Events Leading to Loss Of Tolerance to Myelin Basic Pro*

描述（由申请人提供）：此应用程序侧重于事件， 引起对中枢神经系统中表达的抗原的耐受性的破坏 系统（CNS）。对CNS抗原的耐受性丧失被认为是中枢神经系统疾病的关键因素。 导致多发性硬化症（MS）发展的步骤。 流行病学 研究表明，MS是由暴露于遗传物质引发的。 在生命早期对病原体易感的个体。为了研究耐受性 对中枢神经系统抗原的作用被破坏，我们建立了一个转基因小鼠模型， 所有的T细胞都表达对CNS抗原特异的转基因T细胞受体 髓鞘碱性蛋白（MBP）。这些转基因小鼠发展出中枢神经系统自身免疫 自发性疾病，自发性疾病的发生率随着 增加环境中的微生物暴露。我们将用这种转基因的 研究感染如何导致CNS耐受性破坏的模型 抗原使用疾病诱导的新方法。初步数据显示， 自身免疫是 在此诱导 转基因模型 感染 肺炎链球菌和B族链球菌（GBS），但不是由几种 其他细菌菌株。 我们还表明，MBP特异性TCR不 似乎与细菌抗原交叉反应。其他初步数据 证明内源性MBP通常通过以下途径加工和呈递： 外周抗原呈递细胞（APC），导致T细胞耐受， 在某些情况下，T细胞无知在其他情况下。 根据这些观察， 我们提出了一个新的假设，即细菌感染会引发 自身免疫性疾病通过增加或改变内源性 MBP表位在外周导致T细胞无知的损失。我们将 利用该 独特的实验 组合系统 与几 转基因、基因敲除和基因敲入小鼠模型在适当的 遗传背景来验证这个假设。

DESCRIPTION (provided by applicant): This application focuses on events that cause a breakdown in tolerance to antigens expressed in the central nervous system (CNS). Loss of tolerance to CNS antigens is believed to be a critical step leading to the development of multiple sclerosis (MS). Epidemiological studies have suggested that MS is triggered by exposure of genetically susceptible individuals to a pathogen(s) early in life. To study how tolerance to CNS antigens is broken, we established a transgenic mouse model in which all T cells express a transgenic T cell receptor specific for the CNS antigen myelin basic protein (MBP). These transgenic mice develop CNS autoimmune disease spontaneously, and the incidence of spontaneous disease increases with increasing microbial exposure in the environment. We will use this transgenic model to investigate how infection results in a breakdown of tolerance to CNS antigens using a novel method of disease induction. Preliminary data show that autoimmunity is induced in this transgenic model by infection with Streptococcus pneumonias and Group B Streptococcus (GBS) but not by several other bacterial strains. We also show that the MBP-specific TCR does not appear to cross-react with bacterial antigens. Additional preliminary data demonstrate that endogenous MBP is normally processed and presented by peripheral antigen-presenting cells (APCs), resulting in T cell tolerance in some cases and T cell ignorance in other cases. Based on these observations, we propose to test a new hypothesis that bacterial infection triggers autoimmune disease by increasing or altering the presentation of endogenous MBP epitopes in the periphery resulting in a loss of T cell ignorance. We will utilize this unique experimental system in combination with several transgenic, knock-out and knock-in mouse models bred onto the appropriate genetic background to test this hypothesis.