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理解取得了相当大的进展，但缺乏有效的治疗方法，而没有显著的副作用，用于诱导和预防复发。我们在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照顾这些患者中获得的见解使我们假设考虑到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。 公共卫生相关性：这是系统性红斑狼疮（SLE）病因研究的更新申请。SLE造成重大的经济损失和痛苦。我们有证据支持这一论点，即狼疮自身抗体的产生是对细菌或病毒分子的免疫反应的结果，这些分子可以刺激一些T细胞，这些T细胞也与自身抗原反应。在这项应用中，我们计划证明这些T细胞存在于我们的身体中，并且它们可以对多种抗原做出反应。这些细胞在我们体内积累一段时间，导致产生针对多种自身抗原的自身抗体和自身反应性T细胞。这些抗体和T细胞对各种器官造成损害，导致疾病初步诊断期间和发作期间的各种临床表现。临床疾病发生在遗传易感个体中，其白色细胞更具反应性和/或其终末器官更容易受损。拟议研究的结果可能使我们能够确定客观的标志物，表明有足够的初始治疗诱导缓解，我们的治疗是有效的维持缓解。从拟议的实验中获得的新知识挑战了当前的教条，并将对我们治疗活动性疾病患者和维持患者生活质量的能力产生影响。

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. PUBLIC HEALTH RELEVANCE: This is a renewal application to study causes of systemic lupus erythematosus (SLE). SLE causes significant economic loss and suffering. We have evidence to support the thesis that lupus autoantibody production is the result of immune responses to bacterial or viral molecules that can stimulate some T cells, which are also reactive with self antigen. In this application we plan to show that these T cells exist in our bodies and that they can respond to multiple antigens. These cells accumulate in our body over a period of time, resulting in the production of autoantibodies to multiple autoantigens and autoreactive T cells. These antibodies and T cells cause damage to various organs, resulting in various clinical presentations during the initial diagnosis of the disease and during flares. Clinical diseases occur in genetically susceptible individuals whose white cells are more reactive and/or their end organs are more susceptible to damage. The results of the proposed studies may allow us to identify objective markers that indicate sufficient initial treatments for the induction of remission and that our therapy is effective for maintenance of remission. The new knowledge obtained from the proposed experiments challenges the current dogma and will have an impact on our ability to treat patients with active disease and to maintain the patients' quality of life.