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的机制和鉴定对SLE相关自身抗原应答的重要HLA-D限制性元件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SLE相关自身抗原的反应性扩增在自身抗体应答的多样化中是重要的。对于目前可用的表达D区分子的转基因小鼠，DR 2和DR 3是控制对重组Ro 60的沉淀抗体应答的大小以及分子间表位扩散到Ro 52的主要决定因素。以SmD为免疫原，DR 3和DQ 6（DQ 6 B1 *0602）在特异性抗SmD抗体的产生中显示出优势。在DR 3转基因小鼠中，检测到分子间B表位向A-RNP、C-RNP和Sm B扩散，在DQ 6转基因小鼠中，检测到抗A-RNP和Sm B的特异性抗体。此外，一种新的狼疮易感小鼠模型，NZM 2328已被表征，并产生了两个独特的同类系。NZM 2328及其同源系将在所提出的实验中有用。本研究旨在探讨SLE相关自身抗原中HLA-D区和T表位在SLE发病中的作用。提出了四个具体目标。目的1：探讨HLA-D分子在SLE发病中的作用。具体目标二：完成SLE相关抗原SmD的T、B表位定位，探讨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：为了确定是否有T细胞反应DR限制性肽映射在特定的目标2中存在于狼疮患者和正常对照。这一建议将提供重要的信息，T细胞受体简并性，T细胞表位和分子模拟在诱导SLE自身免疫的作用。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，实验提出直接测试是否HLA-D基因可以直接支持SLE的发展。了解HLA-D区在SLE发病机制中的作用及其启动事件，对SLE的预防和治疗具有重要意义。

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.