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Interacting Quantitative Trait Loci Control Loss of Peripheral Tolerance and Susceptibility to Autoimmune Ovarian Dysgenesis After Day 3 Thymectomy in Mice¹

Randall J. Roper^2,*, Runlin Z. Ma^*,, Julia E. Biggins^3,*, Russell J. Butterfield^*, Sandra D. Michael, Kenneth S. K. Tung, Rebecca W. Doerge^¶ and Cory Teuscher^4,||

^* Department of Veterinary Pathobiology, University of Illinois, Urbana, IL 61802; Laboratory Animal Center, Institute of Genetics, Chinese Academy of Sciences, Beijing, China; Department of Biological Sciences, State University of New York, Binghamton, NY 13902; Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA 22908; ^¶ Departments of Agronomy and Statistics, Purdue University, West Lafayette, IN 47907; and ^|| Department of Medicine, University of Vermont School of Medicine, Burlington, VT 05405

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)F₁ (B6AF₁) hybrids but not in C57BL/6J mice. Quantitative trait loci (QTL) linkage analysis using a B6AF₁ 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.

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				R. J. Roper, R. D. McAllister, J. E. Biggins, S. D. Michael, S. H. Min, K. S. K. Tung, S. B. Call, J. Gao, and C. Teuscher Aod1 Controlling Day 3 Thymectomy-Induced Autoimmune Ovarian Dysgenesis in Mice Encompasses Two Linked Quantitative Trait Loci with Opposing Allelic Effects on Disease Susceptibility J. Immunol., June 15, 2003; 170(12): 5886 - 5891. [Abstract] [Full Text] [PDF]