EXPLORATION FOR A NEW PATHOGENESIS OF SJOGRENS SYNDROME

干燥综合征新发病机制的探索

• 批准号: 2132291
• 负责人: Denise L Faustman
• 金额: $ 24.35万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-03-01 至 1998-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2132291
• 关键词: MHC class I antigen; Sjogren's syndrome; antigen presentation; autoimmune disorder; complementary DNA; cytokine; cytotoxic T lymphocyte; disease /disorder model; epidemiology; family genetics; female; gene expression; genetic transcription; genetic translation; human subject; interferons; laboratory mouse; lymphocyte; membrane transport proteins; northern blottings; pathologic process; peptides; tissue /cell culture; transfection; western blottings

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.

这项研究深入探讨了低血压的流行、原因和纠正 干燥综合征患者淋巴样细胞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中心 以及疾病的发病机制。它将寻求证据表明 自体多肽递呈是转运蛋白缺陷的结果 蛋白质的功能。这项建议是及时的，因为在 了解糖尿病的自身免疫发病机制，现在应该是 应用于干燥综合征等免疫介导性疾病的研究 疾病。我们最近对自身免疫性糖尿病的研究，无论是在人类还是在 小鼠模型，已经证明内源性的功能缺陷 自体多肽片段在大脑沟中的呈现 组织相容性复合体(MHC)I类分子，与 淋巴细胞表面I类抗原表达减少。我们 认为MHC II类区域有两个基因(Tap-1和Tap-2)，它们 控制内源性多肽对第I类的传递和结合 分子，可能参与了糖尿病耐受缺陷。这笔赠款 将调查有缺陷的MHC I类物质的假设 存在表达/功能并可能致病的患者 干燥综合征。初步结果显示细胞表面低表达 MHC I类分子的存在以及自我呈现的缺陷 干燥综合征患者淋巴细胞中的抗原。这些 结果表明，我们的失败容忍度模型是由于 糖尿病患者的MHC-I类/自体多肽呈递也可用于 干燥综合征。对黄连病机的新认识 干燥综合征可能导致新的诊断和治疗方法 治疗这种严重疾病的方法。因此，这笔赠款的目的是： (1)定量检测小鼠外周血淋巴细胞MHC-I类分子的表达 大量临床表现各异的干燥综合征患者 种族构成；(2)通过以下方式评估I类细胞内加工 生化手段；(3)测定转运蛋白信息和蛋白质 Sjogren‘s综合征细胞；(4)尝试纠正I类低表达 细胞因子治疗干燥综合征细胞；(5)试图纠正 用完整转基因技术在干燥综合征细胞中低表达I类分子 转运蛋白基因；以及，(6)研究I类缺陷小鼠作为一种新的 干燥综合征动物模型。