IMMUNOPATHOGENESIS OF INFLAMMATORY VASCULAR DISEASE

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Our observations in human Sjogren's syndrome (SS), a common connective tissue disorder, have shown that inflammatory vascular disease in this condition is: a relatively common complication, associated in a striking statistically significant manner with the presence of serum rheumatoid factor, and characterized by two main histopathologic prototypes which appear to be mediated by different immunopathologic mechanisms. In parallel, we have investigated the congenic autoimmune mouse strain MRL/Mp as a model of Sjogren's syndrome and have observed: a high frequency of vasculitis, the acceleration of vasculitis in association with the acquisition of high titer RF, and two main types of vascular histopathology which are indistinguishable from those seen in patients with SS. These preliminary observations form the basis for this proposal which will examine the immunopathogenesis of inflammatory vascular disease in human and murine SS, and its direct relationship to RF. Employing immunocytochemistry and a sensitive assay system (ELISA) for the detection of RFs of different isotypes, the immunopathogenesis of vasculitis will be defined in relationship to the acquisition of RF. The specific characteristics of RF which determine pathogenicity will be established. The relative roles of the passive deposition of circulating RF versus its in situ production within the vessel wall will be examined using immunocytochemistry studies employing anti-idiotypic antibodies to RF, passive transfer studies with monoclonal RFs, and cell transfer studies employing populations enriched for immunoglobulin (RF) producing cells. To our knowledge this is the first attempt to study systematically a spontaneously occurring animal model of immune vascular disease. Moreover, the proposed murine studies have direct relevance to a human disorder, i.e. Sjogren's syndrome. It is likely that the mechanisms of inflammatory vascular disease elucidated in this autoimmune connective tissue disorder will have direct relevance for vasculitis occurring in other clinical settings.