Inhibition of Activation‐Induced Cytidine Deaminase (AID) Preserved Spontaneous Germinal Centers but Suppressed Autoimmune Disease in BXD2 Mice

Abstract

Increased expression of AID in B cells as a result of extensive spontaneous germinal centers (GCs) has been found to be associated with the development of arthrogenic and nephrogenic autoantibodies in autoimmune BXD2 mice. To determine if inhibition of AID can prevent the generation of pathogenic autoantibodiese, a transgenic (Tg) BXD2 mouse strain expressing a dominant negative (DN) form of AID cloned downstream of the chicken albumin promoter was generated by direct injection of BXD2 single cell embryos. This AID‐DN gene contains the H56R/E58Q mutation in the AID catalytic domain and the S38A mutation at the phosphorylation site that is essential for interaction of AID with replication protein A. At 6–8‐month of age, there was a significant decrease in the IgG isotype of autoantibodies and autoantibody producing B cells against histone, DNA, and BiP in BXD2 AID‐DN Tg+ mice compared to wild‐type (WT) BXD2 mice. At this age, BXD2 AID‐DN Tg+ mice were protected from development of arthritis. There was also decreased IgG2b and IgG2c containing C1q‐circulating immune complexes and decreased IgG deposition in glomeruli in BXD2 AID‐DN Tg+ mice, compared to WT BXD2 mice. The generation of spontaneous GCs in the spleens of BXD2 AID‐DN Tg+ mice, however, remained comparable to that found in the spleens of WT BXD2 mice. Our results suggest that over‐expression and high activity of AID is a down‐stream product of spontaneous autoreactive GCs that plays an essential role in the generation of pathogenic autoantibodies and development of autoimmune disease in BXD2 mice. This work is supported by Arthritis Foundation, VA Merit Review, American College of Rheumatology, and Daiichi‐Sankyo Co., Ltd.