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

Tan, Qiyuan, Tai, Ningwen, Li, Yangyang, Pearson, James, Pennetti, Sean, Zhou, Zhiguang, Wong, Florence and Wen, Li 2018. Activation-induced cytidine deaminase deficiency accelerates autoimmune diabetes in NOD mice. JCI Insight 3 (1) , 95882. 10.1172/jci.insight.95882

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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-γ 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Publisher: American Society for Clinical Investigation
ISSN: 2379-3708
Date of First Compliant Deposit: 22 January 2018
Date of Acceptance: 5 December 2017
Last Modified: 08 Feb 2018 11:36
URI: http://orca.cf.ac.uk/id/eprint/108328

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