EXPLORATION FOR A NEW PATHOGENESIS OF SJOGRENS SYNDROME

本研究深入探讨了低血糖的患病率、原因和纠正措施。 Sjogren综合征及淋巴细胞MHC Ⅰ类分子的表达 试图确定这种现象是否是自身免疫过程的核心 和疾病发病机制。它将寻求证据， 自体肽呈递是转运蛋白缺陷的结果 蛋白质功能这项建议是及时的，因为 了解糖尿病的自身免疫发病机制，现在应该是 应用于干燥综合征和其他免疫介导的 疾病我们最近对自身免疫性糖尿病的研究，包括人类和 小鼠模型，已经证明了内源性的功能缺陷， 自我肽片段在大细胞沟中的呈递 组织相容性复合体（MHC）I类分子，与 降低淋巴细胞上I类抗原的细胞表面表达。我们 认为MHC II类区域的两个基因（Tap-1和Tap-2）， 控制内源性肽向I类的递送和结合 分子，可能涉及糖尿病耐受缺陷。这笔赠款 将研究缺陷型MHC I类分子 表达/功能存在，并且在患有以下疾病的患者中具有潜在致病性 干燥综合征。初步结果显示细胞表面低表达 MHC I类分子的缺陷以及自我表达的缺陷， 干燥综合征患者淋巴细胞中的抗原。这些 结果表明，我们的模型失败的耐受性造成的不足， 糖尿病中的MHC I类/自身肽呈递也可能在糖尿病中起作用。 干燥综合征。疾病机制的新认识 干燥综合征可能导致新的诊断方法， 治疗这种严重的疾病。因此，这笔赠款的目的是： (1)定量检测人外周血淋巴细胞MHC I类分子表达 大量临床表现多样的干燥综合征患者， 种族组成;（2）评价I类细胞内加工， （3）测定细胞内转运蛋白和蛋白质的含量; 干燥综合征细胞;（4）尝试纠正低I类表达， 通过细胞因子治疗的干燥综合征细胞;（5）尝试纠正 通过切除完整的Sjogren综合征细胞中的低I类表达 转运蛋白基因;和，（6）研究I类缺陷小鼠作为新的 干燥综合征的动物模型。

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.