Immunological Mechanisms in Systemic Autoimmune Disease

描述（由申请人提供）：系统性硬化症（SSc）是一种慢性危及生命的自身免疫性疾病，与严重的血管损伤和皮肤和/或内脏纤维化有关。然而，与其他更常见的系统性自身免疫性疾病（如SLE）相反，易使个体发展为SSc的因素仍然不明确，并且对患有这种疾病的破坏性形式的患者的治疗选择极为有限。有趣的是，尽管SSc和SLE患者都会产生抗核抗体（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。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，该模型允许在MHC II类+细胞或血管内皮上调节“伪自身抗原”的表达，并且有可能在已知的SSc靶向组织中表达。该应用的总体目标是确定特异性T细胞亚群和/或伪自身抗原表达的微环境如何影响自身抗体库和全身性自身免疫性疾病的临床病程。该应用程序的具体目的如下：(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，如果可以，它们是否优先从被认为是SSc免疫系统靶向的组织中释放出来。(2)确定“伪自身抗原”特异性T细胞的功能能力如何影响自身抗体库的同型和特异性，以及在系统表达伪自身抗原的小鼠中引发的系统性自身免疫性疾病的类型。(3)通过比较MHC II类+细胞（常规抗原呈递细胞）表达伪自身抗原和血管内皮细胞表达伪自身抗原的结果，确定伪自身抗原表达的微环境如何影响自身抗体库和小鼠引发的系统性自身免疫性疾病的类型。这些研究将涉及供体DO11 T细胞，倾向于Th1， Th2或Th17表型，以及继承(a)由不变链启动子或血管内皮启动子驱动的四环素反激活子和(2)由四环素反激活子调节表达的膜相关卵清蛋白融合蛋白的受体小鼠。从野生型、lpr或金色DO11小鼠中获得的T细胞将包括在分析中，因为在许多实验环境中发现FasL的过表达会引发慢性纤维化反应。我们的结果应该为SSc的机制基础提供重要的见解，并为这种毁灭性疾病提供新的治疗策略。

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.