HLA B27 AND EXPERIMENTAL SPONDYLOARTHROPATHY

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HLA-B27 is a human class I MHC allele that is found with strikingly increased prevalence in patients with the spondyloarthropathies (SpA). Because microbial agents have also been implicated in the pathogenesis of the SpA, these disorders are thought to arise through interactions, as yet poorly understood, between environmental agents and a genetically susceptible host. Elucidation of the basis for the association between B27 and disease would therefore enhance our understanding of the roles that both genes and environmental agents play in producing chronic inflammatory diseases. This application describes a project in which the role of HLA- B27 in disease will be studied in an animal model, namely, rats transgenic for HLA-B27 that develop a spontaneous disease sharing many clinical and histologic features with the human SpA. The disease of these transgenic rats can be adoptively transferred to normal, nontransgenic rats by bone marrow transplantation. At least two populations of cells appear necessary for the development of disease: a non-lymphocyte population derived from B27 transgenic bone marrow, and a source of T cells. In Specific Aim I, in vivo adoptive transfer will be used to characterize the critical non- lymphocyte population derived from B27 transgenic bone marrow. The proposed experiments are based on the hypothesis that this is a population of antigen-presenting cells. In Specific Aim II, a series of studies will be aimed at identifying the T cells mediating the disease, including in vivo depletion with monoclonal antibodies, transfer of T cell subsets to transgenic athymic nude rats, and characterization of cytokine production and reactivity with microbial antigens that have been implicated in human SpA. In Specific Aim III, disease-prone B27 rats raised in a germfree environment will be studied to test the hypothesis that microbial agents are critical to the development of B27-associated disease. In Specific Aim IV, mutant B27 molecules will be studied in transgenic rats to examine the role of specific B27 amino acids in disease pathogenesis. The overall goal of the project is to use in vivo experiments to define the critical cells, environmental influences, and transgenes necessary and sufficient for induction of B27-associated disease in rats. The results of these studies will form the rational basis for identifying the molecular basis for B27- associated disease in humans.