Local BAFF gene silencing suppresses Th17-cell generation and ameliorates autoimmune arthritis.
Rheumatoid arthritis (RA) is a chronic disease characterized by synovial inflammation and joint damage. Although both T cells and B cells mediate the disease pathogenesis, proinflammatory cytokines are critically involved. The TNF superfamily member B cell-activating factor (BAFF) plays an important role in humoral immunity and in autoimmune diseases, including RA. Here, we show that intra-articular injection of lentivirus expressing shRNA for BAFF gene silencing provides long-term suppression of arthritic development in a collagen-induced arthritis model. Local BAFF gene targeting inhibited proinflammatory cytokine expression, suppressed generation of plasma cells and Th17 cells, and markedly ameliorated joint pathology. Lentivirus targets dendritic cells in the joint tissue and BAFF gene silencing inhibits dendritic cell maturation and their function in driving Th17-cell differentiation in vitro. Moreover, we revealed a previously unrecognized role for BAFF in promoting the expansion of Th17 cells and demonstrated IL-17 as a crucial effector cytokine for BAFF-mediated proinflammatory effects during collagen-induced arthritis development. Taken together, these findings identify BAFF as a valuable gene-silencing target potentially for the effective treatment of RA.
Lai Kwan Lam
Queenie
Q
Department of Pathology, University of Hong Kong, Pokfulam Road, Hong Kong, China.
King Hung Ko
Otis
O
Zheng
Bo-Jian
BJ
Lu
Liwei
L
D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000628:therapy*; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000628:therapy*; D001327:Autoimmune Diseases / Q000276:immunology / Q000628:therapy*; D053264:B-Cell Activating Factor / Q000235:genetics*; D002460:Cell Line; D020868:Gene Silencing; D015316:Genetic Therapy; D006801:Humans; D007165:Immunosuppression Therapy; D020381:Interleukin-17 / Q000276:immunology; D016086:Lentivirus; D051379:Mice; D008810:Mice, Inbred C57BL; D034741:RNA, Small Interfering / Q000235:genetics; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology
D053264:B-Cell Activating Factor; D020381:Interleukin-17; D034741:RNA, Small Interfering; C505720:Tnfsf13b protein, mouse