免疫学
自身抗体
免疫系统
自身免疫
抗体
B细胞
免疫球蛋白A
生物
免疫球蛋白G
医学
作者
Meagan E. Chriswell,Adam R. Lefferts,Michael R. Clay,Alexander Hsu,Jennifer Seifert,Marie L. Feser,Cliff Rims,Michelle S. Bloom,Elizabeth A. Bemis,Sucai Liu,Megan D. Maerz,Daniel N. Frank,M. Kristen Demoruelle,Kevin D. Deane,Eddie A. James,Jane H. Buckner,William H. Robinson,V. Michael Holers,Kristine A. Kuhn
出处
期刊:Science Translational Medicine
[American Association for the Advancement of Science (AAAS)]
日期:2022-10-26
卷期号:14 (668)
被引量:39
标识
DOI:10.1126/scitranslmed.abn5166
摘要
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 Lachnospiraceae and Ruminococcaceae. After generating bacterial isolates within the Lachnospiraceae/Ruminococcaceae genus Subdoligranulum 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 Subdoligranulum isolate 7 but not isolate 1 colonized germ-free mice, it stimulated TH17 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.
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