Mechanisms for HLA-DQ mediated disease protection and susceptibility

描述（由申请人提供）：1型糖尿病（T1 D）是一种自身免疫性代谢疾病，其特征在于胰腺β细胞的破坏。在与疾病风险相关的众多染色体区域中，HLA基因座具有迄今为止最强的疾病关联。特别地，HLA-DQA 1 *0301/DQB 1 *0302（DQ 8）和HLA-DQA 1 *0501/DQB 1 *0201（DQ 2）杂合的受试者具有最高的风险。相反，HLA-DQA 1 *0102/DQB 1 *0602（DQ 6）与疾病保护相关。虽然这些遗传方面是很好地建立，DQ分子赋予疾病保护或易感性的功能机制仍然相对未解决。我们建议直接检查DQ限制性T细胞在T1 D发病机制和疾病保护中的作用。本研究将采用独特的试剂和新技术，广泛收集DQ限制性T细胞克隆和DQ转染细胞系，其具体目的如下：目的1：阐明DQ介导的糖尿病易感性的功能机制。目的2：探讨DQ对糖尿病的保护作用机制。目的3：直接研究DQ限制性T细胞在T1 D发病机制中的作用。利用DQ 2、DQ 8、DQ 2/8和DQ 6单体和多聚体以及诸如离体四聚体富集和高通量转录物分析的尖端技术，我们将鉴定由易感HLA-DQ赋予的导致自身耐受性破坏的不同功能属性和由保护性HLA-DQ赋予的恢复耐受性的相反属性。我们预期这些属性将包括IL-2和TCR信号传导、抗原呈递和细胞因子谱。利用来自世界上最大的T1 D登记中心之一的样本和强大的纵向样本集合，我们将利用具有把握度（预期把握度> 90%）的匹配病例对照设计来比较DQ和DR自身反应性预测T1 D状态的能力。将进行第二次尝试，以确定DQ和DR自身反应性之间的相关程度。我们预期HLA-DQ应答将提供比HLA-DR应答更有意义的相关性。这项研究的完成将阐明T1 D进展中的重要早期事件，提出重要的新治疗途径，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（T1 D）相关的基因，但HLA基因与这种疾病的关联性最强。利用来自世界上最大的T1 D患者登记处之一的样本，并应用独特的技术，我们将直接研究这些基因在T1 D中的功能作用。这些观察结果将阐明疾病进展中的重要早期事件，提供新的生物标志物，并提出重要的新治疗途径。

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.