Events Leading to Loss Of Tolerance to Myelin Basic Pro*

描述（由申请人提供）：此申请侧重于以下事件

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.