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: 7527648
• 负责人: Ann Marshak-Rothstein
• 金额: $ 35.75万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 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 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7527648
• 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; Protein Overexpression; Public Health; Research; Serum; Skin; Skin Abnormalities; Specificity; Systemic Lupus Erythematosus; Systemic Scleroderma; T-Lymphocyte; T-Lymphocyte Subsets; TLR7 gene; Tetracycline; Tetracyclines; Thinking; Tissues; Trans-Activators; Transgenic Mice; Transgenic Model; Tumor Necrosis Factor Ligand Superfamily Member 6; Vascular Endothelium; base; fibrillin; insight; invariant chain; mortality; novel; novel therapeutics; promoter; response; 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; Protein Overexpression; Public Health; Research; Serum; Skin; Skin Abnormalities; Specificity; Systemic Lupus Erythematosus; Systemic Scleroderma; T-Lymphocyte; T-Lymphocyte Subsets; TLR7 gene; Tetracycline; Tetracyclines; Thinking; Tissues; Trans-Activators; Transgenic Mice; Transgenic Model; Tumor Necrosis Factor Ligand Superfamily Member 6; Vascular Endothelium; base; fibrillin; insight; invariant chain; mortality; novel; novel therapeutics; promoter; response

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.

描述（由申请人提供）：全身性硬化症（SSC）可能是慢性生命威胁自身免疫性疾病，与严重的血管损伤和皮肤和/或内部器官的纤维化有关。然而，与其他更常见的全身性自身免疫性疾病（如SLE）相比，使人偏爱SSC的因素仍然不确定，并且针对患有毁灭性形式的这种疾病的患者的治疗选择极为有限。有趣的是，尽管SSC和SLE患者均出现抗核抗体（ANAS），但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组织损伤的离散方面。缺乏合适的动物模型阻碍了该领域的研究。我们最近开发了一种新型的转基因模型，该模型允许在MHC II类+细胞或血管内皮上调节“伪自动抗原”的表达，并在SSC中靶向的其他组织表达的潜力。该应用的总体目标是确定伪自动抗原表达的特定T细胞子集和/或微环境如何影响自身抗体库和全身自身免疫性疾病的临床过程。应用程序的具体目的如下：（1）确定与SSC通常相关的自身抗原是否可以激活B细胞和/或树突状细胞，如果是的，是否优先释放出它们是从SSC中免疫系统靶向的组织中优先释放的。 （2）确定“假自动抗原” - 特定T细胞的功能能力如何影响自身抗体库的同型和特异性以及在系统地表达伪自动抗原的小鼠中引起的全身性自身免疫性疾病的类型。 (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.这些研究将涉及供体DO11 T细胞，该细胞偏向于Th1，Th2或Th17表型以及继承（a）由不变链促进剂或血管启动子或血管内皮启动子和（2）膜相关的Ovalbumin fusity Protanter的四环素反式激活剂驱动的四环素反式激活剂的表达者的表达者At ant ant ant and the the17或th17表型和受体小鼠。从WildType，LPR或GLD DO11小鼠获得的T细胞将包括在分析中，因为在许多实验环境中发现FASL的过表达会触发慢性纤维化反应。我们的结果应为SSC的机械基础提供重要的见解，并指出这种毁灭性疾病的新治疗策略。 公共卫生相关性：目前没有可靠的治疗方法可用于全身性硬化症（SSC），这是一种具有明显的发病率和死亡率的毁灭性疾病。这项研究可能导致对触发SSC发展的因素和可能证明可用于限制受伤患者疾病进展有用的策略的因素。