T Cell Epitope Mimicry for Autoimmune Responses in SLE

T 细胞表位模拟对 SLE 自身免疫反应的影响

基本信息

批准号：
8291356
负责人：
Umesh S Deshmukh
金额：
$ 42.45万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-16 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8291356
关键词：
Accounting Address Affect American Antibodies Antigens Antinuclear Antibodies Apoptotic Autoantibodies Autoantigens Autoimmune Diseases Autoimmune Responses Autoimmunity B-Cell Activation B-Lymphocyte Epitopes B-Lymphocytes Binding Cells Chromosome Mapping Clinical Complex Data Defect Development Disease Disease susceptibility Dominant Genetic Conditions Employee Strikes Environmental Risk Factor Epitopes Event Exposure to Female Frequencies General Population Generations Genes Genetic Predisposition to Disease Goals HLA-D Antigens HLA-DR Antigens HLA-DR3 Antigen Haplotypes Human Herpesvirus 4 Hybridomas Hyperactive behavior Immune response Incidence Individual Infection Infectious Agent Interferons Kidney Lead Literature Lupus Maps Mediating Memory Microbe Modeling Molecular Molecular Mimicry Monitor Mus Nature Organ Pathogenesis Pathway interactions Patients Peptides Play Predisposing Factor Process Production Proteins Regulation Regulatory T-Lymphocyte Relative (related person)Research Role Salivary Gland Diseases Serum Shapes SmD antigen Specificity Susceptibility Gene Symptoms Systemic Lupus Erythematosus T cell response T memory cell T-Cell Activation T-Cell Development T-Lymphocyte T-Lymphocyte Epitopes Testing Therapeutic Time To autoantigen Toll-like receptors Transgenic Mice Viral Antigens Virus Work autoreactive T cell base genetic element genetic risk factor genome wide association study high risk microbial microorganism microorganism antigen mimicry patient population response

项目摘要

Systemic lupus erythematosus (SLE) is a complex, autoimmune disorder predominantly affecting young females. Despite being multigenic, the HLA complex in general and HLA-DR in particular remains the most dominant genetic risk factor for disease susceptibility. A striking feature is the strong association of autoantibody specificities with some HLA haplotypes. This proposal addresses the mechanisms for this close association. In this proposal we will test the hypotheses that in lupus patients, molecular mimicry with microbial peptides is responsible for the selective enrichment of T cells reactive with lupus- associated autoantigens. Depending on microbial exposure, the HLA dictates the nature of cross- reactive peptides it binds and thereby the autoantigen selection. This process leads to activation of self- reactive T cells, autoantibody production, epitope spreading and end organ damage. Using Ro60 as the candidate autoantigen and HLA-DR and -DQ transgenic mice, following specific aims are proposed: to seek evidence for our hypothesis 1) To identify the molecular mimics of T cell epitopes on Ro60. 2) To demonstrate that multiple exposures to peptide mimics of Ro60 T cell epitopes influences the Ro60 reactive T cell repertoire. 3) To determine the pathogenic potential of anti-Ro60 initiated autoimmune responses in lupus-prone NZM2328 mice transgenic for HLA-DR3 and -DQ2. The findings from this proposal will clearly demonstrate that T cell responses to lupus-associated antigens can initiate autoimmune responses in SLE. This will shift the current paradigm that SLE is predominantly a B cell mediated disease to a more rational model in which both T and B cells have their unique roles in disease manifestation. This will provide a theoretical framework from which rational therapeutic approach can be devised.

系统性红斑狼疮 (SLE) 是一种复杂的自身免疫性疾病，主要影响年轻人女性。尽管是多基因的，但 HLA 复合体，尤其是 HLA-DR 仍然是最重要的。疾病易感性的最主要遗传危险因素。一个显着的特点是强烈的关联性一些 HLA 单倍型的自身抗体特异性。该提案解决了此问题的机制密切关联。在本提案中，我们将测试以下假设：在狼疮患者中，分子拟态与微生物肽一起负责选择性富集与狼疮反应的 T 细胞相关自身抗原。根据微生物暴露情况，HLA 决定了交叉反应的性质。它结合的反应性肽，从而选择自身抗原。这个过程会导致自我激活反应性 T 细胞、自身抗体产生、表位扩散和终末器官损伤。使用Ro60作为候选自身抗原和HLA-DR和-DQ转基因小鼠，提出以下具体目标：为我们的假设寻找证据 1) 鉴定 Ro60 上 T 细胞表位的分子模拟物。 2) 至证明多次暴露于 Ro60 T 细胞表位的肽模拟物会影响 Ro60 反应性 T 细胞库。 3) 确定抗Ro60引发的自身免疫的致病潜力 HLA-DR3 和 -DQ2 转基因易患狼疮的 NZM2328 小鼠的反应。由此得出的结论该提案将清楚地证明 T 细胞对狼疮相关抗原的反应可以启动 SLE 中的自身免疫反应。这将改变目前 SLE 主要是 B 细胞的范式将疾病介导为更合理的模型，其中 T 细胞和 B 细胞在疾病中都有其独特的作用表现。这将为合理的治疗方法提供一个理论框架。设计的。