HLA-D Region in Systemic Lupus Erythematosus Pathogenesis

系统性红斑狼疮发病机制中的 HLA-D 区域

• 批准号: 7659646
• 负责人: Shu Man Fu
• 金额: $ 32.75万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7659646
• 关键词: Antibodies; Antibody Formation; Antigen-Antibody Complex; Antigens; Autoantibodies; Autoantigens; Autoimmune Responses; Autoimmunity; B-Lymphocyte Epitopes; Biological Assay; Candidate Disease Gene; Chronic; Complex; Data; Development; Disease; Environmental Risk Factor; Epitope Mapping; Epitopes; Event; Experimental Animal Model; Generations; Genes; Genetic; Genetic Predisposition to Disease; Glomerulonephritis; HLA-D Antigens; HLA-DR Antigens; Histocompatibility Antigens Class II; Hybridomas; Immune response; Indium; Link; Lupus; Major Histocompatibility Complex; Maps; Mediating; Microbe; Modeling; Molecular; Molecular Mimicry; Mus; Nature; Organ; Pathogenesis; Patients; Pattern; Peptide Mapping; Peptides; Prevention therapy; Process; Production; Recombinants; Research Personnel; Role; Sequence Homology; Sialadenitis; SmD antigen; Specificity; Systemic Lupus Erythematosus; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; Transgenes; Transgenic Mice; Transgenic Organisms; base; congenic; cross reactivity; cytokine; enzyme linked immunospot assay; lupus prone mice; man; mutant; prototype; research study; response; systemic autoimmune disease

DESCRIPTION (provided by applicant): Significant progress has been made to elucidate the mechanism of lupus autoantibody diversification and to identify important HLA-D restriction elements in response to SLE-related autoantigens. Crossreactive autoantibodies and the expansion of antigen-specific T cells reactive to one or more SLE-related autoantigens are important in the diversification of autoantibody response. With current available transgenic mice expressing D region molecules, DR2 and DR3 are the dominant determinants controlling the magnitude of the precipitating antibody response to recombinant Ro60, and for intermolecular epitope spreading to Ro52. With SmD as the immunogen, DR3 and DQ6 (DQ6B1*0602) were shown to be dominant in the generation of specific anti-SmD antibodies. In DR3 transgenic mice, intermolecular B epitope spreading to A-RNP, C-RNP, and SmB was found. In the case of the DQ6 transgenics, specific antibodies to A-RNP and SmB were detected. In addition, a new model of lupus prone mice, NZM2328 has been characterized and two unique congenic lines have been generated. The NZM2328 and its congenic lines will be useful in the proposed experiments. Based on these findings, this application is to explore the role of HLA-D region and T epitopes in SLE related autoantigens in the pathogenesis of SLE. Four specific aims are proposed. Specific Aim 1: To determine the role of HLA-D molecules in the pathogenesis of SLE. Specific Aim 2: To complete the mapping of T and B epitopes of the selected SLE related antigen SmD and to determine the mechanism of autoantibody diversification. Specific Aim 3: To determine the structural requirement for peptides from SLE related autoantigens. Specific Aim 4: To determine whether T cells reactive to DR restricted peptides mapped in specific aim 2 are present in patients with lupus and in normal controls. This proposal will provide significant information regarding the role of T cell receptor degeneracy, T cell epitopes and molecular mimicry in the induction of autoimmunity in SLE. The proposed experiments will provide new information regarding autoantibody diversification and may also provide data or clues regarding the nature of the initiating antigens. In addition, experiments are proposed to test directly whether HLA-D genes can directly support the development of SLE. The understanding of the role of HLA- D region in the pathogenesis of SLE and the initiation events is crucial in our approach for the prevention and therapy of this disorder.

描述（由申请人提供）：已经取得了重大进展来阐明狼疮自身抗体多样化的机制，并确定对与SLE相关的自身抗原的重要HLA-D限制元素。交叉反应性自身抗体和抗原特异性T细胞对一个或多个与SLE相关的自身抗原的反应对自身抗体反应的多样化很重要。对于表达D区域分子的电流可用的转基因小鼠，DR2和DR3是控制重组RO60沉淀抗体反应的大小的主要决定因素，对于分子间表位扩散到RO52。以SMD为免疫原，DR3和DQ6（DQ6B1*0602）在特定抗SMD抗体的产生中占主导地位。在DR3转基因小鼠中，发现分子间B表位扩散到A-RNP，C-RNP和SMB。在DQ6转基因的情况下，检测到针对A-RNP和SMB的特异性抗体。此外，已经表征了一种新的狼疮小鼠，NZM2328的新模型，并生成了两种独特的先流线。 NZM2328及其先天线将在拟议的实验中有用。基于这些发现，此应用是探索HLA-D区域和T表位在SLE相关自身抗原中在SLE发病机理中的作用。提出了四个具体目标。具体目标1：确定HLA-D分子在SLE发病机理中的作用。具体目标2：完成所选SLE相关抗原SMD的T和B表位的映射，并确定自身抗体多样化的机理。特定目的3：确定与SLE相关自身抗原的肽的结构需求。特定目的4：确定狼疮患者和正常对照的患者中是否存在对特定目标2中映射的DR限制肽的反应。该建议将提供有关T细胞受体退化，T细胞表位和分子模仿在SLE诱导自身免疫性中的作用的重要信息。拟议的实验将提供有关自身抗体多样化的新信息，还可以提供有关启动抗原性质的数据或线索。此外，提出了实验以直接测试HLA-D基因是否可以直接支持SLE的发展。对HLA-D区域在SLE发病机理和起始事件中的作用的理解对于我们预防和治疗该疾病的方法至关重要。