Division of Rheumatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Sci Transl Med. 2022 Oct 26;14(668):eabn5166. doi: 10.1126/scitranslmed.abn5166.
The mucosal origins hypothesis of rheumatoid arthritis (RA) proposes a central role for mucosal immune responses in the initiation or perpetuation of the systemic autoimmunity that occurs with disease. However, the connection between the mucosa and systemic autoimmunity in RA remains unclear. Using dual immunoglobulin A (IgA) and IgG family plasmablast-derived monoclonal autoantibodies obtained from peripheral blood of individuals at risk for RA, we identified cross-reactivity between RA-relevant autoantigens and bacterial taxa in the closely related families and . After generating bacterial isolates within the genus from the feces of an individual, we confirmed monoclonal antibody binding and CD4 T cell activation in individuals with RA compared to control individuals. In addition, when isolate 7 but not isolate 1 colonized germ-free mice, it stimulated T17 cell expansion, serum RA-relevant IgG autoantibodies, and joint swelling reminiscent of early RA, with histopathology characterized by antibody deposition and complement activation. Systemic immune responses were likely due to mucosal invasion along with the generation of colon-isolated lymphoid follicles driving increased fecal and serum IgA by isolate 7, because B and CD4 T cell depletion not only halted intestinal immune responses but also eliminated detectable clinical disease. In aggregate, these findings demonstrate a mechanism of RA pathogenesis through which a specific intestinal strain of bacteria can drive systemic autoantibody generation and joint-centered antibody deposition and immune activation.
类风湿关节炎（RA）的黏膜起源假说提出，黏膜免疫反应在疾病发生时全身自身免疫的启动或持续中起核心作用。然而，RA 中黏膜与全身自身免疫之间的联系仍不清楚。我们使用源自 RA 风险个体外周血的双免疫球蛋白 A（IgA）和 IgG 家族浆母细胞衍生的单克隆自身抗体，鉴定出 RA 相关自身抗原与密切相关的 和 家族中的细菌分类群之间的交叉反应性。在从个体粪便中生成 属内的细菌分离物后，我们在 RA 患者中证实了单克隆抗体结合和 CD4 T 细胞激活，而在对照个体中则没有。此外，当分离物 7 而不是分离物 1 定植于无菌小鼠时，它刺激了 T17 细胞的扩增、血清 RA 相关 IgG 自身抗体以及类似于早期 RA 的关节肿胀，其组织病理学特征为抗体沉积和补体激活。全身性免疫反应可能是由于黏膜入侵以及定植的淋巴滤泡生成导致分离物 7 增加粪便和血清 IgA，因为 B 和 CD4 T 细胞耗竭不仅阻止了肠道免疫反应，而且消除了可检测的临床疾病。总的来说，这些发现表明了 RA 发病机制的一种机制，即特定的肠道细菌株可以驱动全身性自身抗体的产生以及关节中心的抗体沉积和免疫激活。
