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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    ABSTRACT: LINE-1 (abbreviated L1) is a major class of retroelements in humans and mice. If unrestricted, retroelements accumulate in the cytoplasm and insert their DNA into the host genome, with the potential to cause autoimmune disease and cancer. Retroviruses and other retroelements are inhibited by proteins of the APOBEC family, of which activation-induced cytidine deaminase (AID) is a member. Although AID is mainly known for being a DNA mutator shaping the antibody repertoire in B lymphocytes, we found that AID also restricts de novo L1 integrations in B- and non-B-cell lines. It does so by decreasing the protein level of open reading frame 1 (ORF1) of both exogenous and endogenous L1. In activated B lymphocytes, AID deficiency increased L1 mRNA 1.6-fold and murine leukemia virus (MLV) mRNA 2.7-fold. In cell lines and activated B lymphocytes, AID forms cytoplasmic high-molecular-mass complexes with L1 mRNA, which may contribute to L1 restriction. Because AID-deficient activated B lymphocytes do not express ORF1 protein, we suggest that ORF1 protein expression is inhibited by additional restriction factors in these cells. The greater increase in MLV compared to L1 mRNA in AID-deficient activated B lymphocytes may indicate less strict surveillance of retrovirus.
    Full-text · Article · Nov 2012 · PLoS ONE
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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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    ABSTRACT: Common variable immunodeficiency (CVID) presents in up to 25% of patients with autoimmune (AI) manifestations. Given the frequency and early onset in some patients with CVID, AI dysregulation seems to be an integral part of the immunodeficiency. Antibody-mediated AI cytopenias, most often affecting erythrocytes and platelets make up over 50% of these patients. This seems to be distinct from mainly cell-mediated organ-specific autoimmunity. Some patients present like patients with AI lymphoproliferative syndrome. Interestingly, in the majority of patients with AI cytopenias the immunological examination reveals a dysregulated B and T cell homeostasis. These phenotypic changes are associated with altered signaling through the antigen receptor which may well be a potential risk factor for disturbed immune tolerance as has been seen in STIM1 deficiency. In addition, elevated B cell-activating factor serum levels in CVID patients may contribute to survival of autoreactive B cells. Of all genetic defects associated with CVID certain alterations in TACI, CD19, and CD81 deficiency have most often been associated with AI manifestations. In conclusion, autoimmunity in CVID offers opportunities to gain insights into general mechanisms of human autoimmunity.
    Preview · Article · Jul 2012 · Frontiers in Immunology
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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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    ABSTRACT: The Hyper-immunoglobulin M syndromes (HIGM) are a heterogeneous group of genetic disorders resulting in defects of immunoglobulin class switch recombination (CSR), with or without defects of somatic hypermutation (SHM). They can be classified as defects of signalling through CD40 causing both a humoral immunodeficiency and a susceptibility to opportunistic infections, or intrinsic defects in B cells of the mechanism of CSR resulting in a pure humoral immunodeficiency. A HIGM picture can also be seen as part of generalized defects of DNA repair and in antibody deficiency syndromes, such as common variable immunodeficiency. CD40 signalling defects may require corrective therapy with bone marrow transplantation. Gene therapy, a potential curative approach in the future, currently remains a distant prospect. Those with a defective CSR mechanism generally do well on immunoglobulin replacement therapy. Complications may include autoimmunity, lymphoid hyperplasia and, in some cases, a predisposition to lymphoid malignancy.
    Full-text · Article · Feb 2010 · British Journal of Haematology
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