Journal
JOURNAL OF IMMUNOLOGY
Volume 198, Issue 11, Pages 4255-4267Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1700024
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Funding
- National Cancer Institute [P30CA034196]
- National Institutes of Health [P01-AI42288, DK-46266, DK-95735, OD-020351, DK101735, CA138646, 1F32DK111078]
- Jackson Laboratory Principal Investigator Grant [TJL DIF FY13 KDM]
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B lymphocytes play a key role in type 1 diabetes (T1D) development by serving as a subset of APCs preferentially supporting the expansion of autoreactive pathogenic T cells. As a result of their pathogenic importance, B lymphocyte-targeted therapies have received considerable interest as potential T1D interventions. Unfortunately, the B lymphocyte-directed T1D interventions tested to date failed to halt b cell demise. IgG autoantibodies marking humans at future risk for T1D indicate that B lymphocytes producing them have undergone the affinity-maturation processes of class switch recombination and, possibly, somatic hypermutation. This study found that CRISPR/Cas9-mediated ablation of the activation-induced cytidine deaminase gene required for class switch recombination/somatic hypermutation induction inhibits T1D development in the NOD mouse model. The activation-induced cytidine deaminase protein induces genome-wide DNA breaks that, if not repaired through RAD51-mediated homologous recombination, result in B lymphocyte death. Treatment with the RAD51 inhibitor 4,49-diisothiocyanatostilbene-2, 29-disulfonic acid also strongly inhibited T1D development in NOD mice. The genetic and small molecule-targeting approaches expanded CD73(+) B lymphocytes that exert regulatory activity suppressing diabetogenic T cell responses. Hence, an initial CRISPR/Cas9-mediated genetic modification approach has identified the AID/RAD51 axis as a target for a potentially clinically translatable pharmacological approach that can block T1D development by converting B lymphocytes to a disease-inhibitory CD73(+) regulatory state.
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