Interacting Quantitative Trait Loci Control Loss of Peripheral Tolerance and Susceptibility to Autoimmune Ovarian Dysgenesis After Day 3 Thymectomy in Mice

Day 3 thymectomy (D3Tx) results in a loss of peripheral tolerance mediated by CD4 + CD25 + T cells and the development of autoimmune ovarian dysgenesis (AOD) in A/J and (C57BL/6J × A/J)F 1 (B6AF 1 ) hybrids but not in C57BL/6J mice. Quantitative trait loci (QTL) linkage analysis using a B6AF 1 × C57BL/6J backcross population verified Aod1 and Aod2 that were previously mapped as qualitative traits. Additionally, three new QTL intervals, Aod3 , Aod4 , and Aod5 , on chromosomes 1, 2, and 7, respectively, influencing specific subphenotypes of AOD were identified. QTL linkage analysis using the A × B and B × A recombinant inbred lines verified Aod3 and confirmed linkage to H2. Aod5 colocalized with Mater , an ovarian-specific autoantigen recognized by anti-ovarian autoantibodies in the sera of D3Tx mice. Sequence analysis of Mater identified allelic, strain-specific splice variants between A/J and C57BL/6J mice making it an attractive candidate gene for Aod5 . Interaction analysis revealed significant epistatic effects between Aod1–5 and Gasa2 , a locus associated with susceptibility to D3Tx-induced autoimmune gastritis, as well as with H2 . These results indicate that the QTL controlling D3Tx-induced autoimmune phenomenon are both organ specific and more generalized in their effects with respect to the genesis and activity of the immunoregulatory mechanisms maintaining peripheral tolerance.