Molecular analysis of HLA genes and gene products has implicated a small number of key genes and associated haplotypes accounting for the association of HLA with rheumatoid arthritis (RA). Studies over the last 3 years have pinpointed specific nucleotide variation among closely related genes as potentially contributing directly to disease susceptibility. We now have an opportunity to develop a detailed understanding of the molecular genetic contribution of RA-associated HLA genes to immune recognition, which will, in turn, lead to new approaches to specific diagnosis and intervention strategies in susceptible individuals. We will investigate the structure and function of a specific RA- associated nucleotide segment of the HLA-DR beta gene implicated as a critical epitope in immune recognition: using a panel of specific oligonucleotide probes. We will also analyze the possible contribution of additional linked genetic markers on RA-associated haplotypes. We will study expression of a few specific DR beta alleles implicated as putative susceptibility genes, for insight into transcriptional variation in situ in synovial biopsies. Another important new direction will be a large prospective clinical study to evaluate the relationship between specific DR beta allelic variants defined bY oligonucleotide probes with clinical parameters at diagnosis and with progression of disease. We anticipate that results of these studies will directly contribute to a detailed and focused molecular perspective on the contributions of HLA genes to the pathogenesis of RA.