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: 7271175
• 负责人: Shu Man Fu
• 金额: $ 32.79万
• 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 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7271175
• 关键词: Antibodies; Antibody Formation; Antigen-Antibody Complex; Antigens; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; B-Lymphocyte Epitopes; Biological Assay; Candidate Disease Gene; Chronic; Class; 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; man; mutant; prototype; research study; response

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)：在阐明狼疮自身抗体多样化的机制和确定重要的人类白细胞抗原-D限制元件对系统性红斑狼疮相关自身抗原的反应方面取得了重大进展。交叉反应性自身抗体和对一个或多个SLE相关自身抗原反应的抗原特异性T细胞的扩增在自身抗体反应的多样化中是重要的。在目前可获得的表达D区分子的转基因小鼠中，DR2和DR3是控制重组Ro60的沉淀抗体应答和分子间表位扩散到Ro52的主要决定因素。以SMD为免疫原，DR3和DQ6(DQ6B1*0602)在产生特异性抗SMD抗体中占主导地位。在DR3转基因小鼠中，发现分子间B表位延伸到A-RNP、C-RNP和SMB。在DQ6转基因的情况下，检测到了A-RNP和SMB的特异性抗体。此外，还鉴定了一种新的狼疮易感小鼠模型NZM2328，并产生了两个独特的同源基因系。NZM2328及其同源品系将在拟议的实验中发挥作用。基于这些发现，本研究旨在探讨SLE相关自身抗原中的人类白细胞抗原-D区和T表位在SLE发病机制中的作用。提出了四个具体目标。目的1：探讨人类白细胞抗原-D分子在系统性红斑狼疮发病机制中的作用。具体目的2：完成所选SLE相关抗原SMD的T和B表位的定位，并确定自身抗体多样化的机制。具体目的3：确定SLE相关自身抗原对多肽的结构要求。特异性目的4：确定特异性目的2定位的对DR限制性多肽有反应的T细胞是否存在于狼疮患者和正常人中。这一建议将提供关于T细胞受体退行性变、T细胞表位和分子模拟在诱导SLE自身免疫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，还可能提供关于启动抗原的性质的数据或线索。此外，还建议通过实验直接测试人类白细胞抗原-D基因是否能直接支持系统性红斑狼疮的发生。了解人类白细胞抗原-D区在系统性红斑狼疮发病机制中的作用及其发生的始动事件，对于防治系统性红斑狼疮具有重要意义。