类风湿滑膜关节中的异位淋巴结构(ELSs)维持对局部表达的自身抗原的自身反应性。我们最近鉴定了重组单克隆抗体(RA-rmAb),局部分化的类风湿性关节炎(RA)滑膜B细胞,特异性识别成纤维细胞样滑膜细胞(FLSs)。这里,我们旨在鉴定FLS衍生的自身抗原促进局部自身免疫的特异性,以及抗FLS抗体在促进慢性炎症中的功能作用.与来自FLS提取物的60kDa条带反应的抗FLSRA-rmAb的子集证明了对HSP60的特异性和对其他基质自身抗原的部分交叉反应性(即,钙网蛋白/波形蛋白),但不是瓜氨酸化的纤维蛋白原。抗FLSRA-rmAb,但不是抗中性粒细胞胞外捕获rmAbs,在胶原诱导的关节炎小鼠模型中表现出致病特性。在患者中,抗HSP60抗体在RA与骨关节炎(OA)滑液中优先检测.使用大量RNA-Seq和GeoMx-DSP分析的滑膜HSPD1和CALR基因表达与淋巴髓样RA病理类型密切相关,在ELS周围主要观察到HSP60蛋白表达。此外,我们观察到,在使用利妥昔单抗清除B细胞后,滑膜HSP60基因表达显著降低,这与治疗反应密切相关.总的来说,我们报告说,滑膜基质来源的自身抗原是致病性自身抗体靶向的,并且与特定的RA病理类型相关。对患者分层具有潜在价值,并可作为B细胞消耗疗法反应的预测因子。
Ectopic lymphoid structures (ELSs) in the rheumatoid synovial joints sustain autoreactivity against locally expressed
autoantigens. We recently identified recombinant monoclonal antibodies (RA-rmAbs) derived from single, locally differentiated rheumatoid arthritis (RA) synovial B cells, which specifically recognize fibroblast-like synoviocytes (FLSs). Here, we aimed to identify the specificity of FLS-derived
autoantigens fueling local autoimmunity and the functional role of anti-FLS antibodies in promoting chronic inflammation. A subset of anti-FLS RA-rmAbs reacting with a 60 kDa band from FLS extracts demonstrated specificity for HSP60 and partial cross-reactivity to other stromal
autoantigens (i.e., calreticulin/vimentin) but not to citrullinated fibrinogen. Anti-FLS RA-rmAbs, but not anti-neutrophil extracellular traps rmAbs, exhibited pathogenic properties in a mouse model of collagen-induced arthritis. In patients, anti-HSP60 antibodies were preferentially detected in RA versus osteoarthritis (OA) synovial fluid. Synovial HSPD1 and CALR gene expression analyzed using bulk RNA-Seq and GeoMx-DSP closely correlated with the lympho-myeloid RA pathotype, and HSP60 protein expression was predominantly observed around ELS. Moreover, we observed a significant reduction in synovial HSP60 gene expression followed B cell depletion with rituximab that was strongly associated with the treatment response. Overall, we report that synovial stromal-derived
autoantigens are targeted by pathogenic autoantibodies and are associated with specific RA pathotypes, with potential value for patient stratification and as predictors of the response to B cell-depleting therapies.