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Activation-induced cytidine deaminase deficiency accelerates autoimmune diabetes in NOD mice.

ABSTRACT: B cells play an important role in type 1 diabetes (T1D) development. However, the role of B cell activation-induced cytidine deaminase (AID) in diabetes development is not clear. We hypothesized that AID is important in the immunopathogenesis of T1D. To test this hypothesis, we generated AID-deficient (AID-/-) NOD mice. We found that AID-/-NOD mice developed accelerated T1D, with worse insulitis and high levels of anti-insulin autoantibody in the circulation. Interestingly, neither maternal IgG transferred through placenta, nor IgA transferred through milk affected the accelerated diabetes development. AID-/-NOD mice showed increased activation and proliferation of B and T cells. We found enhanced T-B cell interactions in AID-/-NOD mice, with increased T-bet and IFN-? expression in CD4+ T cells in the presence of AID-/- B cells. Moreover, excessive lymphoid expansion was observed in AID-/-NOD mice. Importantly, antigen-specific BDC2.5 CD4+ T cells caused more rapid onset of diabetes when cotransferred with AID-/- B cells than when cotransferred with AID+/+ B cells. Thus, our study provides insights into the role of AID in T1D. Our data also suggest that AID is a negative regulator of immune tolerance and ablation of AID can lead to exacerbated islet autoimmunity and accelerated T1D development.

SUBMITTER: Tan Q

PROVIDER: S-EPMC5821212 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Activation-induced cytidine deaminase deficiency accelerates autoimmune diabetes in NOD mice.

Tan Qiyuan Q Tai Ningwen N Li Yangyang Y Pearson James J Pennetti Sean S Zhou Zhiguang Z Wong F Susan FS Wen Li L

JCI insight 20180111 1

B cells play an important role in type 1 diabetes (T1D) development. However, the role of B cell activation-induced cytidine deaminase (AID) in diabetes development is not clear. We hypothesized that AID is important in the immunopathogenesis of T1D. To test this hypothesis, we generated AID-deficient (AID-/-) NOD mice. We found that AID-/-NOD mice developed accelerated T1D, with worse insulitis and high levels of anti-insulin autoantibody in the circulation. Interestingly, neither maternal IgG ...[more]

PMID: 29321370

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Project description:Patients with inflammatory bowel disease (IBD) have an increased risk of colorectal cancer, particularly in ulcerative colitis (UC) when the majority of colon epithelial cells may be exposed to inflammation-associated mutagenesis. In addition to mutagenesis generated by oxidative stress, inflammation can induce activation-induced cytidine deaminase (Aicda), a mutator enzyme in the APOBEC family, within colon epithelial cells. This study tested the hypothesis that deletion of the Aicda gene could protect against the development of inflammation-associated colorectal cancers, using a model of UC-like colitis in "T/I" mice deficient in TNF and IL10. Results showed that T/I mice that were additionally Aicda-deficient ("TIA" mice) spontaneously developed moderate to severe UC-like colitis soon after weaning, with histologic features and colon inflammation severity scores similar those in T/I mice. Although the mean survival of TIA mice was decreased compared to T/I mice, multivariable analysis that adjusted for age when neoplasia was ascertained showed a decreased numbers of neoplastic colorectal lesions in TIA mice, with a trend toward decreased incidence of neoplasia. Aicda deficiency increased serum IL1α and slightly decreased IL12p40 and M-CSF, as compared with T/I mice, and led to undetectable levels of IgA, IgG1, IgG2a, IgG2b, and IgG3. Taken together, these studies show that Aicda deficiency can decrease the number of neoplastic lesions but is not sufficient to prevent the risk of inflammation-associated colorectal neoplasia in the setting of severe UC-like inflammation. The TIA model may also be useful for assessing the roles of antibody class-switch recombination deficiency and somatic hypermutation on regulation of microbiota and inflammation in the small intestine and colon, as well as the pathogenesis of colitis associated with hyper-IgM syndrome in humans. Further studies will be required to determine the mechanisms that drive early mortality in TIA mice.

Dataset Information

Activation-induced cytidine deaminase deficiency accelerates autoimmune diabetes in NOD mice.

Publications

Activation-induced cytidine deaminase deficiency accelerates autoimmune diabetes in NOD mice.

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