Role of HLA-DR3 in pathogenesis of Systemic lupus erythematosus(SLE)

HLA-DR3在系统性红斑狼疮（SLE）发病机制中的作用

基本信息

批准号：
7989294
负责人：
Vaidehi Radhakrishna Chowdhary
金额：
$ 12.83万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7989294
关键词：
Address Agonist Alleles Antibodies Antigen Presentation Antigen-Antibody Complex Antigens Antinuclear Antibodies Appearance Area Autoantibodies Autoantigens Autoimmune Diseases Autoimmune Process Autoimmune Responses Autoimmunity B-Lymphocytes Binding Biological Assay CD4 Positive T Lymphocytes Carrier Proteins Cell Line Cells Characteristics Chromatin Clinic Complex Congenic Mice Dendritic Cells Development Diagnosis Disease Disease susceptibility Employee Strikes Epitopes Exposure to Frequencies Galactosides Generations Genes Genetic Predisposition to Disease Goals HLA-DR Antigens HLA-DRB1 Haplotypes Heterozygote Histocompatibility Antigens Class II Homozygote Human Immune Tolerance Immune response Immunization Individual Infection Infectious Agent Interferons Kidney Ku70 protein Lead Ligands Linkage Disequilibrium Literature Lupus Lupus Nephritis Memory Methyltransferase Microarray Analysis Microbe Minnesota Modeling Molecular Molecular Mimicry Monitor Mus Nature Nephritis Nuclear Antigens Organ Particulate Partner in relationship Pathogenesis Pathogenicity Pathway interactions Patients Pattern Peptides Peripheral Blood Mononuclear Cell Phagocytosis Play Poly I-C Predisposition Prevention Process Production Proteins Raynaud Phenomenon Regimen Regulatory T-Lymphocyte Risk Risk Factors Role Salivary Gland Diseases Serum Shapes Sm antigen Specificity Streptococcus Group B Systemic Lupus Erythematosus T cell response T memory cell T-Lymphocyte T-Lymphocyte Epitopes TLR3 gene TLR7 gene Testing Therapeutic Time Tissues Toll-like receptors Transgenes Transgenic Mice Universities Up-Regulation Vibrio cholerae Viral Antigens Virginia Virus Work abstracting autoreactive B cell autoreactive T cell clinical Diagnosis cohort cytokine ds-DNA enzyme linked immunospot assay genetic risk factor genome wide association study high risk human TLR7 protein microbial microorganism microorganism antigen mouse model pathogen patient population research study thymocyte tool trend

项目摘要

DESCRIPTION (provided by applicant): Abstract Systemic lupus erythematosus (SLE) is a complex, multigenic autoimmune disorder with protean manifestations. 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 auto antigens. Depending on microbial exposure, the HLA dictates the nature of cross-reactive peptides it binds and thereby the auto antigen selection. This process leads to activation of self-reactive T cells, autoantibody production, epitope spreading and end organ damage. Using SmD as the candidate auto antigen and HLA-DR3 (DRB1*0301) transgenic mice and HLA-DR3 positive SLE patients, following specific aims are proposed 1) To demonstrate that multiple exposures to peptide mimics of SmD T cell epitopes influence the SmD reactive T cell repertoire 2) To determine the pathogenic potential of anti- SmD initiated autoimmune responses in lupus-prone NZM2328 mice transgenic for HLA-DR3 3) To investigate the ability of HLA-DR3 restricted SmD peptide mimics to activate T cells from HLA- DR3 positive SLE patients 4) To demonstrate that SmD reactive T cell repertoire is different in SLE patient populations from distinct geographical areas using lupus patient cohort from Mayo Clinic, Minnesota and Charlottesville, Virginia. The findings from this proposal will clearly demonstrate that T cell responses to lupus-associated antigens can initiate autoimmune responses in SLE patients with HLA-DR3. This will provide a theoretical framework from which rational therapeutic approach can be devised for treatment and prevention of SLE.

描述（由申请人提供）：摘要系统性红斑狼疮（SLE）是一种复杂的、多基因的自身免疫性疾病，具有多变的表现。一般而言，HLA 复合体，特别是 HLA-DR 仍然是疾病易感性的最主要遗传风险因素。一个显着的特征是自身抗体特异性与某些 HLA 单倍型的紧密关联。该提案解决了这种紧密联系的机制。在本提案中，我们将测试以下假设：在狼疮患者中，微生物肽的分子模拟负责选择性富集与狼疮相关自身抗原反应的 T 细胞。根据微生物暴露情况，HLA 决定其结合的交叉反应肽的性质，从而决定自身抗原的选择。该过程导致自身反应性 T 细胞的激活、自身抗体的产生、表位扩散和终末器官损伤。使用 SmD 作为候选自身抗原以及 HLA-DR3 (DRB1*0301) 转基因小鼠和 HLA-DR3 阳性 SLE 患者，提出了以下具体目标 1) 证明多次暴露于 SmD T 细胞表位的肽模拟物会影响 SmD 反应性T 细胞库 2) 确定抗 SmD 在易患狼疮的 NZM2328 转基因小鼠中引发的自身免疫反应的致病潜力HLA-DR3 3) 研究 HLA-DR3 限制性 SmD 肽模拟物激活 HLA-DR3 阳性 SLE 患者 T 细胞的能力 4) 使用狼疮证明来自不同地理区域的 SLE 患者群体中的 SmD 反应性 T 细胞库是不同的来自明尼苏达州梅奥诊所和弗吉尼亚州夏洛茨维尔的患者队列。该提案的结果将清楚地证明，T 细胞对狼疮相关抗原的反应可以在携带 HLA-DR3 的 SLE 患者中引发自身免疫反应。这将为设计合理的治疗方法来治疗和预防 SLE 提供一个理论框架。