mt-Nd2(a) Modifies resistance against autoimmune type 1 diabetes in NOD mice at the level of the pancreatic β-cell.
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.


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. β-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 β-cell sensitivity to autoimmune T-cell effectors.
Chen
Jing
J
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, USA.
Gusdon
Aaron M
AM
Piganelli
Jon
J
Leiter
Edward H
EH
Mathews
Clayton E
CE
D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000637:transplantation; D002460:Cell Line; D003433:Crosses, Genetic; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000517:prevention & control*; D003922:Diabetes Mellitus, Type 1 / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D005838:Genotype; D007113:Immunity, Innate / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000502:physiology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D009245:NADH Dehydrogenase / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D013154:Spleen / Q000637:transplantation
D009245:NADH Dehydrogenase; C502385:mt-Nd2 protein, mouse