Mice thymectomized at three days of age (D3Tx) develop as adults a variety of organ specific autoimmune diseases. The D3Tx model depends exclusively on perturbation of the normal developing immune system, is T-cell-mediated, and is genetically controlled. After D3Tx, organ specific autoantigens expressed at physiologic levels, trigger an autoimmune response capable of eliciting disease. The T-cell repertoire of both neonatal and adult D3Tx-mice is enriched for self-reactive T cells. In the normal adult repertoire, CD4+CD5(low) T cells have the capacity to elicit autoimmune disease when adoptively transferred into nude recipients. Thus the ability to transfer disease is due, in part, to failure of the neonatal thymus to delete autoreactive cells before it is removed. In addition, D3Tx mice are deficient in cD4+CD5(high) regulatory T cells needed to control disease inducing T cells that mature in the adult thymus. These findings indicate that expansion of the autoreactive neonatal T-cell repertoire, frozen by D3Tx, results in disease. The fact that disease susceptibility is genetically controlled leads us to hypothesize that the gene(s) controlling the phenotypic expression of autoimmunity in this model may include those that govern the induction and maintenance of peripheral tolerance to organ specific autoantigens. Previously, we mapped Aod1, the major gene controlling the abrogation of tolerance in D3Tx-induced autoimmune oophoritis to chromosome 16. In this study, we propose to: l) develop reciprocal congenic and recombinant congenic lines carrying the susceptible and resistant Aod1 allele on identical genetic backgrounds; and 2) identify, clone, and characterize the Aod1 locus. It is anticipated that the findings of the studies proposed in this application will extend our understanding of the mechanisms underlying the induction and maintenance of peripheral tolerance to organ specific autoantigens which play a role in the pathogenesis of organ specific autoimmune disease.
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