Dysregulated B cell function and disease pathogenesis in systemic sclerosis.
Dysregulated B cell function and disease pathogenesis in systemic sclerosis.
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DOI：
10.3389/fimmu.2022.999008
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发表时间：
2022
影响因子：
7.3
通讯作者：
Ong, Voon H.
中科院分区：
文献类型：
--
作者：
Beesley, Claire F.;Goldman, Nina R.;Taher, Taher E.;Denton, Christopher P.;Abraham, David J.;Mageed, Rizgar A.;Ong, Voon H.
系统性硬化症（SSc）是一种复杂的免疫介导的风湿性疾病，其特征是皮肤和内脏器官中过量的细胞外基质沉积。B细胞浸润到病变部位如肺泡上皮和小血管中，伴随着确定的临床相关自身抗体的产生，表明B细胞在SSc的发病和发展中起着重要作用。这得到了B细胞和成纤维细胞共培养实验的支持，该实验揭示了B细胞直接增强成纤维细胞中胶原和细胞外基质的合成。此外，来自SSc患者的B细胞产生大量促纤维化细胞因子如IL-6和TGF-β，其与其他免疫和内皮细胞相互作用，促进促纤维化环。此外，与健康供体相比，SSc患者的总B细胞计数增加，并且在幼稚、记忆、过渡和调节B细胞区室的含量中可以发现特定差异。来自SSc患者的B细胞还显示活化标志物如CD 19的差异表达，其可形成与其它免疫介质如T滤泡辅助细胞和树突细胞的相互作用。B细胞在SSc中的关键作用进一步得到利妥昔单抗消除B细胞在一些患者中的治疗益处的支持。还值得注意的是，B细胞信号传导在SSc患者中受损，并且这可能支持B细胞中诱导耐受性的失败，如硬皮病的鼠模型中所示。
Systemic sclerosis (SSc) is a complex, immune-mediated rheumatic disease characterised by excessive extracellular matrix deposition in the skin and internal organs. B cell infiltration into lesional sites such as the alveolar interstitium and small blood vessels, alongside the production of defined clinically relevant autoantibodies indicates that B cells play a fundamental role in the pathogenesis and development of SSc. This is supported by B cell and fibroblast coculture experiments revealing that B cells directly enhance collagen and extracellular matrix synthesis in fibroblasts. In addition, B cells from SSc patients produce large amounts of profibrotic cytokines such as IL-6 and TGF-β, which interact with other immune and endothelial cells, promoting the profibrotic loop. Furthermore, total B cell counts are increased in SSc patients compared with healthy donors and specific differences can be found in the content of naïve, memory, transitional and regulatory B cell compartments. B cells from SSc patients also show differential expression of activation markers such as CD19 which may shape interactions with other immune mediators such as T follicular helper cells and dendritic cells. The key role of B cells in SSc is further supported by the therapeutic benefit of B cell depletion with rituximab in some patients. It is notable also that B cell signaling is impaired in SSc patients, and this could underpin the failure to induce tolerance in B cells as has been shown in murine models of scleroderma.
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