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.
Document Type
Article
Publication Date
6-1-2017
JAX Source
J Immunol 2017 Jun 1; 198(11):4255-4267
Volume
198
Issue
11
First Page
4255
Last Page
4267
ISSN
1550-6606
PMID
28461573
Grant
DK-46266, DK-95735, OD-020351, CA138646, CA034196
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. J Immunol 2017 Jun 1; 198(11):4255-4267.
Recommended Citation
Ratiu J,
Racine J,
Hasham MG,
Wang Q,
Branca J,
Chapman H,
Zhu J,
Donghia NM,
Philip VM,
Schott WH,
Wasserfall C,
Atkinson M,
Mills K,
Leeth C,
Serreze DV.
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. J Immunol 2017 Jun 1; 198(11):4255-4267