The B-cell receptor in developing B-cell precursors is produced via the rearrangement of randomly selected V, and J segments of the Ig heavy and light chain loci. This Ig gene recombination is crucial to increase the diversity of the B-cell repertoire however, due to its stochastic nature, a substantial number of newly synthesized BCRs bind autoantigens. It was recently estimated that more than 50% of newly generated B cells are autoreactive . Studies using transgenic mice carrying autoreactive BCR genes indicate that autoreactive B cells are normally silenced by immunological tolerance mechanisms including clonal deletion, receptor editing and anergy . However, in humans and mice that are prone to autoimmune diseases, the B-cell tolerance mechanisms seem to be overwhelmed by genetic or acquired defects. This concept is underscored by the finding that unregulated control of B-cell activation or proliferation due to the deficiency of the inhibitory Fcc receptor , the protein phosphatase Shp1, or the protein kinase Cd causes autoimmune diseases . As a Carfilzomib consequence, B-cell-targeting therapies have become one of the most effective treatments for autoimmue diseases . Although enhanced growth of B cells coupled with enlarged GC has been observed in AID2/2 humans and mice, the potential contribution of AID to autoimmunity remains largely unknown. To better define the role of AID in autoimmunity, we carefully analyzed AID2/2 mice at different ages. We found that aged mice spontaneously developed gastritis with pathological features similar to human type A gastritis and murine experimental autoimmune gastritis. The disease could be reconstituted in nu/nu mice by adoptive transfer of CD4 + T cells isolated from inflamed gastric tissue. Anti-gastric-mucosa-specific Ab were elevated in gastritis-positive, but not in gastritis-negative AID2/2 mice, indicating that autoreactive B cells are propagated in the gastritis-positive AID2/2 mice. Importantly, gastritis development was preceded by formation of tertiary lymphoid organs . Self-reactive B cells, likely generated because of increased BCR diversity in the absence of AID, in TLOs could capture large amounts of gastric autoantigens to present to T cells, and MG132 reciprocally receive T-cell help. Consequently, such a vicious cycle through a B-T collaboration could facilitate the generation of gastric antigen-specific CD4 T cells, which ultimately cause the pathology of autoimmune gastritis. The data presented here show that AID is necessary not only for B cell homeostasis but also for negative regulation of autoimmune disorders. In the present study we have shown that as they age, AID2/2 mice sequentially develop lymphoid neogenesis followed by severe gastritis. Consequently, AID2/2 mice had a significantly shorter lifespan compared to wild type mice.