Role of the C8orf13-BLK region in biopsy-proven giant cell arteritis

Torres, Orlando; Palomino-Morales, Rogelio; Vázquez-Rodríguez, Tomás R.; Castañeda, Santos; Morado, Inmaculada C.; Miranda‐Filloy, José A.; Ortego-Centeno, Norbérto; Fernández-Gutiérrez, Benjamín; Martín, Javier

doi:10.1016/j.humimm.2010.02.016

Cited by 8 publications

(7 citation statements)

References 38 publications

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“…Interestingly, HVCN1-deficient mice exhibit autoimmune phenotypes including splenomegaly, nephritis, and autoantibody production (38). Polymorphisms of C8orf13-BLK are associated with autoimmune diseases (39)(40)(41). Altogether, these data suggest that the activation of AtM through TLR9 signaling could lead to a Th1 pro-inflammatory state, which could facilitate tolerance breakage in HCV infection.…”

Section: Stimulated Hcv-cv Atm Harbor a Specific Tnfα-centered Transcriptional Profilementioning

confidence: 95%

TLR9 signalling in HCV-associated atypical memory B cells triggers Th1 and rheumatoid factor autoantibody responses

Comarmond

Lorin

Marques

et al. 2019

Journal of Hepatology

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Background & Aims: Hepatitis C virus (HCV) infection contributes to the development of autoimmune disorders such as cryoglobulinemia vasculitis (CV). However, it remains unclear why only some HCV-infected individuals develop CV. HCV-CV is characterized by expansions of anergic CD19 + CD27 + CD21 low/atypical memory B cells (AtM). Here, we report the mechanisms by which AtM participate to HCV-associated autoimmunity. Methods: Phenotype and function of peripheral AtM were studied by multi-color flow cytometry and co-culture assays with effector T cells and regulatory T cells in twenty chronically HCV-CV patients, 10 chronically HCV-infected patients without CV and 8 healthy donors. We performed gene expression profile analysis of AtM stimulated or not by TLR9. Immunoglobulin gene repertoire and antibody reactivity profiles of AtM-expressing IgM antibodies were analyzed following single B cell FACS sorting and expression-cloning of monoclonal antibodies. Results: We show Tbet + CD11c + CD27 + CD21 -AtM B-cell expansions in HCV-CV patients as compared to HCV controls without CV. TLR9 activation of AtM induces a specific transcriptional signature centered on TNFα overexpression, and an enhanced secretion of TNFα and rheumatoid factor-type IgMs in HCV-CV patients. AtM stimulated through TLR9 promote type 1 effector T-cell activation and reduce the proliferation of CD4 + CD25 hi CD127 -/low FoxP3 + regulatory T cells. AtM expansions display intraclonal diversity with immunoglogulin features of antigen-driven maturation. AtM-derived IgM monoclonal antibodies do not react against ubiquitous autoantigens or HCV antigens including NS3 and E2 proteins. Rather, AtMderived antibodies target unique epitopes on the human IgG Fc region and possess rheumatoid factor activity. Conclusion: Our data strongly suggest a central role for TLR9 activation of AtM in driving HCV-CV autoimmunity through rheumatoid factors production and type 1 T-cell response. Highlights  TLR-9 activation of atypical memory B (AtM) cells have central role in breaking tolerance in HCV-CV patients.  TLR9 signaling on AtM, via the secretion of TNFa, have deleterious effects by stimulating proliferation and activation of effector Th1 cells  Rheumatoid factors molecules produced by AtM recognized distinct IgG-Fc epitopes and do not cross-reacted against HCV proteins, confirming that molecular mimicry between HCV and human IgG proteins is not the trigger of HCV-associated autoimmunity.

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Section: Stimulated Hcv-cv Atm Harbor a Specific Tnfα-centered Transcriptional Profilementioning

confidence: 95%

TLR9 signalling in HCV-associated atypical memory B cells triggers Th1 and rheumatoid factor autoantibody responses

Comarmond

Lorin

Marques

et al. 2019

Journal of Hepatology

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“…1). [11,12,16,17,19,20,23–28,31–51] The specific characteristics and quality scores are provided in Table 1. All of the studies were case–control studies.…”

Section: Resultsmentioning

confidence: 99%

“…All of the studies were case–control studies. Of these 33 articles, 4 articles reported on different countries, [11,17,27,34] 2 articles reported on different ethnicities, [31,42] 4 articles reported on different types of systemic scleroses or idiopathic inflammatory myopathies, [24,27,35,44] and 13 articles reported on different sites of BLK polymorphisms [11,20,23–25,27,28,33,36,38,41–43] and were treated as independent studies. Therefore, we divide the 33 articles into 66 specific case–control studies of BLK (68,874 cases and 90,684 controls).…”

Section: Resultsmentioning

confidence: 99%

“…[17] Many randomized controlled trials (RCTs) have explored the relationship between BLK rs13277113 and other autoimmune diseases, such as polymyositis (PM), [18] dermatomyositis (DM), [18] multifocal motor neuropathy (MMN), [19] and giant cell arteritis (GCA). [20] Several studies have also shown that BLK rs2736340 was associated with SLE, [21] and Kawasaki disease, [22] and is possibly involved in RA, [23] PM, [24] DM, [24] GCA, [20] primary Sjögren syndrome (PSS), [25] primary antiphospholipid syndrome (PAS), [26] and SSc. [27] Until now, studies found that BLK rs4840568 was merely related to SLE.…”

Section: Introductionmentioning

confidence: 99%

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B-cell lymphocyte kinase polymorphisms rs13277113, rs2736340, and rs4840568 and risk of autoimmune diseases

Zeng

Fang²,

Weng³

et al. 2017

Medicine

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“…Some other reports showed marginally significant associations of polymorphism either with susceptibility to visual ischemic manifestations or severe ischemic manifestations within a cohort of GCA patients. The first is exemplified by the minor allele T of CD40 (rs1883832 C/T polymorphism) [103], the latter is true for A allele of rs13277113 (A/G), which is located between C8orf13 and B-lymphoid kinase (BLK) genes [104].…”

Section: Genetic Studies Of Gca and Pmr With Relevance Of Gc Treatmentioning

confidence: 99%

Genetic Predispositions of Glucocorticoid Resistance and Therapeutic Outcomes in Polymyalgia Rheumatica and Giant Cell Arteritis

Smutný

Barvı́k

Veleta

et al. 2019

JCM

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Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are closely related chronic inflammatory diseases. Glucocorticoids (GCs) are first-choice drugs for PMR and GCA, although some patients show poor responsiveness to the initial GC regimen or experience flares after GC tapering. To date, no valid biomarkers have been found to predict which patients are at most risk for developing GC resistance. In this review, we summarize PMR- and GCA-related gene polymorphisms and we associate these gene variants with GC resistance and therapeutic outcomes. A limited number of GC resistance associated-polymorphisms have been published so far, mostly related to HLA-DRB1*04 allele. Other genes such ICAM-1, TLR4 and 9, VEGF, and INFG may play a role, although discrepancies are often found among different populations. We conclude that more studies are required to identify reliable biomarkers of GC resistance. Such biomarkers could help distinguish non-responders from responders to GC treatment, with concomitant consequences for therapeutic strategy.

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Role of the C8orf13-BLK region in biopsy-proven giant cell arteritis

Cited by 8 publications

References 38 publications

TLR9 signalling in HCV-associated atypical memory B cells triggers Th1 and rheumatoid factor autoantibody responses

TLR9 signalling in HCV-associated atypical memory B cells triggers Th1 and rheumatoid factor autoantibody responses

B-cell lymphocyte kinase polymorphisms rs13277113, rs2736340, and rs4840568 and risk of autoimmune diseases

Genetic Predispositions of Glucocorticoid Resistance and Therapeutic Outcomes in Polymyalgia Rheumatica and Giant Cell Arteritis

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