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      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.

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          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.

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          Author and article information

          Journal
          J. Immunol.
          Journal of immunology (Baltimore, Md. : 1950)
          The American Association of Immunologists
          1550-6606
          0022-1767
          Jun 01 2017
          : 198
          : 11
          Affiliations
          [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.
          Article
          jimmunol.1700024
          10.4049/jimmunol.1700024
          28461573
          e08dca5d-2534-48e7-a0a1-6590cb550bd8
          History

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