MHC association in autoimmune arthritis

包括关节炎在内的许多自身免疫性疾病的易感性和严重性是 已知与特定的II类MHC等位基因密切相关，但 这些联系仍然是未知的。我们已经发现第二类等位基因的形式 异常低稳定性的II类相关不变链肽(CLIP)复合体 在易感性的等位基因中有不成比例的表现 自身免疫力。我们最近的工作表明，II类/片段亲和力的变化会影响 模型抗原呈递中II类分子的稳定性、寿命和丰度 细胞(APC)，并能调节抗原提呈。变种的机制 II类/片段亲和力可能影响自身免疫的易感性，包括 中央选择事件或外围容忍或激活事件，所有这些事件都是 受抗原提呈控制。 在这里，我们建议研究不同的II类/片段亲和力是否会影响 自身免疫性疾病在整个动物中的发病机制。我们将：1)建立2个短期 其中剪辑对II类的亲和力已被调节的小鼠模型，使用两个 易患关节炎的单倍型。这将通过重组受辐射的小鼠来实现 用野生型片段表达不变链的HSC(与MHC II亲和力低)或 突变片段(对MHC II具有高亲和力)；2)测量II类/片段的效果 亲和力对初级APC类型II类稳定性、寿命和丰度的影响 小鼠，包括在炎性刺激的背景下；3)确定调制 BM来源的APC中的II类/CLIP亲和力调节KRN模型中的疾病和关键 该模型的免疫学特征。这些实验的结果将塑造未来 研究，在这些研究中，我们将把这项工作扩展到第二个关节炎小鼠模型， AS开发了一种长期模型，用稳定的小鼠研究关节炎的发病机制 快递高亲和力片段/ii。如果高亲和力片段在造血细胞中的表达 足以预防疾病，它可能会为个人提供新的治疗选择 有患关节炎的风险。尽管多年来人们已经知道某些蛋白质，即人类白细胞抗原 蛋白质是关节炎和其他衰弱疾病的关键遗传风险因素 自身免疫性疾病，对这种遗传联系的解释仍然存在 未知。我们将在关节炎的小鼠模型上进行实验，以测试 对这种联系的机制提出了新的假设。如果成功，我们的 实验将对疾病发生和发展的机制(S)有新的认识 关节炎的发病机制，并可能为人类提供新的治疗方法 这些人患关节炎的风险很高。

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. 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.