Immunological Mechanisms in Systemic Autoimmune Disease

描述(申请人提供)：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，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，与其他更常见的系统性自身免疫性疾病如系统性红斑狼疮相比，易患SSc的因素仍然不明确，对患有破坏性疾病的患者的治疗选择极其有限。有趣的是，尽管SSc和SLE患者都会产生抗核抗体(ANA)，但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组织损伤的不同方面。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，允许在MHC II+类细胞或血管内皮细胞上调节“伪自身抗原”的表达，并允许其他已知的SSC靶向组织表达的可能性。这项应用的总体目标是确定特定的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系统性自身免疫性疾病的临床过程。该应用的具体目的如下：(1)确定与SSC常规相关的自身抗原是否能激活B细胞和/或树突状细胞，如果是，它们是否优先从SSC中被认为是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谱的同型和特异性，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病的类型。(3)通过比较MHC-II+细胞(常规抗原提呈细胞)和血管内皮细胞表达的伪自身抗原的结果，确定伪自身抗原表达的微环境对小鼠自身抗体库和诱发的系统性自身免疫病类型的影响。这些研究将涉及偏向Th1、Th2或Th17表型的供体DO11 T细胞，以及继承了(A)由不变链启动子或血管内皮启动子驱动的四环素反式激活剂和(2)由四环素反式激活剂调节表达的膜相关卵白蛋白融合蛋白的受体小鼠。从野生型、LPR或GLD DO11小鼠中获得的T细胞将被包括在分析中，因为在许多实验设置中发现FasL的过度表达会触发慢性纤维化反应。我们的研究结果将为了解SSc的机制基础提供重要的见解，并为这一毁灭性疾病提供新的治疗策略。 与公共卫生相关：目前，系统性硬化症(SSC)的许多表现都没有得到证实的治疗方法，这是一种发病率和死亡率都很高的破坏性疾病。这项研究可能导致对触发SSc发展的因素和可能被证明对限制患者疾病进展有用的策略的重大洞察。

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.