MHC association in autoimmune arthritis

MHC 与自身免疫性关节炎的关系

• 批准号: 8093106
• 负责人: Elizabeth D Mellins
• 金额: $ 4.82万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-28 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8093106
• 关键词: Affect; Affinity; Alleles; Animal Model; Animals; Antigen Presentation; Antigen-Presenting Cells; Arthritis; Autoimmune Diseases; Autoimmunity; Biological Models; Bone Marrow; Cells; Chronic Childhood Arthritis; Complex; Disease; Epitopes; Event; Future; Genetic; Goals; Haplotypes; Hematopoietic; Hematopoietic stem cells; Immune response; Immunologics; Individual; Inflammatory; K/BxN model; Laboratories; Light; Link; Longevity; MHC Class II Genes; Measures; Modeling; Mus; Mutant Strains Mice; Mutate; Pathogenesis; Peptides; Peripheral; Personal Communication; Phenotype; Predisposition; Proteins; Rheumatoid Arthritis; Risk; Severities; Shapes; Stimulus; Surface; Testing; Variant; Work; autoimmune arthritis; cell type; genetic risk factor; high risk; invariant chain; mouse model; novel; novel therapeutics; peripheral tolerance; reconstitution; research study

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.

许多自身免疫性疾病（包括关节炎）的易感性和严重程度 已知与特定的 II 类 MHC 等位基因密切相关，但其机制 这些关联仍然未知。我们发现 II 类等位基因形成 与 II 类相关的不变链肽 (CLIP) 的稳定性异常低的复合物 在赋予易感性的等位基因中所占比例不成比例 自身免疫。我们最近的工作表明 II 类/CLIP 亲和力的变化会影响 模型抗原呈递中 II 类分子的稳定性、寿命和丰度 细胞（APC）并可以调节抗原呈递。变异的机制 II 类/CLIP 亲和力可能会影响自身免疫的易感性，包括 中枢选择事件或外周耐受或激活事件，所有这些都是 由抗原呈递控制。 在这里，我们建议研究不同的 II 类/CLIP 亲和力是否会影响 整个动物自身免疫性疾病的发病机制。我们将：1）建立2个短期 小鼠模型，其中 CLIP 对 II 类的亲和力已被调节，使用两个 关节炎倾向的单倍型。这将通过用以下物质重建受辐射的小鼠来实现 使用野生型 CLIP（对 MHC II 具有低亲和力）表达不变链的 HSC 或 突变的 CLIP（与 MHC II 具有高亲和力）； 2) 测量II类/CLIP的影响 对这些初级 APC 类型的 II 类稳定性、寿命和丰度的亲和力 小鼠，包括在炎症刺激的情况下； 3）判断是否调制 BM 衍生的 APC 中 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 研究中，我们还将这项工作扩展到第二种关节炎小鼠模型 开发一个长期模型来研究关节炎的发病机制，使用稳定的小鼠 表达高亲和力 CLIP/Ii。如果造血细胞中高亲和力 CLIP 的表达是 足以预防疾病，它可能为个人提供新的治疗选择 关节炎的风险。尽管多年来人们已经知道某些蛋白质，HLA 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。我们将在关节炎小鼠模型中进行实验来测试 这种关联机制的新假设。如果成功的话，我们的 实验将为疾病发生和发生的机制提供新的线索 关节炎的发病机制，并可能为人们提供新的治疗方法 关节炎高危人群。

项目成果

Reduced locomotor activity correlates with increased severity of arthritis in a mouse model of antibody-induced arthritis.

在抗体诱导的关节炎小鼠模型中，运动活动的减少与关节炎严重程度的增加相关。

• DOI: 10.4236/ojra.2014.41010
• 发表时间: 2014
• 期刊: Open journal of rheumatology and autoimmune diseases
• 作者: Rajasekaran,Narendiran;Tran,Ricky;Pascual,Conrado;Xie,Xinmin;Mellins,ElizabethD
• 通讯作者: Mellins,ElizabethD

Transgene expression in various organs post BM-HSC transplantation.

• DOI: 10.1016/j.scr.2013.10.010
• 发表时间: 2014-01
• 期刊: STEM CELL RESEARCH
• 影响因子: 1.2
• 作者: Wang, Nan;Rajasekaran, Narendiran;Hou, Tieying;Mellins, Elizabeth D.
• 通讯作者: Mellins, Elizabeth D.

Comparison of transduction efficiency among various lentiviruses containing GFP reporter in bone marrow hematopoietic stem cell transplantation.

不同含GFP报告基因的慢病毒在骨髓造血干细胞移植中的转导效率比较。

• DOI: 10.1016/j.exphem.2013.07.002
• 发表时间: 2013
• 期刊: Experimental hematology
• 影响因子: 2.6
• 作者: Wang,Nan;Rajasekaran,Narendiran;Hou,Tieying;Lisowski,Leszek;Mellins,ElizabethD
• 通讯作者: Mellins,ElizabethD