mt-Nd2(a) Modifies resistance against autoimmune type 1 diabetes in NOD mice at the level of the pancreatic beta-cell.
Animals, CD4-Positive-T-Lymphocytes, Cell-Line, Crosses-Genetic, Diabetes-Mellitus-Experimental, Diabetes-Mellitus-Type-1, Genotype, Immunity-Innate, Insulin-Secreting-Cells, Mice-Inbred-NOD, NADH-Dehydrogenase, Polymorphism-Single-Nucleotide, Spleen
Diabetes 2011 Jan; 60(1):355-9.
OBJECTIVE: To investigate whether a single nucleotide polymorphism (SNP) in the mitochondrial gene for NADH dehydrogenase 2 (mt-Nd2) can modulate susceptibility to type 1 diabetes in NOD mice. RESEARCH DESIGN AND METHODS: NOD/ShiLtJ mice conplastic for the alloxan resistant (ALR)/Lt-derived mt-Nd2(a) allele (NOD.mt(ALR)) were created and compared with standard NOD (carrying the mt-Nd2(c) allele) for susceptibility to spontaneous autoimmune diabetes, or to diabetes elicited by reciprocal adoptive splenic leukocyte transfers, as well as by adoptive transfer of diabetogenic T-cell clones. beta-Cell lines derived from either the NOD (NIT-1) or the NOD.mt(ALR) (NIT-4) were also created to compare their susceptibility to cytolysis by diabetogenic CD8(+) T-cells in vitro. RESULTS: NOD mice differing at this single SNP developed spontaneous or adoptively transferred diabetes at comparable rates and percentages. However, conplastic mice with the mt-Nd2(a) allele exhibited resistance to transfer of diabetes by the CD4(+) T-cell clone BDC 2.5 as well as the CD8(+) AI4 T-cell clones from T-cell receptor transgenic animals. NIT-4 cells with mt-Nd2(a) were also more resistant to AI4-mediated destruction in vitro than NIT-1 cells. CONCLUSIONS: Conplastic introduction into NOD mice of a variant mt-Nd2 allele alone was not sufficient to prevent spontaneous autoimmune diabetes. Subtle nonhematopoietic type 1 diabetes resistance was observed during adoptive transfer experiments with T-cell clones. This study confirms that genetic polymorphisms in mitochondria can modulate beta-cell sensitivity to autoimmune T-cell effectors.
Chen, J; Gusdon, A M.; Piganelli, J; Leiter, E H.; and Mathews, C E., "mt-Nd2(a) Modifies resistance against autoimmune type 1 diabetes in NOD mice at the level of the pancreatic beta-cell." (2011). Faculty Research 2011. 18.