Seronegative spondyloarthropathies are a group of inflammatory diseases in which the spine, peripheral joints, skin, eyes and other tissues of the body may be involved. There is a strong association of the HLA-B27 antigen with several of the diseases. In most cases the disease occurs after gastrointestinal infection with one of several species of enterobacteria. Thus, the evidence is very strong that HLA-B27 molecule and enterobacteria are involved. Yet only a small percentage of B27 positive individuals come down with the inflammatory disease. This suggests that other genetic and environmental parameters must also be involved in the disease process. In order to understand the etiology, mechanism, and pathogenesis as well as formulate protocols for preventive immunotherapeutic procedures an animal model is needed. Transgenic mice expressing the HLA-B27 gene derived from a patient with ankylosing spondylitis was used in conjunction with Yersinia enterocolitica 0:8 WA strain isolated from a patient with reactive arthritis to generate a mouse model for spondyloarthropathies. Interesting and provocative preliminary observations have been made which will be followed up. New transgenic mice expressing a hybrid human B27/mouse, K gene would be utilized in an attempt to generate autoreactive T cells which may be pathogenic in joint tissue. Mice which lack the beta2 microglobulin, mouse endogenous class I molecules and CD8+ T cells generated by gene targeting and homologous recombination will be utilized to make B27 the predominant class I molecules in the transgenic mice. New transgenic mice with high gene copy number of the B27 gene will be generated in both B27 and a control B8 gene to determine the possible role of chromosomal perturbation in the disease process. A mouse model for reactive arthritis restricted by mouse endogenous MHC genes will also be developed as a model for the human disease. A transgenic mouse expressing a human CD8 gene will be introduced into the B27+ mouse to enhance a class I restricted response. A possible role for bacterial superantigens and heat shock proteins in activating self reactive T cells or inducing tolerance will be investigated. These studies should provide new insights into the mechanisms to enable future research on gene manipulation and immunotherapy for prevention as well as treatment of spondyloarthropathies.
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