Immunological Mechanisms in Systemic Autoimmune Disease

系统性自身免疫性疾病的免疫学机制

• 批准号: 8259486
• 负责人: Ann Marshak-Rothstein
• 金额: $ 34.4万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-08 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8259486
• 关键词: Accounting; Activated Lymphocyte; Activities of Daily Living; Address; Animal Model; Antibodies; Antigen-Antibody Complex; Antigen-Presenting Cells; Antigens; Area; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; B-Lymphocytes; Binding; Blood Vessels; Cells; Chimeric Proteins; Chronic; Clinical; Complex; Dendritic Cells; Development; Disease; Disease Progression; E-Cadherin; Etiology; Exhibits; Fibrosis; Goals; Heart; Immune system; Immunoglobulin G; Inbred BALB C Mice; Individual; Inflammatory; Inherited; Kidney; Lead; Life; Lung; MHC Class II Genes; Membrane; Modeling; Monoclonal Antibodies; Morbidity - disease rate; Mus; Mutation; Nuclear; Nuclear Antigens; Nuclear Extract; Organ; Outcome; Ovalbumin; Patients; Phenotype; Predisposing Factor; Research; Serum; Skin; Skin Abnormalities; Specificity; Systemic Lupus Erythematosus; Systemic Scleroderma; T-Lymphocyte; T-Lymphocyte Subsets; TLR7 gene; Tetracyclines; Tissues; Trans-Activators; Transgenic Mice; Transgenic Model; Tumor Necrosis Factor Ligand Superfamily Member 6; Vascular Endothelium; abstracting; base; fibrillin; insight; invariant chain; mortality; novel; novel therapeutics; overexpression; promoter; response; systemic autoimmune disease

Project Summary/Abstract Systemic Sclerosis (SSc) can be a chronic life threatening autoimmune disorder associated with severe vascular damage and fibrosis of the skin and/or internal organs. Nevertheless, the factors that predispose individuals to the development of SSc, as opposed to other more common systemic autoimmune diseases such as SLE, remain ill-defined, and treatment options for patients afflicted with devastating forms of this disease are extremely limited. Intriguingly, although both SSc and SLE patients develop anti-nuclear antibodies (ANAs), each disease is associated with a distinct set of specificities that may reflect discrete aspects of tissue damage. Research in this area has been hampered by the lack of suitable animal models. We have recently developed a novel transgenic model that allows for the regulated expression of a "pseudo- autoantigen" on either MHC class II+ cells or on the vascular endothelium, and the potential for expression by other tissues known to be targeted in SSc. The overall goal of this application is to determine how specific T cell subsets and/or the microenvironment of pseudo-autoantigen expression influence the autoantibody repertoire and the clinical course of systemic autoimmune disease. The specific aims of the application are as follows: (1) Determine whether the autoantigens routinely associated with SSc can activate B cells and/or dendritic cells, and if so, whether they are preferentially released from tissues thought to be targeted by the immune system in SSc. (2) Determine how the functional capacity of "pseudo-autoantigen"- specific T cells influences the isotype and specificity of the autoantibody repertoire as well as the type of systemic autoimmune disease that is elicited in mice that systemically express the pseudo-autoantigen. (3) Determine how the microenvironment of pseudo-autoantigen expression influences the autoantibody repertoire and the type of systemic autoimmune disease that is elicited in mice by comparing the outcome of pseudo- autoantigen expression by MHC class II+ cells (conventional antigen presenting cells) to pseudo-autoantigen express by cells of the vascular endothelium. These studies will involve donor DO11 T cells, skewed to a Th1, Th2, or Th17 phenotype, and recipient mice that inherit (a) a tetracycline transactivator driven by either an invariant chain promoter or a vascular endothelial promoter and (2) a membrane-associated ovalbumin fusion protein whose expression is regulated by a tetracycline transactivator. T cells obtained from wildtype, lpr, or gld DO11 mice, will be included in the analysis since over-expression of FasL has been found to trigger a chronic fibrotic response in numerous experimental settings. Our results should provide important insights into the mechanistic basis of SSc and point to new therapeutic strategies for this devastating disease. Project Narrative: No proven treatment is currently available for many manifestations of Systemic Sclerosis (SSc), a devastating disease with significant morbidity and mortality. This study could lead to significant insights into the factors that trigger the development of SSc and strategies that might prove useful in limiting the progression of disease in afflicted patients.

项目总结/摘要 系统性硬化症（SSc）可能是一种慢性危及生命的自身免疫性疾病， 皮肤和/或内脏的血管损伤和纤维化。然而，那些容易导致 与其他更常见的全身性自身免疫性疾病相反， 如系统性红斑狼疮，仍然没有明确的定义，以及对患有这种破坏性形式的患者的治疗选择 疾病非常有限。有趣的是，尽管SSc和SLE患者都出现了抗核抗体， 抗体（ANA），每种疾病都与一组不同的特异性相关，这些特异性可能反映了离散的 组织损伤方面。由于缺乏合适的动物模型，这一领域的研究受到阻碍。 我们最近开发了一种新的转基因模型，该模型允许“假- 在MHC II类+细胞或血管内皮细胞上的“自身抗原”，以及通过 其他已知在SSc中靶向的组织。本应用程序的总体目标是确定如何 特异性T细胞亚群和/或假自身抗原表达的微环境影响免疫应答。 自身抗体库和系统性自身免疫病的临床过程。的具体目标 应用如下：（1）确定与SSc常规相关的自身抗原是否可以 激活B细胞和/或树突细胞，如果是，它们是否优先从被认为 在SSc中被免疫系统靶向。(2)确定“假自身抗原”的功能能力- 特异性T细胞影响自身抗体库的同种型和特异性， 在系统性表达假自身抗原的小鼠中引发的系统性自身免疫疾病。（三） 确定假自身抗原表达的微环境如何影响自身抗体库 以及通过比较假免疫的结果， MHC II类+细胞（常规抗原呈递细胞）的自身抗原表达为假自身抗原 由血管内皮细胞表达。这些研究将涉及供体DO 11 T细胞，偏向于Th 1， Th 2或Th 17表型的受体小鼠，以及遗传了（a）四环素反式激活因子的受体小鼠，所述四环素反式激活因子由 不变链启动子或血管内皮启动子，和（2）膜结合卵清蛋白融合体 表达受四环素反式激活因子调节的蛋白质。从野生型、lpr或 gld DO 11小鼠将被包括在分析中，因为已经发现FasL的过表达触发了一种免疫反应。 慢性纤维化反应。我们的研究结果应该提供重要的见解， SSc的机制基础，并指出这种毁灭性疾病的新的治疗策略。项目叙述： 对于系统性硬化症（SSc）的许多表现，目前还没有经过证实的治疗方法， 一种具有显著发病率和死亡率的毁灭性疾病。这项研究可能会导致 对触发SSc发展的因素和可能 证明可用于限制患病患者的疾病进展。