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 x A/J)F(1) (B6AF(1)) hybrids but not in C57BL/6J mice. Quantitative trait loci (QTL) linkage analysis using a B6AF(1) x 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 x B and B x 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.
Department of Veterinary Pathobiology, University of Illinois, Urbana, IL 61802, USA.
Randall J
RJ
Roper
Runlin Z
RZ
Ma
Julia E
JE
Biggins
Russell J
RJ
Butterfield
Sandra D
SD
Michael
Kenneth S K
KS
Tung
Rebecca W
RW
Doerge
Cory
C
Teuscher
D000595:Amino Acid Sequence; D000818:Animals; D000941:Antigens; D001284:Atrophy; D001324:Autoantigens; D002874:Chromosome Mapping; D004527:Egg Proteins / Q000737:chemistry; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006059:Gonadal Dysgenesis / Q000235:genetics* / Q000276:immunology; D007108:Immune Tolerance; D008297:Male; D008565:Membrane Proteins / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010049:Ovarian Diseases / Q000235:genetics* / Q000276:immunology; D010053:Ovary / Q000276:immunology; D017027:Protein Tyrosine Phosphatases / Q000276:immunology; D019655:Quantitative Trait, Heritable; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D013934:Thymectomy
D000941:Antigens; D001324:Autoantigens; D004527:Egg Proteins; D008565:Membrane Proteins; C416503:Nalp5 protein, mouse; D017027:Protein Tyrosine Phosphatases; C516863:Ptprn protein, mouse; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8