Mechanism of MHC Association with Type 1 Diabetes

描述(由申请人提供)：许多自身免疫性疾病的易感性和严重性，包括1型糖尿病(T1D)，已知与特定的II类MHC等位基因密切相关，但这些关联的机制仍不清楚。我们发现，在自身免疫易感性的等位基因中，与第II类相关不变链肽(CLIP)形成异常低稳定性复合体的第II类等位基因的比例不成比例。我们最近的工作表明，II类/CLIP亲和力的变化会影响模型抗原提呈细胞(APC)中II类分子的稳定性、寿命和丰度，并可以调节抗原提呈。因此，II类/CLIP亲和力的变化可能影响自身免疫易感性的机制包括中央选择事件或外周耐受或激活事件的变化，所有这些变化都由抗原提呈控制。 在这里，我们建议研究不同的II类/CLIP亲和力是否会影响整个动物的自身免疫性疾病的发病机制。我们将：1)建立一个短期的T1D小鼠模型，其中CLIP对II类的亲和力已经被调节；这将通过重组受照射的疾病前NOD小鼠的HSC表达不变链来实现，野生型CLIP(对MHC II的亲和力低)或突变的CLIP(对MHC II具有高亲和力)；2)测量II类/CLIP亲和力对这些小鼠原始APC类型II类的稳定性、寿命和丰度的影响，包括在炎症刺激的情况下；3)确定BM来源的APC中II类/CLIP亲和力的调节是否调节了疾病和该模型中的关键免疫学特征。这些实验的结果将塑造未来的研究，在这些研究中，我们将在长期模型中扩展这项工作，使用稳定表达高亲和力CLIP/II的小鼠来研究糖尿病的发病机制。如果高亲和力CLIP在造血细胞中的表达足以保护疾病，将为T1D高危个体提供新的治疗选择。尽管多年来人们已经知道，某些蛋白质，即人类白细胞抗原蛋白，是1型糖尿病和其他衰弱的自身免疫性疾病的关键遗传风险因素，但这种遗传联系的解释仍然不清楚。我们将在糖尿病小鼠模型上进行实验，以测试这种关联机制的新假说。如果成功，我们的实验将为糖尿病的疾病起始和发病机制(S)提供新的线索，并可能为糖尿病高危人群提供新的治疗方法。

DESCRIPTION (provided by applicant): Susceptibility to and severity of many autoimmune diseases, including type 1 diabetes (T1D), are known to be closely linked with particular class II MHC alleles, but the mechanism of these associations remains unknown. We have found that class II alleles that form unusually low-stability complexes with class II- associated invariant chain peptides (CLIP) are disproportionately represented among alleles that confer susceptibility to autoimmunity. Our recent work indicates that variations in class II/CLIP affinity affect the stability, longevity, and abundance of class II molecules in model antigen presenting cells (APC) and can modulate antigen presentation. Mechanisms by which variations in class II/CLIP affinity could influence susceptibility to autoimmunity thus include alterations in central selection events or peripheral tolerance or activation events, all of which are controlled by antigen presentation. Here, we propose to study whether varying class II/CLIP affinity can influence autoimmune disease pathogenesis in a whole animal. We will: 1) Establish a short-term mouse model of T1D in which the affinity of CLIP for class II has been modulated; this will be achieved by reconstituting irradiated, pre-disease NOD mice with HSC expressing invariant chains with wild type CLIP (with low affinity for MHC II) or mutated CLIP (with high affinity for MHC II); 2) Measure the effects of class II/CLIP affinity on class II stability, longevity, and abundance in primary APC types from these mice, including in the context of inflammatory stimuli; 3) Determine whether modulation of class II/CLIP affinity in BM-derived APC modulates disease and key immunologic features in this model. The results of these experiments will shape future studies, in which we will extend this work in a long-term model to investigate diabetes pathogenesis using mice that stably express high-affinity CLIP/Ii. If expression of high affinity CLIP in hematopoietic cells is sufficient for disease protection, it will provide new therapeutic options for individuals at risk for T1D. Although it has been known for a number of years that certain proteins, the HLA proteins, are a critical genetic risk factor for type 1 diabetes and other debilitating autoimmune diseases, the explanation for this genetic link has remained unknown. We will perform experiments in a mouse model of diabetes to test a novel hypothesis for the mechanism of this association. If successful, our experiments will shed new light on the mechanism(s) of disease initiation and pathogenesis in diabetes, and may suggest new treatment approaches for people who are at high risk for diabetes.