Pathogenetic Aspects of Systemic Sclerosis: A View Through the Prism of B Cells

Μελισσαρόπουλος, Κωνσταντίνος; Iliopoulos, George; Sakkas, Lazaros I.; Daoussis, Dimitrios

doi:10.3389/fimmu.2022.925741

Cited by 86 publications

(15 citation statements)

References 116 publications

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“…The mechanisms underlying the development of these distinct antibodies in SSc are widely unclear, but accumulating data suggest a specific genetic background in combination with environmental and stochastic factors, as well as properties of the antigens themselves are key in antigen selection and antibody production ( 6 – 9 ). Moreover, the pathogenetic role of these autoantibodies in SSc is still a subject of ongoing research ( 10 ). Newer data suggest that antibodies could be pathogenic or at least contribute to the perennation of the disease ( 8 , 11 , 12 ).…”

Section: Introductionmentioning

confidence: 99%

Comprehensive autoantibody profiles in systemic sclerosis: Clinical cluster analysis

Höppner

Tabeling²,

Casteleyn³

et al. 2023

Front. Immunol.

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BackgroundSystemic sclerosis (SSc) belongs to the group of connective tissue diseases and is associated with the occurrence of disease-specific autoantibodies. Although it is still controversial whether these antibodies contribute to pathogenesis, there are new insights into the development of these specific antibodies and their possible pathophysiological properties. Interestingly, they are associated with specific clinical manifestations, but for some rarer antibodies this association is not fully clarified. The aim of this study is a comprehensive analysis of the serum autoantibody status in patients with SSc followed by correlation analyses of autoantibodies with the clinical course of the disease.MethodsSerum from SSc patients was analyzed using a line blot (EUROLINE, EUROIMMUN AG) for SSc-related autoantibodies. Autoantibodies to centromere, Topo-1, antimitochondrial antibodies (AMA) M2 subunit, angiotensin II type 1 receptors (AT1R) and endothelin-1 type-A-receptors (ETAR) were also determined by ELISA. We formed immunological clusters and used principal components analysis (PCA) to assign specific clinical characteristics to these clusters.ResultsA total of 372 SSc patients were included. 95.3% of the patients were antinuclear antibody positive and in 333 patients at least one SSc specific antibody could be detected. Four immunological clusters could be found by PCA. Centromere, Topo-1 and RP3 all formed own clusters, which are associated with distinct clinical phenotypes. We found that patients with an inverted phenotype, such as limited cutaneous SSc patients within the Topo-1 cluster show an increased risk for interstital lung disease compared to ACA positive patients. Anti-AT1R and anti-ETAR autoantibodies were measured in 176 SSc patients; no association with SSc disease manifestation was found. SSc patients with AMA-M2 antibodies showed an increased risk of cardiovascular events.ConclusionIn our in large cluster analysis, which included an extended autoantibody profile, we were able to show that serologic status of SSc patients provides important clues to disease manifestation, co-morbidities and complications. Line blot was a reliable technique to detect autoantibodies in SSc and detected rarer autoantibodies in 42% of our patients.

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Section: Introductionmentioning

confidence: 99%

Comprehensive autoantibody profiles in systemic sclerosis: Clinical cluster analysis

Höppner

Tabeling²,

Casteleyn³

et al. 2023

Front. Immunol.

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“…Despite evidence of improved overall survival and treatment options, obtaining efficacious disease-modifying treatment for SSc is a serious clinical challenge. Therefore, identification of promising therapeutic agents for SSc is needed urgently [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Baicalein alleviates fibrosis and inflammation in systemic sclerosis by regulating B-cell abnormalities

Peng

et al. 2023

BMC Complement Med Ther

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Background Systemic sclerosis (SSc; also known as “scleroderma”) is an autoimmune disorder characterized by extensive fibrosis, vascular changes, and immunologic dysregulation. Baicalein (phenolic flavonoid derived from Scutellaria baicalensis Georgi) has been used to treat the pathological processes of various fibrotic and inflammatory diseases. In this study, we investigated the effect of baicalein on the major pathologic characteristics of SSc: fibrosis, B-cell abnormalities, and inflammation. Methods The effect of baicalein on collagen accumulation and expression of fibrogenic markers in human dermal fibroblasts were analyzed. SSc mice were produced by injecting bleomycin and treated with baicalein (25, 50, or 100 mg/kg). The antifibrotic features of baicalein and its mechanisms were investigated by histologic examination, hydroxyproline assay, enzyme-linked immunosorbent assay, western blotting and flow cytometry. Results Baicalein (5–120 μM) significantly inhibited the accumulation of the extracellular matrix and fibroblast activation in transforming growth factor (TGF)-β1- and platelet derived growth factor (PDGF)-induced human dermal fibroblasts, as evidenced by abrogated deposition of total collagen, decreased secretion of soluble collagen, reduced collagen contraction capability and downregulation of various fibrogenesis molecules. In a bleomycin-induced model of dermal fibrosis in mice, baicalein (25–100 mg/kg) restored dermal architecture, ameliorated inflammatory infiltrates, and attenuated dermal thickness and collagen accumulation in a dose-dependent manner. According to flow cytometry, baicalein reduced the proportion of B cells (B220+ lymphocytes) and increased the proportion of memory B cells (B220+CD27+ lymphocytes) in the spleens of bleomycin-induced mice. Baicalein treatment potently attenuated serum levels of cytokines (interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-17A, tumor necrosis factor-α), chemokines (monocyte chemoattractant protein-1, macrophage inflammatory protein-1 beta) and autoantibodies (anti-scleroderma 70 (Scl-70), anti-polymyositis-scleroderma (PM-Scl), anti-centromeres, anti-double stranded DNA (dsDNA). In addition, baicalein treatment can significantly inhibit the activation of TGF-β1 signaling in dermal fibroblasts and bleomycin-induce mice of SSc, evidenced by reducing the expression of TGF-β1 and IL-11, as well as inhibiting both small mother against decapentaplegic homolog 3 (SMAD3) and extracellular signal-related kinase (ERK) activation. Conclusions These findings suggest that baicalein has therapeutic potential against SSc, exerting modulating B-cell abnormalities, anti-inflammatory effects, and antifibrosis.

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“…Apart from IBD, fibrosis is a common complication of various diseases, such as Idiopathic Pulmonary Fibrosis (IPF) ( 6 ), Chronic Kidney Disease (CKD) ( 7 ), Systemic Sclerosis (SSc) ( 8 ) and Chronic Liver Diseases (CLD) ( 9 ) and in all cases, a successful anti-fibrotic treatment is yet to be found. Regarding intestinal fibrosis, it is most commonly symptomatic in CD rather than in UC, and in some cases, its occurrence may lead to intestinal strictures, which are amenable only to excision ( 2 ).…”

Section: Introductionmentioning

confidence: 99%

Co-expression of fibrotic genes in inflammatory bowel disease; A localized event?

Dovrolis

Filidou²,

Tarapatzi³

et al. 2022

Front. Immunol.

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IntroductionExtracellular matrix turnover, a ubiquitous dynamic biological process, can be diverted to fibrosis. The latter can affect the intestine as a serious complication of Inflammatory Bowel Diseases (IBD) and is resistant to current pharmacological interventions. It embosses the need for out-of-the-box approaches to identify and target molecular mechanisms of fibrosis.Methods and resultsIn this study, a novel mRNA sequencing dataset of 22 pairs of intestinal biopsies from the terminal ileum (TI) and the sigmoid of 7 patients with Crohn’s disease, 6 with ulcerative colitis and 9 control individuals (CI) served as a validation cohort of a core fibrotic transcriptomic signature (FIBSig), This signature, which was identified in publicly available data (839 samples from patients and healthy individuals) of 5 fibrotic disorders affecting different organs (GI tract, lung, skin, liver, kidney), encompasses 241 genes and the functional pathways which derive from their interactome. These genes were used in further bioinformatics co-expression analyses to elucidate the site-specific molecular background of intestinal fibrosis highlighting their involvement, particularly in the terminal ileum. We also confirmed different transcriptomic profiles of the sigmoid and terminal ileum in our validation cohort. Combining the results of these analyses we highlight 21 core hub genes within a larger single co-expression module, highly enriched in the terminal ileum of CD patients. Further pathway analysis revealed known and novel inflammation-regulated, fibrogenic pathways operating in the TI, such as IL-13 signaling and pyroptosis, respectively.DiscussionThese findings provide a rationale for the increased incidence of fibrosis at the terminal ileum of CD patients and highlight operating pathways in intestinal fibrosis for future evaluation with mechanistic and translational studies.

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Pathogenetic Aspects of Systemic Sclerosis: A View Through the Prism of B Cells

Cited by 86 publications

References 116 publications

Comprehensive autoantibody profiles in systemic sclerosis: Clinical cluster analysis

Comprehensive autoantibody profiles in systemic sclerosis: Clinical cluster analysis

Baicalein alleviates fibrosis and inflammation in systemic sclerosis by regulating B-cell abnormalities

Co-expression of fibrotic genes in inflammatory bowel disease; A localized event?

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