Our goal is to understand the functional significance and evolution of the polymorphism at the HLA-DP region and its relationship to disease susceptibility. Polymorphism at other HLA class II loci, DRB1 and DQB1 has been implicated for some time in predisposition to a variety of diseases. The role of the extensive polymorphism at the DPB1 locus (>80 alleles identified thus far) in disease predisposition is much less well understood. It is our hypothesis that specific combinations of alleles at multiple HLA loci determine the extent of susceptibility to a given disease. We will focus on three diseases: pauciarticular juvenile rheumatoid arthritis, type 1 diabetes, and cervical carcinoma. These diseases appear to have DPB1 associations as well as associations with specific alleles at the DRB1 and/or DQB1 locus. Our high resolution immobilized probe typing methods for the class II and class I loci will be applied to patient and control samples from a variety of populations. Family based material allows the analysis of haplotype sharing, transmission ratios, and linkage disequilibrium patterns as well as stratification analysis to see whether some of the associated alleles at DPB1, or any other individual HLA locus, confer increased risk or simply reflect linkage disequilibrium with high risk alleles at other HLA loci. Studying how HLA allelic diversity has evolved and how it is distributed in various human populations can provide insights into functional significance. The hypothesis that the patchwork patterns of polymorphism at the DPB1 and at other HLA loci reflects the operation of gene conversion (segmental exchange) will be tested by using a PCR-based method to measure the frequency of rare variant DPB1 sequences in sperm and the evolution of DPB1 diversity will be analyzed via phylogenetic analysis of exon2 and adjacent intron sequences from human and non- human primates. The hypothesis that HLA disease associations reflect the differential tendency to promote Th1 and Th2 responses following specific antigen stimulation of CD4+T cells will be examined using quantitative kinetic PCR to monitor cytokine expression. This method will be applied to HPV-infected cervical samples and an in vitro system with GAD peptide stimulation to study the HLA associations with cervical cancer and type 1 diabetes.
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