Small Molecule Inhibitor suppresses Tfh cell development in germinal center and reduces the severity of inflammation in a collagen-induced arthritis mouse model

Abstract

Abstract Background Rheumatoidarthritis (RA) is a autoimmune disease characterized by the accumulation of inflammatory cells in the joints, leading to hyperproliferation of synovial cells and tissue destruction. Our previous data showed autoreactive B cells could be induced by T follicular helper (Tfh) cells to undergo clonal expansion with in germinal center (GC), and ultimately differentiate into autoantibody producing plasma cells in RA. Here, we further investigated the role of Tfh cells in RA pathogenesis and the therapeutic effect of a small molecule inhibitor targeting Tfh cells (SMI-Tfh) in collagen-induced arthritis (CIA)mouse model. Methods CIA model was induced by immunization with chicken type II collagen in DBA/1 mice. Disease progression was monitored daily by the paw swollenness. Following the onset of clinical arthritis, mice were treated with SMI-Tfh. At the end of the study, blood, spleen, and affected paws were collected. Pathological changes were examined by H&E staining of tissue sections. Immunofluorescent histochemistry (IHC) staining and flow cytometry analysis were used to identify Tfh cells (CD4+CXCR5+ICOS+) in spleen and blood. Results Arthritis onset was developed at day 21 and with peak on day 42 after initial immunization. Destruction of articular cartilage, increased inflammatory cells and Tfh infiltration were observed in the synovial tissue. Mice treated with SMI-Tfh had significantly reduced Tfh cells in GC of the spleen (p<0.01) and less arthritis feature (p<0.05) in CIA mouse. Conclusion SMI-Tfh selectively inhibits GC-Tfh cells in the spleen and abrogates the severity of inflammatory arthritis. It may serve as a novel therapy by interfering with autoreactive GC-Tfh cells development in RA.