Evidence that MHC I-E dampens thyroid autoantibodies and prevents spreading to a second thyroid autoantigen in I-A(k) NOD mice.

NOD.H2(k) and NOD.H2(h4) mice carry the major histocompatibility complex (MHC) class II molecule I-A(k) associated with susceptibility to experimentally induced thyroiditis. Dietary iodine-enhanced spontaneous thyroid autoimmunity, well known in NOD.H2(h4) mice, has not been investigated in NOD.H2(k) mice. We compared NOD.H2(h4) and NOD.H2(k) strains for thyroiditis and autoantibodies to thyroglobulin (TgAb) and thyroid peroxidase (TPOAb) without or with dietary sodium iodide (NaI) for up to 32 weeks. TgAb levels were significantly higher in NOD.H2(h4) compared with NOD.H2(k) mice on NaI, and TPOAb developed in NOD.H2(h4) mice but not in NOD.H2(k) mice. DNA exome analysis revealed, in addition to the differences in the chromosome (Chr) 17 MHC regions, that NOD.H2(k) mice, and particularly NOD.H2(h4) mice, have substantial non-MHC parental DNA. KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis highlighted thyroid autoimmunity and immune-response genes on Chr 17 but not on Chr 7, and 15 parental B10.A4R DNA. Studies of parental strains provided no evidence for non-MHC gene contributions. The exon 10 Tg haplotype, associated with experimentally induced thyroiditis, is absent in NOD.H2(h4) and NOD.H2(k) mice and is not a marker for spontaneous murine thyroid autoimmunity. In conclusion, the absence of I-E is a likely explanation for the difference between NOD.H2(h4) and NOD.H2(k) mice in TgAb levels and, as in humans, autoantibody spreading to TPO.

Idd13 is involved in determining immunoregulatory DN T-cell number in NOD mice.

Immunoregulatory T cells have been identified as key modulators of peripheral tolerance and participate in preventing autoimmune diseases. CD4(-)CD8(-) (double negative, DN) T cells compose one of these immunoregulatory T-cell subsets, where the injection of DN T cells confers protection from autoimmune diabetes progression. Interestingly, genetic loci defining the function and number of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) coincide with at least some autoimmune disease susceptibility loci. Herein, we investigate the impact of major insulin-dependent diabetes (Idd) loci in defining the number of DN T cells. We demonstrate that although Idd3, Idd5 and Idd9 loci do not regulate DN T-cell number, NOD mice congenic for diabetes resistance alleles at the Idd13 locus show a partial restoration in DN T-cell number. Moreover, competitive and non-competitive bone marrow chimera experiments reveal that DN T-cell number is defined by a bone marrow-intrinsic, but DN T-cell-extrinsic, factor. This suggests that non-autonomous candidate genes define DN T-cell number in secondary lymphoid organs. Together, our results show that the regulation of DN T-cell number in NOD mice is at least partially conferred by alleles at the Idd13 locus.