HLA-D Region in Systemic Lupus Erythematosus Pathogenesis

描述（由申请人提供）：在阐明狼疮自身抗体多样化机制和识别sle相关自身抗原应答的重要HLA-D限制因子方面取得了重大进展。交叉反应性自身抗体和抗原特异性T细胞对一种或多种slee相关自身抗原反应的扩增在自身抗体反应的多样化中很重要。在目前可用的表达D区分子的转基因小鼠中，DR2和DR3是控制重组Ro60沉淀抗体反应大小和分子间表位向Ro52扩散的主要决定因素。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表位向A-RNP、C-RNP和SmB扩散。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进行了鉴定，并产生了两个独特的基因系。NZM2328及其基因系将在实验中发挥重要作用。基于这些发现，本应用旨在探讨SLE相关自身抗原HLA-D区和T表位在SLE发病中的作用。提出了四个具体目标。特异性目的1：确定HLA-D分子在SLE发病机制中的作用。特异性目的2：完成选定SLE相关抗原SmD的T和B表位的定位，确定自身抗体分化的机制。特异性目的3：确定SLE相关自身抗原对肽的结构需求。特异性目的4：确定特异性目的2中定位的DR限制性肽是否在狼疮患者和正常对照中存在反应性T细胞。这一提议将提供关于T细胞受体变性、T细胞表位和分子拟态在SLE自身免疫诱导中的作用的重要信息。提出的实验将提供有关自身抗体多样化的新信息，也可能提供有关初始抗原性质的数据或线索。此外，我们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我们预防和治疗这种疾病的方法至关重要。

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.