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J Immunol. 2017 Jun 1;198(11):4255-4267. doi: 10.4049/jimmunol.1700024. Epub 2017 May 1.

Genetic and Small Molecule Disruption of the AID/RAD51 Axis Similarly Protects Nonobese Diabetic Mice from Type 1 Diabetes through Expansion of Regulatory B Lymphocytes.

Author information

1
The Jackson Laboratory, Bar Harbor, ME 04609.
2
Graduate Program in Genetics, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA 02111.
3
Department of Animal and Poultry Sciences, Virginia Polytechnic and State University, Blacksburg, VA 24061.
4
Department of Pathology, University of Florida, Gainesville, FL 32610; and.
5
Cyteir Therapeutics, Cambridge, MA 02138.
6
Department of Animal and Poultry Sciences, Virginia Polytechnic and State University, Blacksburg, VA 24061; dave.serreze@jax.org cmcphee@vt.edu.
7
The Jackson Laboratory, Bar Harbor, ME 04609; dave.serreze@jax.org cmcphee@vt.edu.

Abstract

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 β 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 4,4'-diisothiocyanatostilbene-2, 2'-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.

PMID:
28461573
PMCID:
PMC5474749
DOI:
10.4049/jimmunol.1700024
[Indexed for MEDLINE]
Free PMC Article

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