Abstract
ALR mice are closely related to type-1 diabetes mellitus (T1DM)-prone NOD mice. The ALR genome confers systemically elevated free radical defenses, dominantly protecting their pancreatic islets from free radical generating toxins, cytotoxic cytokines, and diabetogenic T cells. The ALR major histocompatibility complex (MHC) (H2 gx haplotype) is largely, but not completely identical with the NOD H2 g7 haplotype, sharing alleles from H2-K through the class II and distally into the class III region. This same H2 gx haplotype in the related CTS strain was linked to the Idd16 resistance locus. In the present study, ALR was outcrossed to NOD to fine map the Idd16 locus and establish chromosomal regions carrying other ALR non-MHC-linked resistance loci. To this end, 120 (NOD×ALR)×NOD backcross progeny females were monitored for T1DM and genetic linkage analysis was performed on all progeny using 88 markers covering all chromosomes. Glucosuria or end-stage insulitis developed in 32 females, while 88 remained both aglucosuria and insulitis free. Three ALR-derived resistance loci segregated. As expected, one mapped to Chromosome 17, with peak linkage mapping just proximal to H2-K. A novel resistance locus mapped to Chr 8. A pairwise scan for interactions detected a significant interaction between the loci on Chr 8 and Chr 17. On Chr 3, resistance segregated with a marker between previously described Idd loci and coinciding with an independently mapped locus conferring a suppressed superoxide burst by ALR neutrophils (Susp). These results indicate that the Idd16 resistance allele, defined originally by linkage to the H2 gx haplotype of CTS, is immediately proximal to H2-K. Two additional ALR-contributed resistance loci may be ALR-specific and contribute to this strain's ability to dissipate free-radical stress.
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Acknowledgements
This work was supported by the Juvenile Diabetes Research Foundation International, the American Diabetes Association and the National Institutes of Health grants F32DK09889, F32DK09865, DK27722, DK36175, DK46266, and DK51090. Institutional shared services (TJL) were supported by National Cancer Institute Cancer Center Support Grant CA34196. The expert technical assistance of Mr. Bruce Regimbal is gratefully acknowledged. All experiments complied with the current laws of The United States.
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Mathews, C.E., Graser, R.T., Bagley, R.J. et al. Genetic analysis of resistance to Type-1 Diabetes in ALR/Lt mice, a NOD-related strain with defenses against autoimmune-mediated diabetogenic stress. Immunogenetics 55, 491–496 (2003). https://doi.org/10.1007/s00251-003-0603-8
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DOI: https://doi.org/10.1007/s00251-003-0603-8