Activation-Induced Cytidine Deaminase Deficiency Causes Organ-Specific Autoimmune Disease

Centre d'Immunologie de Marseille-Luminy, CNRS-Inserm, France
PLoS ONE (Impact Factor: 3.23). 02/2008; 3(8):e3033. DOI: 10.1371/journal.pone.0003033
Source: PubMed


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.

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    • "But these patients also suffer from lymphadenopathies and autoimmune or inflammatory disorders (including diabetes mellitus, polyarthritis, autoimmune hepatitis, hemolytic anemia, immune thrombocytopenia, Crohn's disease and chronic uveitis) [58], [59] – seemingly disparate conditions that are at odds with the known function of AID. Also, AID knockout mice develop lymphoid hyperplasia and autoimmunity [60]–[62]. The lymphoid hyperplasia in AID-deficient humans [59], [63]–[65] and mice [61], [62] has been interpreted as being due to a lack of class-switched IgA, which would lead to an expansion of anaerobic commensal bacteria in the small intestine [61]. "
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    • "This could represent a disturbed peripheral differentiation and selection. Increased autoimmunity associated with poor germinal center function has also been observed in deficiency of the AID (Hase et al., 2008), but no abnormalities of AID expression or function have been described in CVID at this point. "
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    • "Potential mechanisms for the autoimmune process have been reviewed (Jesus et al, 2008). It has also been postulated that the B cell lymphoproliferation characteristic of the condition leads to the development of ectopic lymphoid tissue in non lymphoid organs, predisposing to organ specific autoimmunity (Hase et al, 2008). Autoimmune complications would also be expected to occur in UNG-deficient forms of the disorder. "
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