IL‐17 Upregulates Regulator of G‐protein Signaling (Rgs)13 and Rgs16 for the Formation of Autoreactive Germinal Centers in BXD2 Mice

Abstract

The lupus and arthritis prone BXD2 mice develop a large number of spontaneous germinal centers (GCs) in the spleens and dramatically elevated sera levels of autoantibodies. Sera from BXD2 mice exhibited significantly elevated IL‐17, but not IFN‐γ or IL‐4, compared to B6 mice. Under the optimal TH‐17 polarization condition, 9% and 20% of purified CD4 T cells from B6 and BXD2 mice were polarized into TH‐17 cells, respectively, in vitro. Supplementation of IL‐6 and IL‐23 was not required for the development of TH‐17 CD4+ T cells from the unfractionated spleen cells from the BXD2 mice but was required for their development from the spleens of B6 mice. Quantitative real‐time PCR analysis indicated that purified CD4 T cells and purified B cells from BXD2 mice express high levels of Il17 and Il17r, respectively. In situ confocal fluorescent microscopy showed that TH‐17 CD4 T cells and IL‐17R+ IgM+ B cells were localized preferentially in the PNA+ GC region in the spleens of the BXD2 mice. Treatment of BXD2 mice with anti‐IL‐17 neutralization antibody (250 μg/mouse q.3 days × 4) resulted in dissipation of B cells from CD4 T cells, decreased percentage of PNA+Fas+ GC B cells, and decreased number of B cells that produce IgG antibodies against histone, BiP, and DNA. IL‐17 upregulated the expression of Rgs13 and Rgs16 and suppressed the CXCL12‐induced migration response to both CD4 and B cells. Our results demonstrate a novel pathogenic mechanism of IL‐17 independently of its chronic inflammatory effects in autoimmune disease. IL‐17 induced spontaneous formation of GCs provided the optimal microenvironment for the production of pathogenic autoantibodies. This work is supported by Arthritis Foundation, VAMC Merit Review, ACR, and Daiichi‐Sankyo Co. Ltd.