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: 8449030
• 负责人: Shu Man Fu
• 金额: $ 44.71万
• 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 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8449030
• 关键词: Adoptive Transfer; Adverse effects; Affect; Affinity; Age; Antibodies; Antigens; Autoantibodies; Autoantigens; Autoimmune Process; Autoimmunity; B-Lymphocytes; Biological Markers; Cells; Clinical; Complex; Dendritic Cells; Dependence; Detection; Diagnosis; Disease; Disease remission; Disease susceptibility; Dominant Genetic Conditions; Economics; Female; Flare; Frequencies; Genes; Genetic; Grant; HLA-D Antigens; HLA-DR Antigens; HLA-DR3 Antigen; Histocompatibility Antigens Class II; Immune response; Immune system; In Vitro; Individual; Kidney; Knowledge; Leukocytes; Lupus; Maintenance; Maintenance Therapy; Modeling; Molecular; Morbidity - disease rate; Mus; Mycophenolate; Natural Killer Cells; Nature; Organ; Pathogenesis; Patient Care; Patients; Pharmaceutical Preparations; Pharmacological Treatment; Population; Production; Proteins; Quality of life; Relapse; Remission Induction; Research; Resistance; Small Nuclear Ribonucleoproteins; Specificity; Susceptibility Gene; Systemic Lupus Erythematosus; T-Lymphocyte; T-Lymphocyte Epitopes; Therapeutic Intervention; Time; Transgenic Mice; Viral; Work; autoreactive T cell; congenic; disease diagnosis; disorder later incidence prevention; effective therapy; in vivo; insight; macrophage; man; microbial; mortality; novel; prototype; public health relevance; research study; response; systemic autoimmune disease

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is a prototype of systemic autoimmune disease that affects predominantly females in their productive ages. It causes significant morbidity and mortality. Despite considerable progress in our understanding of its pathogenesis, effective therapies without significant side effects for induction and prevention of relapse are wanting. Our research in lupus genetics and the mechanism of diversification of lupus related autoantibodies and the insight gained in taking care of these patients led us to postulate the hypothesis that takes into consideration the three main features of SLE: 1) the HLA-D complex is a dominant genetic loci for disease susceptibility; 2) there is a considerable latent period between the detection of the first autoantibody (auto-Ab) and clinical manifestation with evidence of auto-Ab diversification; and 3) both the initial clinical presentation and relapses are protean in that one or more organs can be involved in an apparently stochastic fashion. Our hypothesis states that lupus susceptibility genes exert their effect on either autoimmunity or resistance to end organ damage. Autoantibodies are generated by the activation of cross-reactive T cells to environmental antigens and lupus related autoantigens in a HLA-DR restricted fashion. Over a period of time (years in man), the culmination of these autoreactive T cells occurs, resulting in diverse auto-Ab responses and initial clinical presentation in susceptible hosts. Remission results from the reduction of these autoreactive T cells and the reduction of diversification of auto-Ab relativities. Relapses occur with repeated stimulation of molecular mimics in hosts with heightened basal activation levels in their immune system. The clinical presentation in relapses depends on the nature of the mimics. In this competitive renewal application, experiments are proposed to seek evidence to support this hypothesis. Three aim are proposed: 1) To elucidate the mechanisms of autoantibody diversification; 2) To generate TCR transgenic mice with single and dual (multiple) specificities to provide a large number of autoreactive T cells to establish adoptive transfer models to study the activation of single vs dual reactive T cells in vitro and in vivo; and 3) To demonstrate that NZM2328.DR3 and its congenic lines such as NZM2328.c1R27DR3 mice that have no endogenous class II antigen are suitable hosts for antigen induced auto-Ab and are good models for induction of remission and relapses. The expected results of the proposed experiments will support our hypothesis. Our hypothesis is novel and challenges the current paradigms in the pathogenesis of SLE. It provides a logical explanation for the three main features of SLE. It gives a frame work for the identification of seeking biomarkers for responsiveness to inductive treatments for remission and for maintenance therapies. The hypothesis identifies logical targets for therapeutic interventions.

描述（由申请人提供）：系统性红斑狼疮（SLE）是一种典型的系统性自身免疫性疾病，主要影响育龄女性。它造成严重的发病率和死亡率。尽管我们对其发病机制的了解取得了相当大的进展，但仍然需要没有显着副作用的有效疗法来诱导和预防复发。我们对狼疮遗传学和狼疮相关自身抗体多样化机制的研究以及在治疗这些患者中获得的见解使我们提出了一个假设，该假设考虑了SLE的三个主要特征：1）HLA-D复合体是疾病易感性的显性遗传位点;（2）首次自身抗体（auto-Ab）的检测与临床表现之间有相当长的潜伏期，并有自身抗体多样化的证据;和3）初始临床表现和复发都是多变的，因为一个或多个器官可以以明显随机的方式受累。我们的假设指出，狼疮易感基因发挥自身免疫或抵抗终末器官损伤的影响。自身抗体是通过以HLA-DR限制性方式激活对环境抗原和狼疮相关自身抗原的交叉反应性T细胞而产生的。在一段时间内（人类数年），这些自身反应性T细胞达到顶峰，导致不同的自身抗体反应和易感宿主的初始临床表现。缓解是由于这些自身反应性T细胞的减少和自身抗体相关性多样化的减少。在免疫系统基础激活水平升高的宿主中，反复刺激分子模拟物会发生复发。复发的临床表现取决于模拟物的性质。在这个竞争性更新应用中，提出了实验来寻求证据来支持这一假设。提出了三个目标：1）阐明自身抗体多样化的机制; 2）建立TCR单抗和双抗转基因小鼠，（多重）特异性，以提供大量自身反应性T细胞，从而建立过继转移模型，以在体外和体内研究单反应性T细胞与双反应性T细胞的活化; 3）证明NZM2328.DR3及其同源系如无内源性II类抗原的NZM2328.c1R27DR3小鼠是抗原诱导自身抗体的合适宿主，并且是诱导缓解和复发的良好模型。所提出的实验的预期结果将支持我们的假设。我们的假设是新颖的，并挑战了目前的模式在SLE的发病机制。它为SLE的三个主要特征提供了逻辑解释。它提供了一个框架工作的识别寻求生物标志物的反应诱导治疗缓解和维持治疗。该假说确定了治疗干预的逻辑目标。