Mechanisms for HLA-DQ mediated disease protection and susceptibility

描述(申请人提供)：1型糖尿病(T1D)是一种自身免疫性代谢性疾病，以胰岛β细胞破坏为特征。在众多与疾病风险相关的染色体区域中，到目前为止，人类白细胞抗原基因座与疾病的相关性最强。特别是，人类白细胞抗原-DQA1*0301/DQB1*0302(DQ8)和人类白细胞抗原-DQA1*0501/DQB1*0201(DQ2)杂合子的风险最高。相反，人类白细胞抗原-DQA1*0102/DQB1*0602(DQ6)与疾病保护相关。虽然这些遗传因素已经得到了很好的证实，但DQ分子提供疾病保护或易感性的功能机制仍然相对未解。我们建议直接研究DQ限制性T细胞在T1D发病机制和疾病保护中的作用。这项工作将应用独特的试剂和新技术，并广泛收集DQ限制性T细胞克隆和DQ转基因细胞系，其具体目的如下：目的1：阐明DQ介导的糖尿病易感性的作用机制。目的2：阐明DQ介导的糖尿病保护作用机制。目的：直接探讨DQ限制性T细胞在T1D发病机制中的作用。利用DQ2、DQ8、DQ2/8和DQ6单体和多聚体以及体外四聚体浓缩和高通量转录分析等前沿技术，我们将识别导致自身耐受崩溃的易感HLA-DQ赋予的不同功能属性，以及保护性HLA-DQ赋予的恢复耐受的相反属性。我们预计这些属性将包括IL-2和TCR信号、抗原呈递和细胞因子谱。利用来自世界上最大的T1D登记机构之一的样本和强大的纵向样本收集，我们将利用匹配的病例对照设计来比较DQ和DR自动反应性预测T1D状态的能力。将进行第二次尝试，以确定DQ和DR自动反应性之间的相关程度。我们期望人类白细胞抗原-DQ反应将比人类白细胞抗原-DR反应提供更有意义的相关性。这项研究的完成将阐明T1D进展过程中的重要早期事件，为治疗提供重要的新途径，并为疾病监测提供新的生物标志物。 公共卫生相关性：最近的研究已经确定了许多与1型糖尿病(T1D)相关的基因，但到目前为止，人类白细胞抗原基因与这种疾病的相关性最强。利用来自世界上最大的T1D患者登记之一的样本并应用独特的技术，我们将直接检查这些基因在T1D中的功能作用。这些观察将阐明疾病进展中的重要早期事件，提供一个新的生物标记物，并为治疗提供重要的新途径。

DESCRIPTION (provided by applicant): Type 1 diabetes (T1D) is an autoimmune metabolic disease characterized by destruction of pancreatic beta cells. Among numerous chromosomal regions that are linked to disease risk, the HLA locus has by far the strongest disease association. In particular, subjects who are heterozygous for HLA- DQA1*0301/DQB1*0302 (DQ8) and HLA-DQA1*0501/DQB1*0201 (DQ2) have the highest risk. In contrast, HLA- DQA1*0102/DQB1*0602 (DQ6) is associated with disease protection. While these genetic aspects are well established, the functional mechanisms by which DQ molecules confer disease protection or susceptibility remain relatively unresolved. We propose to directly examine the role of DQ restricted T cells in T1D pathogenesis and protection from disease. This work, which will apply unique reagents and new technologies and extensive collections of DQ-restricted T cell clones and DQ-transfected cell lines will have the following specific aims: Aim 1: To delineate the functional mechanisms of DQ mediated diabetes susceptibility. Aim 2: To delineate the functional mechanisms of DQ mediated diabetes protection. Aim 3: To directly examine the role of DQ restricted T cells in the pathogenesis of T1D. Utilizing DQ2, DQ8, DQ2/8 and DQ6 monomers and multimers and cutting edge techniques such as ex vivo tetramer enrichment and high throughput transcript analysis, we will identify the distinct functional attributes conferred y susceptible HLA-DQ that lead to the breakdown of self-tolerance and opposing attributes conferred by protective HLA-DQ that restore tolerance. We expect that these attributes will include IL-2 and TCR signaling, antigen presentation, and cytokine profile. Utilizing samples from one of the world's largest T1D registry and a formidable collection of longitudinal samples, we will utilize a matched case-control design that is powered (expected power >90 percent) to compare the ability of DQ and DR auto-reactivity to predict T1D status. A secondary attempt will be made to establish the degree of correlation between DQ and DR auto-reactivity. We expect that HLA-DQ responses will provide a more meaningful correlation than HLA-DR responses. Completion of this study will illuminate important early events in the progression of T1D, suggesting important new avenues for therapy and providing a novel biomarker for disease monitoring. PUBLIC HEALTH RELEVANCE: Recent studies have identified numerous genes that are linked to type 1diabetes (T1D), but HLA genes have by far the strongest association with this disease. Utilizing samples from one of the world's largest T1D patient registries and applying unique technologies, we will directly examine the functional role of these genes in T1D. These observations will illuminate important early events in disease progression, providing a new biomarker and suggesting important new avenues for therapy.