EXPLORATION FOR A NEW PATHOGENESIS OF SJOGRENS SYNDROME

本研究深入探讨了低血压的患病率、原因和纠正方法

This study addresses in-depth the prevalence, cause, and correction of low MHC class I expression on lymphoid cells in Sjogren's syndrome and will seek to determine if the phenomenon is central to the autoimmune process and disease pathogenesis. It will seek evidence that insufficient autologous peptide presentation is the result of defective transporter protein function. The proposal is timely because of advances in understanding the autoimmune pathogenesis of diabetes, which should now be applied to the study of Sjogren's syndrome and other immune-mediated disease. Our recent studies of autoimmune diabetes, both in humans and in murine models, have demonstrated a functional defect in endogenous presentation of self-peptide fragments in the groove of major histocompatibility complex (MHC) class I molecules, associated with decreased cell surface expression of class I antigens on lymphocytes. We believe that two genes (Tap-1 and Tap-2) in the MHC class II region, which control the delivery and association of endogenous peptides to class I molecules, may be involved in the diabetic tolerance defect. This grant will investigate the hypothesis that defective MHC class I expression/function is present and potentially pathogenic in patients with Sjogren's syndrome. Preliminary results show low cell surface expression of MHC class I molecules as well as a defect in the presentation of self- antigens in lymphocytes from individuals with Sjogren's syndrome. These results suggest that our model of failed tolerance caused by insufficient MHC class I/self-peptide presentation in diabetes may also be operative in Sjogren's syndrome. A new understanding of the disease mechanism in Sjogren's syndrome could lead to novel approaches to diagnosis and treatment of this serious disease. The aims of this grant are therefore: (1) Quantitate MHC class I expression on peripheral blood lymphocytes from large numbers of Sjogren's syndrome patients of diverse clinical and ethnic composition; (2) Evaluate class I intracellular processing by biochemical means; (3) Measure transporter message and protein in Sjogren's syndrome cells; (4) Attempt to correct low class I expression in Sjogren's syndrome cells by cytokine treatments; (5) Attempt to correct low class I expression in Sjogren's syndrome cells by transfecting intact transporter genes; and, (6) Investigate class I deficient mice as a new animal model for Sjogren's syndrome.