- Alireza Rezaiemanesh
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran,
| | - Mahdi Mahmoudi
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran, and
| | - Ali Akbar Amirzargar
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran,
- Molecular Immunology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahdi Vojdanian
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran, and
| | - Ahmad Reza Jamshidi
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran, and
| | - Mohammad Hossein Nicknam
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran,
- Molecular Immunology Research Center, Tehran University of Medical Sciences, Tehran, Iran
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41
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Xue X, Soroosh P, De Leon-Tabaldo A, Luna-Roman R, Sablad M, Rozenkrants N, Yu J, Castro G, Banie H, Fung-Leung WP, Santamaria-Babi L, Schlueter T, Albers M, Leonard K, Budelsky AL, Fourie AM. Pharmacologic modulation of RORγt translates to efficacy in preclinical and translational models of psoriasis and inflammatory arthritis. Sci Rep 2016; 6:37977. [PMID: 27905482 PMCID: PMC5131364 DOI: 10.1038/srep37977] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Accepted: 10/27/2016] [Indexed: 12/14/2022] Open
Abstract
The IL-23/IL-17 pathway is implicated in autoimmune diseases, particularly psoriasis, where biologics targeting IL-23 and IL-17 have shown significant clinical efficacy. Retinoid-related orphan nuclear receptor gamma t (RORγt) is required for Th17 differentiation and IL-17 production in adaptive and innate immune cells. We identified JNJ-54271074, a potent and highly-selective RORγt inverse agonist, which dose-dependently inhibited RORγt-driven transcription, decreased co-activator binding and promoted interaction with co-repressor protein. This compound selectively blocked Th17 differentiation, significantly reduced IL-17A production from memory T cells, and decreased IL-17A- and IL-22-producing human and murine γδ and NKT cells. In a murine collagen-induced arthritis model, JNJ-54271074 dose-dependently suppressed joint inflammation. Furthermore, JNJ-54271074 suppressed IL-17A production in human PBMC from rheumatoid arthritis patients. RORγt-deficient mice showed decreased IL-23-induced psoriasis-like skin inflammation and cytokine gene expression, consistent with dose-dependent inhibition in wild-type mice through oral dosing of JNJ-54271074. In a translational model of human psoriatic epidermal cells and skin-homing T cells, JNJ-54271074 selectively inhibited streptococcus extract-induced IL-17A and IL-17F. JNJ-54271074 is thus a potent, selective RORγt modulator with therapeutic potential in IL-23/IL-17 mediated autoimmune diseases.
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MESH Headings
- Administration, Oral
- Animals
- Arthritis, Rheumatoid/drug therapy
- Arthritis, Rheumatoid/genetics
- Arthritis, Rheumatoid/metabolism
- Cell Differentiation/drug effects
- Cells, Cultured
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Gene Expression Regulation/drug effects
- Interleukin-17/metabolism
- Interleukins/metabolism
- Mice
- Nuclear Receptor Subfamily 1, Group F, Member 3/genetics
- Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism
- Peptides, Cyclic/administration & dosage
- Peptides, Cyclic/pharmacology
- Psoriasis/drug therapy
- Psoriasis/genetics
- Psoriasis/metabolism
- Th17 Cells/cytology
- Th17 Cells/drug effects
- Th17 Cells/metabolism
- Transcription, Genetic
- Interleukin-22
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Affiliation(s)
- Xiaohua Xue
- Janssen Research & Development, La Jolla, California, United States
| | - Pejman Soroosh
- Janssen Research & Development, La Jolla, California, United States
| | | | - Rosa Luna-Roman
- Janssen Research & Development, La Jolla, California, United States
| | - Marciano Sablad
- Janssen Research & Development, La Jolla, California, United States
| | | | - Jingxue Yu
- Janssen Research & Development, La Jolla, California, United States
| | - Glenda Castro
- Janssen Research & Development, La Jolla, California, United States
| | - Homayon Banie
- Janssen Research & Development, La Jolla, California, United States
| | | | - Luis Santamaria-Babi
- Translational Immunology (PCB/UB), Department of Physiology and Immunology, Universitat de Barcelona Barcelona, Spain
| | - Thomas Schlueter
- Department of Research, Phenex Pharmaceuticals AG, Heidelberg, Germany
| | - Michael Albers
- Department of Research, Phenex Pharmaceuticals AG, Heidelberg, Germany
| | - Kristi Leonard
- Janssen Research & Development, Spring House, Pennsylvania, United States
| | | | - Anne M. Fourie
- Janssen Research & Development, La Jolla, California, United States
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Vidal-Castiñeira JR, López-Vázquez A, Diaz-Peña R, Diaz-Bulnes P, Martinez-Camblor P, Coto E, Coto-Segura P, Bruges-Armas J, Pinto JA, Blanco FJ, Sánchez A, Mulero J, Queiro R, Lopez-Larrea C. A Single Nucleotide Polymorphism in the Il17ra Promoter Is Associated with Functional Severity of Ankylosing Spondylitis. PLoS One 2016; 11:e0158905. [PMID: 27415816 PMCID: PMC4945092 DOI: 10.1371/journal.pone.0158905] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Accepted: 06/23/2016] [Indexed: 11/24/2022] Open
Abstract
The aim of this study was to identify new genetic variants associated with the severity of ankylosing spondylitis (AS). We sequenced the exome of eight patients diagnosed with AS, selected on the basis of the severity of their clinical parameters. We identified 27 variants in exons and regulatory regions. The contribution of candidate variants found to AS severity was validated by genotyping two Spanish cohorts consisting of 180 cases/300 controls and 419 cases/656 controls. Relationships of SNPs and clinical variables with the Bath Ankylosing Spondylitis Disease Activity and Functional Indices BASDAI and BASFI were analyzed. BASFI was standardized by adjusting for the duration of the disease since the appearance of the first symptoms. Refining the analysis of SNPs in the two cohorts, we found that the rs4819554 minor allele G in the promoter of the IL17RA gene was associated with AS (p<0.005). This variant was also associated with the BASFI score. Classifying AS patients by the severity of their functional status with respect to BASFI/disease duration of the 60th, 65th, 70th and 75th percentiles, we found the association increased from p60 to p75 (cohort 1: p<0.05 to p<0.01; cohort 2: p<0.01 to p<0.005). Our findings indicate a genetic role for the IL17/ILRA axis in the development of severe forms of AS.
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Affiliation(s)
| | | | - Roberto Diaz-Peña
- Immunology Department, Hospital Universitario Central de Asturias, Oviedo, Spain
- Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Talca, Chile
| | - Paula Diaz-Bulnes
- Immunology Department, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Pablo Martinez-Camblor
- Department of Statistics, Hospital Universitario Central de Asturias, Oviedo, Spain
- Facultad de Ciencias de la Educación, Universidad Autónoma de Chile, Santiago de Chile, Chile
| | - Eliecer Coto
- Molecular Genetics Department, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Pablo Coto-Segura
- Dermatology II Department, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Jacome Bruges-Armas
- Institute for Molecular and Cell Biology (IBMC), University of Porto, Porto, Portugal
| | - Jose Antonio Pinto
- Rheumatology Service, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), A Coruña, Spain
| | - Francisco Jose Blanco
- Rheumatology Service, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), A Coruña, Spain
| | - Alejandra Sánchez
- Rheumatology Service, Puerta del Hierro University Hospital, Majadahonda, Madrid
| | - Juan Mulero
- Rheumatology Service, Puerta del Hierro University Hospital, Majadahonda, Madrid
| | - Ruben Queiro
- Rheumatology Service, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Carlos Lopez-Larrea
- Immunology Department, Hospital Universitario Central de Asturias, Oviedo, Spain
- Fundación Renal Iñigo Álvarez de Toledo, Madrid, Spain
- * E-mail:
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Abdollahi E, Tavasolian F, Momtazi-Borojeni AA, Samadi M, Rafatpanah H. Protective role of R381Q (rs11209026) polymorphism in IL-23R gene in immune-mediated diseases: A comprehensive review. J Immunotoxicol 2016; 13:286-300. [PMID: 27043356 DOI: 10.3109/1547691x.2015.1115448] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Interleukin-23 (IL-23) is a regulator of cellular immune responses involved in controlling infection and autoimmune diseases. Strong evidence has shown that IL-23 plays a role in the maintenance of immune responses by influencing the proliferation and survival of IL-17-producing T-helper (TH)-17 cells. The critical role of the IL-23/TH17 axis in immune-mediated diseases has emerged from different studies. It has also been seen that polymorphisms in the IL-23 receptor (IL-23R) gene might influence IL-23 responses. Interestingly, a functional single nucleotide polymorphism (SNP) in the IL-23 receptor gene (IL-23R; rs11209026, 1142 G wild-type A reduced function, Arg381Gln, R381Q) seems to confer a measure of protection against development of inflammatory bowel disease (IBD; Crohn's disease, ulcerative colitis), ankylosing spondylitis, rheumatoid arthritis, psoriasis, thyroiditis, recurrent spontaneous abortion and asthma, suggesting that a perturbation in the IL-23 signaling pathway is likely to be relevant to the pathophysiology of these diseases. The aim of this review was to provide an evaluation of what is currently known about the protective role of R381Q variant in IL-23R gene in immune-based diseases.
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Affiliation(s)
- Elham Abdollahi
- a Department of Medical Immunology , School of Medicine, Mashhad University of Medical Sciences , Mashhad , Iran ;,b Shahid Sadoughi University of Medical Science , Yazd , Iran ;,c Student Research Committee, Mashhad University of Medical Sciences , Mashhad , Iran
| | - Fataneh Tavasolian
- d Department of Immunology , School of Medical Sciences, Tarbiat Modares University , Tehran , Iran
| | - Amir Abbas Momtazi-Borojeni
- c Student Research Committee, Mashhad University of Medical Sciences , Mashhad , Iran ;,e Department of Medical Biotechnology , Mashhad University of Medical Sciences , Mashhad , Iran
| | - Morteza Samadi
- f Department of Immunology , Shahid Sadoughi University , Yazd , Iran ;,g Reproductive Immunology Research Center, Shahid Sadoughi University , Yazd , Iran
| | - Houshang Rafatpanah
- h Research Center for HIV/AIDS, HTLV1 and Viral Hepatitis, Iranian Academic for Education, Culture and Research (ACECR), Mashhad Branch , Mashhad , Iran ;,i Inflammation/Inflammatory Diseases Research Center, Mashhad University of Medical Sciences , Mashhad , Iran
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Rysnik O, McHugh K, van Duivenvoorde L, van Tok M, Guggino G, Taurog J, Kollnberger S, Ciccia F, Baeten D, Bowness P. Non-conventional forms of HLA-B27 are expressed in spondyloarthritis joints and gut tissue. J Autoimmun 2016; 70:12-21. [PMID: 27036372 PMCID: PMC4871811 DOI: 10.1016/j.jaut.2016.03.009] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2016] [Revised: 03/11/2016] [Accepted: 03/12/2016] [Indexed: 12/25/2022]
Abstract
Objectives Human leukocyte antigen (HLA)-B27 (B27) is the strongest genetic factor associated with development of Ankylosing Spondylitis and other spondyloarthropathies (SpA), yet the role it plays in disease pathogenesis remains unclear. We investigated the expression of potentially pathogenic non-conventional heavy chain forms (NC) of B27 in synovial and intestinal tissues obtained from SpA patients. We also determined the presence of NC-B27 in joints, lymphoid and gastrointestinal tissue from B27 transgenic (TG1) rats with M.tuberculosis-induced SpA. Methods Expression of NC-B27 in human SpA joints and gut and in (21-3 × 283-2)F1 HLA-B27/Huβ2m rat tissue was determined by immunohistochemistry, flow cytometry and confocal microscopy analysis using HC10 and HD6 antibodies. Results Both HC10- and HD6-reactive HLA molecules were present in synovial tissue from SpA patients. Both NC-B27 and KIR3DL2, a ligand for NC-B27, were expressed in inflamed terminal ileal tissues in patients with early SpA. Infiltrating cells in inflamed joint tissues isolated from B27 TG1 rats expressed high levels of NC-B27. NC-B27 were also expressed in joint-resident cells from ankle and tail joints of B27 TG1 rats prior to clinical arthritis. The expression of NC-B27 on B27 TG1 rat CD11b/c+, CD8α+, cells from spleens and LNs increased with animal age and disease progression. Conclusions Non-conventional HLA class 1 molecules are expressed on resident and infiltrating cells in both synovial and GI tissues in human SpA. NC-B27 expression in joints and lymphoid tissues from B27 TG1 rats prior to the onset of arthritis is consistent with the hypothesis that they play a pathogenic role in SpA.
HLA-B27 predisposes to Ankylosing Spondylitis and related Spondyloarthritis (SpA). Non-conventional HLA-B27 free heavy chains (NC-B27) bind innate immune receptors. NC HLA class I molecules are expressed in joint and gut tissues in human and rat SpA. B27 transgenic rats express NC-B27 prior to arthritis onset. These data support a pathogenic role for non-conventional B27 in SpA.
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Affiliation(s)
- Oliwia Rysnik
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford, UK.
| | - Kirsty McHugh
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford, UK
| | - Leonie van Duivenvoorde
- Amsterdam Rheumatology and Immunology Center, Department of Clinical Immunology and Rheumatology, Department of Experimental Immunology Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Melissa van Tok
- Amsterdam Rheumatology and Immunology Center, Department of Clinical Immunology and Rheumatology, Department of Experimental Immunology Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Giuliana Guggino
- Dipartimento di Biopatologia e Biotecnologie Mediche e Forensi, Dipartimento Biomedico di Medicina Interna e Specialistica, Sezione di Reumatologia, Università di Palermo, Italy
| | - Joel Taurog
- Department of Internal Medicine, Rheumatic Diseases Division, University of Texas Southwestern Medical Center, Dallas, USA
| | - Simon Kollnberger
- Cardiff Institute of Infection & Immunity, Henry Wellcome Building, Heath Park, Cardiff CF14 4XN, UK
| | - Francesco Ciccia
- Dipartimento di Biopatologia e Biotecnologie Mediche e Forensi, Dipartimento Biomedico di Medicina Interna e Specialistica, Sezione di Reumatologia, Università di Palermo, Italy
| | - Dominique Baeten
- Amsterdam Rheumatology and Immunology Center, Department of Clinical Immunology and Rheumatology, Department of Experimental Immunology Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Paul Bowness
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford, UK
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Th17 Cell Pathway in Human Immunity: Lessons from Genetics and Therapeutic Interventions. Immunity 2015; 43:1040-51. [DOI: 10.1016/j.immuni.2015.12.003] [Citation(s) in RCA: 348] [Impact Index Per Article: 34.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2015] [Revised: 11/30/2015] [Accepted: 12/01/2015] [Indexed: 01/01/2023]
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Xia Y, Chen K, Zhang MH, Wang LC, Ma CY, Lin YL, Zhao YR. MicroRNA-124 involves in ankylosing spondylitis by targeting ANTXR2. Mod Rheumatol 2015; 25:784-9. [PMID: 25736362 DOI: 10.3109/14397595.2015.1023887] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
OBJECTIVES A recent genome-wide association study or GWAS identified that anthrax roxin receptor 2 (ANTXR2) was one of the risk loci for ankylosing spondylitis (AS). Previous study also showed that ANTXR2 could potentially affect new bone formation. This study aimed to investigate the possible mechanisms of ANTXR2 involved in AS pathogenesis. METHODS The expression level of ANTXR2 and miR-124 in peripheral blood was detected by quantitative real-time polymerase chain reaction or qRT-PCR. ANTXR2 was predicted to be a target gene of miR-124 by TargetScan, which was confirmed by luciferase reporter assays. Western blot analysis was used to further investigate the effect of miR-124 on c-Jun N-terminal kinase (JNK) activation and evaluate the activated status of autophagy. RESULTS We evidenced that ANTXR2 was downregulated and miR-124 was upregulated in peripheral blood from AS patients. Intriguingly, miR-124 targeted ANTXR2 and overexpression of miR-124 in Jurkat cells notably inhibited ANTXR2 expression. ANTXR2 inhibition by miR-124 promoted JNK activation and induced autophagy. CONCLUSIONS Our results suggested that miR-124 might induce autophagy to participate in AS by targeting ANTXR2, which might be implicated in pathological process of AS.
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Affiliation(s)
- Yu Xia
- a Department of Central Laboratory , Shandong Provincial Hospital affiliated to Shandong University , Jinan , China
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47
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Blocking Interleukin-12 and Interleukin-23 in the Treatment of Axial Spondyloarthritis. CURRENT TREATMENT OPTIONS IN RHEUMATOLOGY 2015. [DOI: 10.1007/s40674-015-0021-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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Abstract
The molecular mechanisms governing T helper (Th) cell differentiation and function have revealed a complex network of transcriptional and protein regulators. Cytokines not only initiate the differentiation of CD4 Th cells into subsets but also influence the identity, plasticity and effector function of a T cell. Of the subsets, Th17 cells, named for producing interleukin 17 (IL-17) as their signature cytokine, secrete a cohort of other cytokines, including IL-22, IL-21, IL-10, IL-9, IFNγ, and GM-CSF. In recent years, Th17 cells have emerged as key players in host defense against both extracellular pathogens and fungal infections, but they have also been implicated as one of the main drivers in the pathogenesis of autoimmunity, likely mediated in part by the cytokines that they produce. Advances in high throughput genomic sequencing have revealed unexpected heterogeneity in Th17 cells and, as a consequence, may have tremendous impact on our understanding of their functional diversity. The assortment in gene expression may also identify different functional states of Th17 cells. This review aims to understand the interplay between the cytokine regulators that drive Th17 cell differentiation and functional states in Th17 cells.
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Affiliation(s)
- Youjin Lee
- Evergrande Center for Immumnologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, 02115, USA
| | - Vijay Kuchroo
- Evergrande Center for Immumnologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, 02115, USA; Genomic and Biotechnology Section, Faculty of Science, King Abdulaziz University, Jeddah, 21589, Saudi Arabia
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49
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Inman RD. Reactive arthritis. Rheumatology (Oxford) 2015. [DOI: 10.1016/b978-0-323-09138-1.00112-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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50
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Yu RY, Brazaitis J, Gallagher G. The human IL-23 receptor rs11209026 A allele promotes the expression of a soluble IL-23R-encoding mRNA species. THE JOURNAL OF IMMUNOLOGY 2014; 194:1062-8. [PMID: 25552541 DOI: 10.4049/jimmunol.1401850] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The human IL23R gene single nucleotide polymorphism rs11209026 A allele confers protection against inflammatory diseases. However, although this difference has been associated with reductions in IL-23-induced IL-17A production and STAT3 phosphorylation, the molecular mechanism underlying these changes remains undefined. Th17 cell maturation depends on IL-23 signaling. Multiple splice forms of the human IL23R transcript exist, and one, Δ9, encodes a soluble form of the receptor. In this study, we asked whether this protective allele was associated with mRNA splicing. Using mini-gene constructs and competitive oligonucleotide binding, we showed that the A allele alters IL-23R α-chain mRNA splicing and favors exon 9 skipping by reducing the binding of the splicing enhancer SF2. This enhances expression of the Δ9 mRNA and consequently diminishes IL-23 signaling. Thus, the presence of the A allele increases expression of the soluble form of IL23R mRNA (which then functions as a decoy receptor) and lowers the ability to develop a Th17 phenotype upon IL-23 stimulation. We further showed that antisense oligonucleotides targeting the SF2 binding site could efficiently induce exon 9 skipping in the presence of the G allele, and thereby replicate the effect of the A allele. Antisense oligonucleotide treatment caused dose-responsive induction of the IL23RΔ9 mRNA and interfered with in vitro differentiation of human Th17 cells, reducing their expression of the signature Th17 cytokines IL-17A and IL-17F. This may represent a novel approach to therapy of Th17-mediated diseases by elevating soluble IL-23R while simultaneously reducing the remaining cell surface receptor density.
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Affiliation(s)
- Raymond Y Yu
- Genetic Immunology Laboratory, HUMIGEN, The Institute for Genetic Immunology, Genesis Biotechnology Group, Hamilton, NJ 08690
| | - Jonathan Brazaitis
- Genetic Immunology Laboratory, HUMIGEN, The Institute for Genetic Immunology, Genesis Biotechnology Group, Hamilton, NJ 08690
| | - Grant Gallagher
- Genetic Immunology Laboratory, HUMIGEN, The Institute for Genetic Immunology, Genesis Biotechnology Group, Hamilton, NJ 08690
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