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Activation-induced cytidine deaminase deficiency accelerates autoimmune diabetes in NOD mice
Qiyuan Tan, … , F. Susan Wong, Li Wen
Qiyuan Tan, … , F. Susan Wong, Li Wen
Published January 11, 2018
Citation Information: JCI Insight. 2018;3(1):e95882. https://doi.org/10.1172/jci.insight.95882.
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Research Article Immunology

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

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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.

Authors

Qiyuan Tan, Ningwen Tai, Yangyang Li, James Pearson, Sean Pennetti, Zhiguang Zhou, F. Susan Wong, Li Wen

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Figure 1

AID deficiency promotes the development of T1D in NOD mice.

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AID deficiency promotes the development of T1D in NOD mice.
(A) Diabetes...
(A) Diabetes incidence in AID–/–NOD mice and their AID+/–NOD and AID+/+NOD littermates. Data were pooled from 3 independent experiments. n = 21–25 mice/female group and n = 12–20 mice/male group. (B) Insulitis in 8-week-old nondiabetic female AID–/–NOD and AID+/+NOD mice. At least 100 islets were examined from 8–9 mice/group. Scale bars: 50 μm. (C) Summary of the absolute cell number of infiltrating CD4+ T cells, CD8+ T cells, and B220+CD19+ B cells in the islets of 10- to 12 week-old female AID–/–NOD and control NOD mice (mixed AID+/–NOD and AID+/+NOD). Data are expressed as mean ± SEM and were pooled from 2 independent experiments. (D) Absolute IGRP+CD8+ T cells. Islet infiltrates from 10- to 12 week-old female AID–/–NOD and control mice were stained with IGRP-tetramer, CD45, CD8, and TCRβ followed with FACS analysis. n = 4 mice/group. *P < 0.05; **P < 0.01; ***P < 0.001, Gehan-Breslow-Wilcoxon survival test (A), χ2 test (B), and Student’s t test (C and D).

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