HLA-D antigens, T cell epitopes and antibody specificity in SLE

描述（由申请人提供）： 在目前的SCOR期间，已经取得了重大进展，阐明狼疮自身抗体多样化的机制，并确定重要的HLA-D限制性元件，以响应SLE相关的自身抗原。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ROM的沉淀抗体应答的大小和分子间表位扩散到Ro 52的主要决定因素。对于SmD免疫，DR 3被证明是占主导地位的SmB特异性抗体的产生。本次竞争性更新申请是为了继续探讨SLE相关自身抗原中HLA-D区和T细胞表位在SLE发病机制中的作用。具体目标1：利用现有的转基因HLA-DR 3和-DR 4小鼠，进一步定位Ro 60、SmD、SmB和A蛋白的T细胞表位。 snRNP颗粒，通过产生抗原特异性TT杂交瘤。具体目标二：目的研究SLE患者及正常对照组HLA-DR 4、HLA-DR 3抗原特异性T细胞的表达。这是弗吉尼亚大学和弗吉尼亚梅森研究中心之间的合作。具体目标3：产生缺失整个小鼠I区并表达各种HLA-D区分子的NZM 2328突变体作为转基因，以确定这些转基因是否能够支持自发性自身抗体产生以及急性和慢性肾小球肾炎的诱导。他们也将进行测试，以确定慢性涎腺炎是否可以诱导CMV。具体目标4：启动一项合作研究，以比较北方印度和弗吉尼亚州中部SLE人群的抗Sm抗体特异性。将对患者和匹配的正常对照进行HLA分型，并进行目标2中概述的研究。这些实验结果将为进一步探讨分子拟态在SLE发病机制中的重要性提供基础。它也可能为自身抗体多样化和这种疾病中终末器官损伤的产生提供新的见解。

DESCRIPTION (provided by applicant): During the current SCOR period, 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 ROM and for intermolecular epitope spreading to Ro52. For SmD immunization, DR3 was shown to be dominant with the generation of specific antibodies for SmB. This competitive renewal application is to continue to explore the role of HLA-D region and T cell epitopes in SLE-related autoantigens in the pathogenesis of SLE. Four specific aims are proposed: Specific Aim 1: To use the existing transgenic HLA-DR3 and -DR4 mouse to map further the T cell epitopes on Ro60, SmD, SmB and the A protein of the snRNP particle, by generation of antigen-specific TT hybridomas. Specific Aim 2: To study antigenspecific T cells by HLA-DR3 and HLA-DR4 SLE patients and matched controls by HLA-DR tetramers loaded with SLE-related antigenic peptides. This is a collaboration between UVa and Virginia Mason Research Center. Specific Aim 3: To generate NZM2328 mutants which lack the entire mouse I region and express the various HLA-D region molecules as transgenes to determine whether these transgenes can support the spontaneous autoantibody generation and the induction of acute and chronic glomerulonephritis. They will also be tested to determine whether chronic sialoadenitis can be induced by CMV. Specific Aim 4: To initiate a collaborative study to compare the antiSm antibody specificity in the SLE populations of northern India and central Virginia. Both patients and matched normal controls will be HLA- typed and studies as outlined in Aim 2 will be performed. The results obtained in these experiments will provide a basis for further exploration of the importance of the molecular mimicry in the pathogenesis of SLE. It might also provide newer insight into autoantibody diversification and the generation of end-organ damage in this disease.