Association of Defective Regulation of Autoreactive Interleukin‐6–Producing Transitional B Lymphocytes With Disease in Patients With Systemic Sclerosis

Taher, Taher E.; Ong, Voon H; Byström, Jonas; Hillion, Sophie; Simon, Quentin; Denton, Christopher P.; Pers, Jacques‐Olivier; Abraham, David; Mageed, Rizgar A.

doi:10.1002/art.40390

Cited by 42 publications

(56 citation statements)

References 49 publications

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“…In addition, these Th17 cells are likely to promote autoantibody production by B cells at least in a subgroup of patients. 89 This is supported by high levels of IL-6 and BAFF in SSc. 59…”

Section: To the Pathogenesis Of Systemic Sclerosis (Ssc)?mentioning

confidence: 89%

“…IL‐17 levels are elevated in the blood of SSc patients compared with healthy individuals . Furthermore, several pro‐inflammatory cytokines including IL‐6 that promote Th17 cell differentiation are produced at high levels by immune cells including B cells . The indirect effects of IL‐17 on fibrosis are likely to be mediated by the effect of IL‐6 on fibroblast proliferation and increased production of pro‐fibrotic factors.…”

Section: Do Th17 Cells Contribute To the Pathogenesis Of Systemic Sclmentioning

confidence: 99%

“…However, in contrast to psoriasis, in SSc patients, these cells react with nuclear antigens rather than keratinocyte‐derived proteins. In addition, these Th17 cells are likely to promote autoantibody production by B cells at least in a subgroup of patients . This is supported by high levels of IL‐6 and BAFF in SSc …”

Section: Do Th17 Cells Contribute To the Pathogenesis Of Systemic Sclmentioning

confidence: 99%

“…88 Furthermore, several pro-inflammatory cytokines including IL-6 that promote Th17 cell differentiation are produced at high levels by immune cells including B cells. 89 The indirect effects of IL-17 on fibrosis are likely to be mediated by the effect of IL-6 on fibroblast proliferation and increased production of pro-fibrotic factors. Thus, in experimental models of SSc, IL-17 stimulates fibroblast proliferation and increases key pro-fibrotic mediators such as TGFβ, connective tissue growth factor and collagen.…”

Section: To the Pathogenesis Of Systemic Sclerosis (Ssc)?mentioning

confidence: 99%

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Functional and phenotypic heterogeneity of Th17 cells in health and disease

Byström

Clanchy

Taher

et al. 2018

Eur J Clin Investigation

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Background Th17 cells have nonredundant roles in maintaining immunity, particularly at mucosal surfaces. These roles are achieved principally through the production of cytokines and the recruitment of other immune cells to maintain the integrity of mucosal barriers and prevent the dissemination of microorganisms. Th17 cells are heterogeneous and exhibit a considerable degree of plasticity. This allows these cells to respond to changing environmental challenges. However, Th17 cells also play pro‐inflammatory roles in chronic autoimmune diseases. The trigger(s) that initiate these Th17 responses in chronic autoimmune diseases remain unclear. Design In this report, we provide an overview of studies involving animal models, patient data, genome wide association studies and clinical trials targeting IL‐17 for treatment of patients to gain a better understanding of the pathogenic roles of Th17 cells play in a range of autoimmune diseases. Results The report sheds light on likely triggers that initiate or perpetuate Th17 responses that promote chronic inflammation and autoimmunity. The divergent effects of tumour necrosis factor alpha blockade on Th17 cells in patients, is explored. Furthermore, we highlight the role of Th17 cells in inducing autoreactive B cells, leading to autoantibody production. Pathogenic bacterial species can change Th17 cell phenotype and responses. These findings provide insights into how Th17 cells could be induced to promoting autoimmune disease pathogenesis. Conclusion This article provides an overview of the distinct roles Th17 cells play in maintaining immunity at mucosal surfaces and in skin mucosa and how their functional flexibility could be linked with chronic inflammation in autoimmune rheumatic diseases.

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“…In addition, these Th17 cells are likely to promote autoantibody production by B cells at least in a subgroup of patients. 89 This is supported by high levels of IL-6 and BAFF in SSc. 59…”

Section: To the Pathogenesis Of Systemic Sclerosis (Ssc)?mentioning

confidence: 89%

Section: Do Th17 Cells Contribute To the Pathogenesis Of Systemic Sclmentioning

confidence: 99%

Section: Do Th17 Cells Contribute To the Pathogenesis Of Systemic Sclmentioning

confidence: 99%

Section: To the Pathogenesis Of Systemic Sclerosis (Ssc)?mentioning

confidence: 99%

See 2 more Smart Citations

Functional and phenotypic heterogeneity of Th17 cells in health and disease

Byström

Clanchy

Taher

et al. 2018

Eur J Clin Investigation

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“…inhibition of β‐catenin signalling, inhibition of tyrosine kinase and B‐cell depletion . The several studies demonstrated that the contribution of B cell and T cell in SSc development and pathogenesis. In addition to the acquired immunological reaction on SSc, the role of the innate immune system in the pathogenesis of SSc is now being increasingly recognized .…”

Section: Introductionmentioning

confidence: 99%

Combination of 5‐aminolevulinic acid and iron prevents skin fibrosis in murine sclerodermatous graft‐versus‐host disease

Liu

Yang

Zhu

et al. 2018

Experimental Dermatology

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Scleroderma or systemic sclerosis (SSc) is a clinically heterogeneous rheumatological autoimmune disease affecting the skin, internal organs and blood vessels. There is at present no effective treatment for this condition. Our study investigated the effects of 5-aminolevulinic acid (5-ALA), which is a precursor of haem synthesis, on graft-vs-host disease (GvHD)-induced SSc murine model. Lymphocytes were intravenously injected from donor mice (B10.D2) into recipient BALB/c mice (recombination-activating gene 2 (Rag-2)-null mice) deficient in mature T and B cells to induce sclerodermatous GvHD (scl-GvHD). To investigate the effect of 5-ALA on scl-GvHD, combination of 5-ALA and sodium ferrous citrate (SFC) was orally administered to the recipient mice for 9 weeks. 5-ALA/SFC treatment significantly reduced progressive inflammation and fibrosis in the skin and ears. Furthermore, 5-ALA/SFC suppressed mRNA expression of transforming growth factor-β, type I collagen and inflammatory cytokines. These results indicate that the 5-ALA/SFC combination treatment has a protective effect against tissue fibrosis and inflammation in a murine scl-GvHD-induced skin and ear inflammation and fibrosis. Furthermore, the efficacy of 5-ALA/SFC suggests important implications of HO-1 protective activity in autoimmune diseases, and therefore, 5-ALA/SFC may have promising clinical applications. These findings suggested that the 5-ALA/SFC treatment may be the potential strategies for SSc.

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A Proinflammatory Cytokine Network Profile in Th1/Type 1 Effector B Cells Delineates a Common Group of Patients in Four Systemic Autoimmune Diseases

Simon

Grasseau

Boudigou

et al. 2021

Arthritis & Rheumatology

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Objective. The effector T cell and B cell cytokine networks have been implicated in the pathogenesis of systemic autoimmune diseases, but the association of these cytokine networks with the heterogeneity of clinical manifestations and immune profiles has not been carefully examined. This study was undertaken to examine whether cytokine profiles can delineate distinct groups of patients in 4 systemic autoimmune diseases (systemic lupus erythematosus, Sjögren's syndrome, rheumatoid arthritis, and systemic sclerosis).Methods. A total of 179 patients and 48 healthy volunteers were enrolled in the multicenter cross-sectional PRECISE Systemic Autoimmune Diseases (PRECISESADS) study. Multi-low-dimensional omics data (cytokines, autoantibodies, circulating immune cells) were examined. Coculture experiments were performed to test the impact of the cytokine microenvironment on T cell/B cell cross-talk.Results. A proinflammatory cytokine profile defined by high levels of CXCL10, interleukin-6 (IL-6), IL-2, and tumor necrosis factor characterized a distinct group of patients in the 4 systemic autoimmune diseases. In each disease, this proinflammatory cluster was associated with a specific circulating immune cell signature, more severe disease, and higher levels of autoantibodies, suggesting an uncontrolled proinflammatory Th1 immune response. We observed in vitro that B cells reinforce Th1 differentiation and naive T cell proliferation, leading to the induction of type 1 effector B cells and IgG production. This process was associated with an increase in CXCL10, IL-6, IL-2, and interferon-γ production.Conclusion. This composite analysis brings new insights into human B cell functional heterogeneity based on T cell/B cell cross-talk, and proposes a better stratification of patients with systemic autoimmune diseases, suggesting that combined biomarkers would be of great value for the design of personalized treatments.

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Association of Defective Regulation of Autoreactive Interleukin‐6–Producing Transitional B Lymphocytes With Disease in Patients With Systemic Sclerosis

Abstract: Our findings provide new insights into mechanisms underlying defective B lymphocyte responses in patients with SSc and their contribution to disease.

Cited by 42 publications

References 49 publications

Functional and phenotypic heterogeneity of Th17 cells in health and disease

Functional and phenotypic heterogeneity of Th17 cells in health and disease

Combination of 5‐aminolevulinic acid and iron prevents skin fibrosis in murine sclerodermatous graft‐versus‐host disease

A Proinflammatory Cytokine Network Profile in Th1/Type 1 Effector B Cells Delineates a Common Group of Patients in Four Systemic Autoimmune Diseases

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