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（申请人提供）：抽象的系统性红斑狼疮（SLE）是一种复杂的多基因自身免疫性疾病，具有蛋白质表现。通常，HLA复合物，特别是HLA-DR仍然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。该提案解决了这种紧密关联的机制。在此提案中，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与狼疮相关的自动抗原反应性的T细胞选择性富集的。根据微生物的暴露，HLA决定了其结合的交叉反应性肽的性质，从而决定了自动抗原选择。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。 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小鼠HLA-DR3 3）研究HLA-DR3限制的SMD肽模拟物模拟于激活HLA-DR3阳性SLE患者的T细胞的能力4）证明SMD反应性T细胞谱图在使用Lupus Virricer Coartia Clinia的不同地理位置的SLE SLE库中与Mayo Chartia和Mayo的Mayota和MiNese，MiNese，Minese，MiNese，MiNese，MiNese，MiNese，Mianne，Mione，Mayo，Mayo.该提案的发现将清楚地表明，T细胞对狼疮相关抗原的反应可以引发HLA-DR3患者SLE患者的自身免疫反应。这将提供一个理论框架，可以从中设计出理性的治疗方法来治疗和预防SLE。