MHC association in autoimmune arthritis

描述（由申请人提供）：已知许多自身免疫性疾病（包括关节炎）的易感性和严重程度与特定的II类MHC等位基因密切相关，但这些关联的机制尚不清楚。我们发现，与II类相关的不变链肽（CLIP）形成异常低稳定性复合物的II类等位基因在赋予自身免疫易感性的等位基因中比例不成比例。我们最近的工作表明，II类/CLIP亲和力的变化影响模型抗原呈递细胞（APC）中II类分子的稳定性、寿命和丰度，并可以调节抗原呈递。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枢选择事件或外周耐受性或激活事件的改变，所有这些都由抗原呈递控制。在这里，我们打算研究II类/CLIP亲和度的变化是否会影响整个动物自身免疫性疾病的发病机制。我们将：1)使用两种易患关节炎的单倍型，建立2个短期小鼠模型，其中CLIP对II类的亲和力已被调节。这将通过重组表达野生型CLIP（对MHC II具有低亲和力）或突变CLIP（对MHC II具有高亲和力）的HSC不变链的辐照小鼠来实现；2)测量II类/CLIP亲和力对来自这些小鼠的初级APC类型的II类稳定性、寿命和丰度的影响，包括在炎症刺激的背景下；3)确定脑卒中源性APC中II类/CLIP亲和力的调节是否能调节KRN模型中的疾病以及该模型中的关键免疫学特征。这些实验的结果将影响未来的研究，在未来的研究中，我们将把这项工作扩展到第二种关节炎小鼠模型，并开发一个长期模型，利用稳定表达高亲和力CLIP/Ii的小鼠来研究关节炎的发病机制。如果造血细胞中高亲和力CLIP的表达足以保护疾病，它可能为关节炎风险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HLA蛋白，是关节炎和其他使人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未知。我们将在小鼠关节炎模型中进行实验，以测试这种关联机制的新假设。如果实验成功，我们的实验将为关节炎的发病机制和发病机制提供新的线索，并可能为关节炎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 arthritis, 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 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 2 short-term mouse models in which the affinity of CLIP for class II has been modulated, using two arthritis-prone haplotypes. This will be achieved by re-constituting irradiated 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 in the KRN model and key immunologic features in this model. The results of these experiments will shape future studies, in which we will extend this work to the second mouse model of arthritis, as well as develop a long-term model to investigate arthritis 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 may provide new therapeutic options for individuals at risk for arthritis. PUBLIC HEALTH RELEVANCE Although it has been known for a number of years that certain proteins, the HLA proteins, are a critical genetic risk factor for arthritis and other debilitating autoimmune diseases, the explanation for this genetic link has remained unknown. We will perform experiments in a mouse model of arthritis 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 arthritis, and may suggest new treatment approaches for people who are at high risk for arthritis.