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

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

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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.

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，但HLA综合体一般，尤其是HLA-DR仍然是疾病易感性的大多数主要遗传危险因素。一个惊人的功能是具有HLA单倍型的自身抗体特异性。该提议解决了此的机制密切关联。在此提案中，我们将测试在狼疮患者中，分子模仿的假设带有微生物肽的原因是T细胞与狼疮的反应性富集相关的自动抗原。根据微生物的暴露，HLA决定了交叉的性质反应性肽它结合，从而进行自身抗原选择。这个过程导致自我激活反应性T细胞，自身抗体产生，表位扩散和最终器官损伤。使用RO60作为候选自动抗原和HLA -DR和-DQ转基因小鼠，遵循特定目的：寻求我们的假设的证据1）鉴定RO60上T细胞表位的分子模仿。 2）到证明对RO60 T细胞表位的肽模拟物的多次暴露会影响RO60 反应性T细胞库。 3）确定抗Ro60的致病潜力引发了自身免疫性 HLA-DR3和-DQ2的狼疮宽NZM2328小鼠转基因的反应。从中的发现提案将清楚地表明，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。这将改变当前范式，因为SLE主要是B单元介导的疾病是一个更合理的模型，其中T和B细胞在疾病中都具有独特的作用表现。这将提供一个理论框架，理性的治疗方法可以是设计。