Chronic spine inflammation is the major abnormality in ankylosing spondylitis (AS), the disease that affects more than 700,000 people only in USA. Although the AS etiology is poorly understood, environmental and genetic components are critical risk factors in this scenario. To date, the strongest known genetic risk factor is the major histocompatibility complex (MHC) and much less is known about non-MHC genes, despite a dozen chromosome regions known to be linked to AS. To study the genetics and pathophysiology of the disease, we have developed a murine model, where the spondylitis is induced by systemic immunization with proteoglycan (proteoglycan-induced spondylitis, PGIS). The model is unique and worthy of study because autoimmune spondylitis is under strong genetic control of non-MHC genes. In preliminary work we have found that on a permissive MHC background only two major loci located on chromosomes 18 (Pgisl) and 2 (Pgis2) jointly control disease susceptibility. Importantly, Pgis2 mainly controls the initial phase of spine inflammation and inflammatory cells infiltration, and Pgisl is primarily responsible for disks resorption and ankylosis. Interaction between these two loci is an essential feature of the disease, since Pgis2 is required for the full penetrance of the Pgisl locus. Both loci were homologous to chromosome segments linked to human AS and were implicated in a number of murine models for human autoimmune diseases. The application will study congenic mice in which Pgisl and Pgis2 susceptibility loci have been transferred from the DBA/2 resistant strain to BALB/c genetic background. Development of spondylitis and immunological loci-specific subphenotypes will be established. We will narrow the size of loci by a sequential two-stage selective phenotyping approach. Identification of the primary genetic factors and discovery of the mechanism for initiation and progression of spondylitis should provide significant insights into the pathogenesis of autoimmune diseases. ? ? ?
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