Activation-induced cytidine deaminase deficiency causes organ-specific autoimmune disease.
Activation-induced cytidine deaminase (AID) expressed by germinal center B cells is a central 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 lymphoid 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 hyperplasia. 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 diseases by negative regulation of autoreactive B cells.
Hase
Koji
K
Research Center for Allergy and Immunology, RIKEN, Yokohama, Kanagawa, Japan.
Takahashi
Daisuke
D
Ebisawa
Masashi
M
Kawano
Sayaka
S
Itoh
Kikuji
K
Ohno
Hiroshi
H
D000818:Animals; D001327:Autoimmune Diseases / Q000201:enzymology* / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D003564:Cytidine Deaminase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D005753:Gastric Mucosa / Q000473:pathology; D005756:Gastritis / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D007125:Immunogenetics; D007249:Inflammation / Q000201:enzymology / Q000473:pathology; D008221:Lymphoid Tissue / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D013047:Specific Pathogen-Free Organisms
D003564:Cytidine Deaminase