The results of both clinical and experimental studies suggest that immunologic mechanisms may be significant in the pathogenesis of idiopathic infertility. The long term goal of this research is to define and characterize the various immunoregulatory genes which control the phenotypic expression of infertility associated with autoimmune disease of the testis. The focus of this application is the characterization of the murine major histocompatibility complex (H-2) linked immune response (Ir) gene Orchitis susceptibility gene-1 (Orch-1). The Orch-I locus controls the phenotypic expression of both autoimmune reactions in the testis as well as associated infertility. Observations made in this laboratory indicate that recombinations within the H-2S/H-2D interval (a distance of approximately 700 kb) define the map position of Orch-1. A comparison of the Orch-I alleles with other markers known to map within the same interval suggests the following gene order H-2S--TNP-Ficoll--Orch-l--TNF--H-2D. Detailed molecular analysis of the interval encoding Orch-1 will be obtained by restriction fragment length polymorphism (RFLP) mapping utilizing existing human cDNAs cloned from this region. Subsequently, a set of overlapping cosmids spanning the Orch-I locus will be isolated. Nonrepetitive sequences from these clones will then be used as probes to analyze recombination break points within the interval and to identify RFLPs among the recombinants whose Orch-I haplotypes are known with the ultimate long term goal being the identification, cloning and sequencing of the Orch-I gene. In addition, preliminary characterization of the mechanism of action of Orch-I will be carried out using bone marrow radiation chimera protocols to map the immunoregulatory effects governed by Orch- 1 to either the bone marrow-derived or target organ compartment. Similarly, both azoospermia and autoimmune responses to sperm and testis antigens have been reported to be associated with the major histocompatibility complex in humans (HLA). Therefore, we postulate that a human Ir gene analogous to Orch-I exists and that it may play a role in the genetic control of auto- and isoimmune responses to sperm and testis antigens in man. The findings of this research should greatly extend our understanding of the relationship between such Ir genes and their mechanisms of action and will undoubtedly extend our understanding of human infertility and autoimmune phenomena.
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