HLA-D Region in Systemic Lupus Erythematosus Pathogenesis

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，主要影响处于生产年龄的女性。它会导致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，但缺乏有效的无显著副作用的诱导和预防复发的治疗方法。我们在狼疮遗传学和狼疮相关自身抗体多样化机制方面的研究以及在照顾这些患者中获得的见解使我们提出了考虑到狼疮三个主要特征的假设：1)HLA-D复合物是疾病易感性的显性遗传位点；2)从检测出第一抗体（auto-Ab）到临床表现有相当长的潜伏期，有证据表明存在auto-Ab多样化；3)最初的临床表现和复发都是千变万化的，因为一个或多个器官可能以一种明显随机的方式受累。我们的假设表明狼疮易感基因在自身免疫或对末端器官损伤的抵抗中发挥作用。自身抗体是通过对环境抗原和狼疮相关自身抗原的交叉反应T细胞的激活，以HLA-DR限制的方式产生的。经过一段时间（人类数年），这些自身反应性T细胞达到高潮，导致易感宿主产生不同的自身抗体反应和最初的临床表现。缓解源于这些自身反应性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可发生复发。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，我们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)阐明自身抗体分化的机制；2)生成单、双（多）特异性的TCR转基因小鼠，提供大量自身反应性T细胞，建立过继转移模型，研究单、双反应性T细胞在体外和体内的活化；3)证明NZM2328。DR3及其同源系如NZM2328。无内源性II类抗原的c1R27DR3小鼠是抗原诱导的auto-Ab的合适宿主，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，挑战了目前关于SLE发病机制的范式。它为SLE的三个主要特征提供了一个合乎逻辑的解释。它提供了一个框架工作，为寻求生物标志物的反应性诱导治疗缓解和维持治疗的鉴定。该假设确定了治疗干预的逻辑目标。

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.