Development of Collagen II (CII)‐induced Arthritis Was Associated with High AID and IL‐17 Expression in BXD2 Mice

Abstract

BXD2 mice develop spontaneous arthritis associated with increased activation‐induced cytidine deaminase (AID), development of pathogenic autoantibodies, and increased TH‐17 T cells. CII arthritis (CIA) was induced to determine the relative contribution of autoantibodies and IL‐17 to the development of arthritis. BXD2 mice with a dominant negative AID transgene (BXD2 AID‐DN Tg) were produced. Autoantibodies for CII and specific triple helical CII epitopes (U1, J1, C1) were determined by isotype‐specific ELISA. Expression of Il17 and Il17r mRNA was determined by RT‐PCR and immunohistochemical staining. Despite the heritage of a CIA‐resistant H2b MHC haplotype, BXD2 mice developed accelerated and more severe CIA compared to DBA/1 mice. Both BXD2 and DBA/1 mice developed significantly higher levels of antibodies to C1, U1, and CII compared to B6 mice (p<0.01). BXD2 mice had an increased T‐ and B‐cell activation after CII injection, and T cells from BXD2 mice exhibited a significantly elevated IL‐17 production, compared to DBA/1 and B6 mice. Anti‐CII antibodies were associated with increased TH‐17 in the spleens and increased IL‐17R on GC B cells in BXD2 mice. The presence of AID‐DN Tg significantly suppressed the development of these autoantibodies. Our results suggest that IL‐17 acting on IL‐17R+ B cells in the spleens may be a novel mechanism for induction of AID leading to the development of CII‐specific antibodies and acceleration of CII arthritis. This work is supported by an NIH T32 Award, VAMC Merit Review Award, American College of Rheumatology, Arthritis Foundation, and Daiichi‐Sankyo Co., Ltd.