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.

对许多自身免疫性疾病的易感性和严重程度，包括关节炎，是

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