Adult neonatal thymectomized (NTx) mice develop, depending upon the day of thymectomy, a spectrum of autoimmune phenomenon ranging from autoantibodies (DOTX and D3Tx) and wasting disease (DOTx) to organ-specific autoimmune diseases (D3Tx) such as autoimmune ovarian dysgenesis (AOD) and autoimmune gastritis (AG). The uniquely distinguishing feature of NTx-induced autoimmunity is it dependency upon the disruption of neonatal thympoiesis and establishment and maintenance of a peripheral CD4+CD25+ T suppressor cell repertoire required for the prevention of autoimmune disease, importantly, D3Tx does not lead to autoimmune disease in all strains of mice indicating that this process is genetically controlled. In this regard, we have identified linkage of D3Tx-induced AOD and its intermediate phenotypes, anti-ovarian autoantibody responsiveness, oophoritis, and atrophy, to five quantitative trait loci (QTL) designated Aodl-Aod5 and to H2 and Gasa2, a QTL controlling susceptibility to D3Tx-induced AG. The working hypothesis underlying our genetic studies on D3Tx-induced AOD is that one or more of the QTL controlling susceptibility to D3Tx-induced autoimmunity plays a role in the genesis and/or functionality of CD4 +CD25+ suppressor T cells mediating peripheral tolerance to self antigens. Toward this end, we have established, or are in the process of establishing, panels of interval specific bi-directional recombinant congenic lines encompassing each of the AOD QTL. To date, we have shown that Aod1 is comprised of two linked QTL (Aodla and Aod1 b)with opposing allelic effects on susceptibility to autoimmune oophoritis; and that stefin A1 (Stfal) and A2 (Stfa2), inhibitors of cathepsin S, a cysteine protease required for autoantigen presentation and the development of autoimmune disease following D3Tx, are candidates for Aod1b. In this application we will: 1) complete the congenic mapping for each of the AOD QTL at a resolution of 1 cM or less and 2) directly assess the IL2 structural polymorphism as a candidate for a shared autoimmune disease QTL underlying Aod2, Idd3, and eae3.
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