Immunological Mechanisms in Systemic Autoimmune Disease

项目摘要/摘要 系统性硬化症(SSC)是一种慢性自身免疫性疾病，与严重的 皮肤和/或内脏的血管损伤和纤维化。尽管如此，倾向于 与其他更常见的系统性自身免疫性疾病不同，个体与SSc的发展有关 例如系统性红斑狼疮，以及对患有破坏性疾病患者的治疗选择仍然不明确 疾病是极其有限的。耐人寻味的是，尽管SSC和SLE患者都出现了抗核 抗体(ANA)，每种疾病都与一组不同的特异性有关，这些特异性可能反映出不同的 组织损伤的各个方面。由于缺乏合适的动物模型，这一领域的研究一直受到阻碍。 我们最近开发了一种新的转基因模型，该模型允许受调控的“伪- 自身抗原“在MHC II+细胞或血管内皮细胞上，并通过 其他已知的SSC靶标组织。此应用程序的总体目标是确定如何 特异性T细胞亚群和/或伪自身抗原表达的微环境影响 自身抗体谱与系统性自身免疫性疾病的临床病程。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/或树突状细胞，如果是，它们是否优先从被认为是 在SSC中成为免疫系统的靶子。(2)确定“伪自身抗原”的功能能力如何- 特异性T细胞影响自身抗体谱系的同型和特异性，以及 在系统表达伪自身抗原的小鼠身上引起的系统性自身免疫性疾病。(3) 确定伪自身抗原表达的微环境如何影响自身抗体谱系 以及在小鼠中引发的系统性自身免疫病的类型，通过比较假性 MHC-II+细胞(常规抗原提呈细胞)对伪自身抗原的表达 由血管内皮细胞表达。这些研究将涉及捐赠者的DO11 T细胞，偏向Th1， Th2或Th17表型，以及继承(A)四环素反式激活剂的受体小鼠 不变链启动子或血管内皮细胞启动子和(2)膜相关卵清蛋白融合 其表达受四环素反式激活剂调节的蛋白质。从野生型、LPR或 GLD DO11小鼠将被包括在分析中，因为已经发现FasL的过度表达会引发 在许多实验环境中的慢性纤维化反应。我们的结果应该会为 SSC的机制基础，并指出了这种毁灭性疾病的新治疗策略。项目说明： 对于系统性硬化症(SSC)的许多表现，目前还没有经过验证的治疗方法， 这是一种发病率和死亡率都很高的毁灭性疾病。这项研究可能会导致 对触发SSC发展的因素和可能的战略的重要见解 事实证明，在限制患者的疾病进展方面是有用的。

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.