Activation-induced cytidine deaminase deficiency causes organ-specific autoimmune disease

Activation-induced cytidine deaminase (AID) expressed by germinal center B cells is a ceptral regulator of somatic hypermutation (SHM) and class switch recombination (CSR). Humans with AID mutations develop not only the autosomal recessive form of hyper-IgM syndrome (HIGM2) associated with B cell hyperplasia, but also autoimmune disorders by unknown mechanisms. We report here that AID^-/- mice spontaneously develop tertiary lympoid organs (TLOs) in non-lymphoid tissues including the stomach at around 6 months of age. At a later stage, AID^-/- mice develop a severe gastritis characterized by loss of gastric glands and epithelial hyperlasia. The disease development was not attenuated even under germ-free (GF) conditions. Gastric autoantigen-specific serum IgM was elevated in AID^-/- mice, and the serum levels correlated with the gastritis pathological score. Adoptive transfer experiments suggest that autoimmune CD4⁺ T cells Mediate gastritis development as terminal effector cells. These results suggest that abnormal B-cell expansion due to AID deficiency can drive B-cell autoimmunity, and in turn promote TLO formation, which ultimately leads to the propagation of organ-specific autoimmune effector CD4⁺ T cells. Thus, AID plays an important role in the containment of autoimmune disease by negative regulation of autoreactive B cells.