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...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2002-08, Vol.169 (3), p.1640-1646
Main Authors: Roper, Randall J, Ma, Runlin Z, Biggins, Julia E, Butterfield, Russell J, Michael, Sandra D, Tung, Kenneth S. K, Doerge, Rebecca W, Teuscher, Cory
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Antigens
Atrophy
Autoantigens
Chromosome Mapping
Egg Proteins - chemistry
Female
Genetic Linkage
Genetic Predisposition to Disease
Gonadal Dysgenesis - genetics
Gonadal Dysgenesis - immunology
Immune Tolerance
Male
Membrane Proteins - immunology
Mice
Mice, Inbred C57BL
Molecular Sequence Data
Ovarian Diseases - genetics
Ovarian Diseases - immunology
Ovary - immunology
Protein Tyrosine Phosphatases - immunology
Quantitative Trait, Heritable
Receptor-Like Protein Tyrosine Phosphatases, Class 8
Thymectomy
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Summary: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.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.169.3.1640