HLA-D Region Systemic Lupus Erythematosus Pathogenesis

HLA-D 区域系统性红斑狼疮发病机制

• 批准号: 6976885
• 负责人: Shu Man Fu
• 金额: $ 45.88万
• 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/6976885
• 关键词: MHC class II antigen; T cell receptor; T lymphocyte; antibody formation; autoantibody; autoantigens; biotechnology; clinical research; cytokine; disease /disorder model; enzyme linked immunosorbent assay; epitope mapping; female; genetic mapping; genetic susceptibility; genetically modified animals; human subject; immunogenetics; laboratory mouse; lupus nephritis; pathologic process; systemic lupus erythematosus; women' s health

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以及鉴定响应SLE相关自身抗原的重要HLA-D限制元件方面已经取得了重大进展。交叉反应性自身抗体以及对一种或多种 SLE 相关自身抗原具有反应性的抗原特异性 T 细胞的扩增对于自身抗体反应的多样化至关重要。对于目前表达 D 区分子的转基因小鼠，DR2 和 DR3 是控制对重组 Ro60 的沉淀抗体反应程度以及向 Ro52 的分子间表位扩散的主要决定因素。以 SmD 作为免疫原，DR3 和 DQ6 (DQ6B1*0602) 在特异性抗 SmD 抗体的生成中起主导作用。在 DR3 转基因小鼠中，发现分子间 B 表位扩散至 A-RNP、C-RNP 和 SmB。在 DQ6 转基因的情况下，检测到 A-RNP 和 SmB 的特异性抗体。此外，还对一种新的狼疮易感小鼠模型 NZM2328 进行了表征，并产生了两个独特的同系系。 NZM2328 及其同类系将在拟议的实验中有用。基于这些发现，本申请旨在探讨SLE相关自身抗原中HLA-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。具体目标 1：确定 HLA-D 分子在 SLE 发病机制中的作用。具体目标2：完成所选SLE相关抗原SmD的T和B表位的定位，并确定自身抗体多样化的机制。具体目标 3：确定 SLE 相关自身抗原肽的结构要求。具体目标 4：确定狼疮患者和正常对照中是否存在对具体目标 2 中绘制的 DR 限制性肽有反应的 T 细胞。该提案将提供有关 T 细胞受体简并性、T 细胞表位和分子拟态在诱导 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，也可能提供有关起始抗原性质的数据或线索。此外，还提出了实验来直接测试HLA-D基因是否可以直接支持SLE的发展。了解 HLA-D 区域在 SLE 发病机制和起始事件中的作用对于我们预防和治疗这种疾病的方法至关重要。