To determine whether functional suppression of the catalytic domain of activation‐induced cytidine deaminase (AID) can suppress the hyperreactive germinal center (GC) responses in BXD2 mice.

We generated transgenic BXD2 mice expressing a dominant‐negative (DN) form of Aicda at the somatic hypermutation site (BXD2‐Aicda‐DN–transgenic mice). Real‐time quantitative reverse transcriptase–polymerase chain reaction was used to determine the expression of Aicda and DNA damage/repair genes. Enzyme‐linked immunosorbent assay was used to measure serum levels of autoantibodies and immune complexes (ICs). Development of GCs and antibody‐containing ICs as well as numbers of proliferative and apoptotic cells were determined using flow cytometry and/or immunohistochemical analyses. Development of arthritis and kidney disease was evaluated histologically in 6–8‐month‐old mice.

Suppression of the somatic hypermutation function of AID resulted in a significant decrease in autoantibody production without affecting the expression of DNA damage–related genes in GC B cells of BXD2‐Aicda‐DN–transgenic mice. There was decreased proliferation, increased apoptosis, increased expression of caspase 9 messenger RNA in GC B cells, and lower numbers of GCs in the spleens of BXD2‐Aicda‐DN–transgenic mice. Decreased GC response was associated with lower levels of IgG‐containing ICs. Anti‐IgM– and anti‐CD40 plus anti‐Ig–induced B cell proliferative responses were decreased in BXD2‐Aicda‐DN–transgenic mice.

Inhibition of the AID somatic hypermutation function in BXD2 mice suppressed development of spontaneous GCs, generation of autoantibody‐producing B cells, and autoimmunity in BXD2 mice. Suppression of AID catalytic function to limit selection‐based survival of GC B cells could become a novel therapy for the treatment of autoimmune disease.