CXCR5-dependent antigen-specific lymphoid neogenesis in a chronic murine model of rheumatoid arthritis
Rheumatoid arthritis (RA) is an inflammatory autoimmune disease with unknown etiology and only partially defined pathogenesis. We established a novel chronic mouse model of antigen-induced arthritis (AIA), in which development of ectopic lymphoid follicles are efficiently induced within the synovial tissue, a hallmark of human RA. Remarkably, all follicles showed topologically segregated B and CD4- and CD8-positive T cell areas, and the formation of active germinal centers with proliferating lymphocytes. Importantly, for the first time we showed that antigen-specific CD138+ plasma cells are generated in ectopic follicles, and circulating autoantibodies directed against peptide C1 of collagen II are produced, which is also the most immunodominant collagen epitope in human RA. The development and organization of these ectopic structures were severely impaired in CXCR5- and CCR7-deficient mice proving that both chemokine receptors are critical signaling molecules in lymphoid neo-genesis during chronic inflammatory autoimmune diseases. Our results reinforce the link between chronic inflammation and the generation of tertiary lymphoid tissue at extra-nodal sites, which in turn drives local self-antigen-dependent interaction of memory/effector B and T lymphocytes resulting in aberrant chronic autoreactive immune responses.