mt-Nd2a Modifies Resistance Against Autoimmune Type 1 Diabetes in NOD Mice at the Level of the Pancreatic β-Cell

  1. Clayton E. Mathews1
  1. 1Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, Florida;
  2. 2Division of Immunogenetics, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania;
  3. 3The Jackson Laboratory, Bar Harbor, Maine.
  1. Corresponding author: Clayton E. Mathews, clayton.mathews{at}pathology.ufl.edu.

Abstract

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-Nd2a allele (NOD.mtALR) were created and compared with standard NOD (carrying the mt-Nd2c 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.mtALR (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-Nd2a 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-Nd2a 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.

Footnotes

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  • Received September 2, 2010.
  • Accepted October 12, 2010.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

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  1. Diabetes vol. 60 no. 1 355-359
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