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
| Autor: | Vivek Philip, David V. Serreze, Clive Wasserfall, William H. Schott, Caroline M. Leeth, Jeremy J. Racine, Qiming Wang, Muneer G. Hasham, Harold D. Chapman, Kevin D. Mills, Jeremy J. Ratiu, Jing Zhu, Jane Branca, Mark A. Atkinson, Nina M Donghia |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
T cell Regulatory B cells Immunology RAD51 Somatic hypermutation 4 4'-Diisothiocyanostilbene-2 2'-Disulfonic Acid Biology Lymphocyte Activation Article Diabetes Mellitus Experimental Mice 03 medical and health sciences 0302 clinical medicine Mice Inbred NOD Cytidine Deaminase medicine Animals Immunology and Allergy 5'-Nucleotidase Autoantibodies NOD mice B-Lymphocytes Regulatory Nuclear Proteins RNA-Binding Proteins Cytidine deaminase Immunoglobulin Class Switching Cell biology DNA-Binding Proteins Diabetes Mellitus Type 1 030104 developmental biology medicine.anatomical_structure Immunoglobulin class switching Somatic Hypermutation Immunoglobulin CRISPR-Cas Systems Carrier Proteins Homologous recombination 030215 immunology |
| Zdroj: | The Journal of Immunology. 198:4255-4267 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.1700024 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|