The long term major objectives of this application are to analyze in detail the major histocompatibility complex genes in ocular cicatricial pemphigoid (OCP). We hope to identify susceptibility genes that are associated with the production of anti-basement membrane zone (BMZ) antibodies. Our preliminary studies indicate a strong association between B44, DR4, DQw3 in OCP. Furthermore, we have developed a radioimmunoassay to detect anti-BMZ antibodies present in very low titers. Our studies in pemphigus indicate that the ability to produce autoantibodies may be linked to MHC genes, and family members that carry the """"""""disease-bearing"""""""" haplotype often have very low titers of pemphigus antibodies. We propose to do complete HLA studies in OCP patients, in order to test the hypothesis that the haplotype (only the phenotypes have so far been studied) B44, DR4, DQw3 together with other Class II alleles and complotypes carry a susceptibility gene for anti-BMZ antibody production and OCP. Nucleotide sequencing of the regions (DQ, DR) carrying the susceptibility gene(s) will be done to determine if there are any amino acid differences between the individuals with and without the anti-BMZ antibody, but have the same extended haplotype or portions of it. Furthermore, comparison of the DR4 of that extended haplotype of OCP patients with other DR4-associated haplotypes, will be very helpful in determining if the DR4 molecule is directly involved in the pathogenesis of OCP. Molecular probes will be used in analyzing in detail the genes associated with OCP and/or anti-BMZ antibody production in an effort to identify disease-specific restriction fragment length polymorphism. These studies are possible because Dr. Stephen Foster of the Mass Eye & Ear Infirmary has 130 patients with OCP. Seventy patients with OCP have been recently studied. Dr. Ahmed is a dermatologist with interest in the immunogenetics of blistering diseases. Dr. Ahmed has the collaboration of two immunogeneticists (Dr. Alper and Dr. Yunis) who will not only provide Dr. Ahmed with the necessary environment and advice to perform and analyze these experiments, but actively participate in the project. Thus the proposal will help in significantly advancing our ability to localize a susceptibility gene for OCP and to study the genetic control of anti-BMZ antibody production.
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