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: 8108311
• 负责人: Shu Man Fu
• 金额: $ 47.07万
• 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/8108311
• 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; 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. 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.

描述（由申请人提供）：系统性红斑狼疮（SLE）是一种系统性自身免疫性疾病，主要影响生育年龄的女性。它导致显着的发病率和死亡率。尽管我们对其发病机制的理解取得了相当大的进展，但仍需要没有明显副作用的有效治疗方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照顾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 复合物是疾病易感性的显性遗传位点； 2）从首次检测到自身抗体（auto-Ab）到出现具有自身抗体多样化证据的临床表现之间有相当长的潜伏期； 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明显随机的方式受累。我们的假设表明，狼疮易感基因对自身免疫或对终末器官损伤的抵抗力发挥作用。自身抗体是通过 T 细胞以 HLA-DR 限制的方式激活对环境抗原和狼疮相关自身抗原的交叉反应而产生的。经过一段时间（人类为数年），这些自身反应性 T 细胞达到顶峰，导致易感宿主出现多种自身抗体反应和初始临床表现。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。当免疫系统基础激活水平升高的宿主中重复刺激分子模拟物时，就会发生复发。复发的临床表现取决于模仿者的性质。在这个竞争性的更新应用中，提出了实验来寻找支持这一假设的证据。提出了三个目标：1）阐明自身抗体多样化的机制； 2) 产生具有单特异性和双（多重）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，研究单反应性T细胞与双反应性T细胞的体外和体内激活情况； 3)证明NZM2328.DR3及其同源系例如没有内源II类抗原的NZM2328.c1R27DR3小鼠是抗原诱导的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，挑战了当前 SLE 发病机制的范式。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，用于识别寻找缓解诱导治疗和维持治疗反应性的生物标志物。该假设确定了治疗干预的逻辑目标。 公共健康相关性：这是一项更新应用程序，旨在研究系统性红斑狼疮 (SLE) 的病因。 SLE 造成重大经济损失和痛苦。我们有证据支持这样的论点：狼疮自身抗体的产生是对细菌或病毒分子免疫反应的结果，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。在此应用中，我们计划证明这些 T 细胞存在于我们的体内，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和自身反应性 T 细胞的自身抗体。这些抗体和 T 细胞会对各种器官造成损害，导致疾病初始诊断期间和发作期间出现各种临床表现。临床疾病发生在具有遗传易感性的个体中，这些个体的白细胞反应性更强和/或其终末器官更容易受到损伤。拟议研究的结果可能使我们能够确定客观标志物，这些标志物表明足以诱导缓解的初始治疗，并且我们的治疗对于维持缓解有效。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。