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：
7893115
负责人：
Umesh S Deshmukh
金额：
$ 43.37万
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/7893115
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 public health relevance response

项目摘要

DESCRIPTION (provided by applicant): 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 application addresses the mechanisms for this close association. In this application 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 application 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. PUBLIC HEALTH RELEVANCE: The current application will identify proteins from infectious agents that might initiate an autoimmune response in systemic lupus erythematosus. This will identify infectious microorganisms that can be predisposing factors for the development of an autoimmune disorder such as lupus.

描述（由申请人提供）：全身性红斑狼疮（SLE）是一种复杂的自身免疫性疾病，主要影响年轻女性。尽管具有多基因元，但HLA复合物通常是疾病易感性的最主要遗传危险因素。一个引人注目的特征是自身抗体特异性与某些HLA单倍型的牢固关联。该应用程序解决了这种紧密关联的机制。在此应用中，我们将测试在狼疮患者中，用微生物肽的分子模拟物是导致T细胞与狼疮相关的自身抗原反应性的T细胞的选择性富集。根据微生物暴露，HLA决定了其结合的交叉反应性肽的性质，从而决定了自身抗原的选择。该过程导致自反应性T细胞，自身抗体产生，表位扩散和最终器官损伤的激活。提出了遵循特定目的的RO60作为候选自动抗原和HLA -DR和-DQ转基因小鼠：为我们的假设寻求证据1）确定RO60上T细胞表位的分子模拟物。 2）证明RO60 T细胞表位的多种暴露对RO60反应性T细胞库影响。 3）为了确定抗Ro60的致病潜力引发了狼疮易免疫反应的NZM2328小鼠HLA-DR3和-DQ2的转基因小鼠。该应用程序的发现将清楚地表明，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。这将使当前的SLE主要是B细胞介导的疾病的范式转变为更合理的模型，在该模型中，T和B细胞在疾病表现中都具有独特的作用。这将提供一个理论框架，可以从中设计出理性的治疗方法。公共卫生相关性：当前的应用程序将鉴定出可能在全身性红斑狼疮中引发自身免疫反应的传染剂的蛋白质。这将确定感染性微生物，这些微生物可能是自身免疫性疾病（例如狼疮）发展的诱发因素。