IMMUNOREGULATORY LOCI IN ORGAN SPECIFIC AUTOIMMUNITY

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Experimental allergic encephalomyelitis (EAE) and insulin-dependent diabetes mellitus (IDDM) are two models of organ-specific autoimmune disease that have been the main focus of contemporary research in autoimmunity. Studies using these models have significantly influenced the current thinking about tolerance and the pathogenic mechanisms leading to disease. However, because of organ physiology and antigen expression, not all of the paradigms established by these studies are applicable to other self antigens. For example, two less popular models, experimental allergic orchitis (EAO) and autoimmune ovarian dysgenesis (AOD), are at the forefront of characterizing the genetic architecture of the immunopathology underlying susceptibility and resistance to disease. Genome exclusion mapping studies of EAO lead to the hypothesis that there are at least two classes of autoimmune disease susceptibility loci: 1) those specific for a particular disease and/or cross, and 2) those shared or common to multiple immunopathologically mediated phenotypes. In fact, the mapping and co-localization of Orch3, the locus controlling dominant resistance to autoimmune orchitis and the focus of this application, with Idd4 on chromosome 11 provide much of the impetus for this hypothesis. Recently, we have reported a similar co-localization for eae7 suggesting that the three loci may be the same gene or tightly linked genes within a multi-gene family. To test this hypothesis at the molecular level definitively one of these loci must be positionally cloned. Toward this end, using a panel of BALB.DBA/2 chromosome 11 congenic mice, we have physically mapped the Orch3 locus on chromosome 11 to an interval approximately 9cM (BALB.D2Orch3CT3). In this study, we will: 1) generate additional BALB.D2Orch3CT3 recombinant congenic mice to narrow down the support interval encoding the locus to a size amenable to positional cloning (less than 1 cM), and 2) construct a yeast artificial chromosome (YAC) contig encompassing Orch3.