HLA-D Region in Systemic Lupus Erythematosus Pathogenesis

描述(申请人提供)：系统性红斑狼疮(SLE)是一种全身性自身免疫性疾病的原型，主要影响处于生育年龄的女性。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有了长足的进步，但在诱导和预防复发方面缺乏有效的、没有明显副作用的治疗方法。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，以及在治疗这些患者中获得的洞察力，使我们提出了假设，该假说考虑了SLE的三个主要特征：1)人类白细胞抗原-D复合体是疾病易感性的显性遗传位点；2)第一种自身抗体的检测到临床表现与自身抗体多样化之间有相当长的潜伏期；以及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能以明显的随机方式受累。我们的假设表明，狼疮易感基因在自身免疫或抵抗终末器官损害方面发挥作用。自身抗体是由对环境抗原和狼疮相关自身抗原的交叉反应T细胞以人类白细胞抗原-DR限制性方式激活而产生的。在一段时间内(在人类中为数年)，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最初临床表现。缓解的结果是这些自身反应性T细胞的减少和自身抗体相关性的多样化的减少。在免疫系统基础激活水平较高的宿主中，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试验的性质。在这种竞争性更新应用中，提出了实验来寻找证据来支持这一假说。目的有三个方面：1)阐明自身抗体多样化的机制；2)建立具有单一和双(多)特异性的TCR转基因小鼠，提供大量的自身反应性T细胞，以建立过继转移模型，以研究体内外单个和双反应性T细胞的激活；3)证明NZM2328.DR3及其同源系，如NZM2328.c1R27DR3小鼠，没有内源性II类抗原，是抗原诱导自身抗体的合适宿主，是诱导缓解和复发的良好模型。拟议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SLE发病机制的范式。它为系统性红斑狼疮的三个主要特征提供了合乎逻辑的解释。它为寻找对诱导治疗、缓解治疗和维持治疗反应的生物标志物提供了一个框架。该假说确定了治疗干预的合理目标。 公共卫生相关性：这是一个研究系统性红斑狼疮(SLE)病因的新应用。系统性红斑狼疮造成巨大的经济损失和痛苦。我们有证据支持这一观点，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细胞也与自身抗原发生反应。在这项申请中，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。这些细胞在我们的体内积累一段时间，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细胞会对各种器官造成损害，导致在疾病初步诊断和疾病发作期间出现不同的临床表现。临床疾病发生在遗传易感的人中，他们的白细胞更具反应性，和/或他们的末端器官更容易受到损害。建议的研究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来诱导缓解，我们的治疗对维持缓解是有效的。从拟议的实验中获得的新知识挑战了目前的教条，并将对我们治疗活动期疾病患者和保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.