Multiple sclerosis (MS) is an autoimmune disease that causes demeylination and axonal loss in the central nervous system (CNS). Although CNS-specific Th1 and Th17 cells have been suggested to initiate the disease, it is still unknown how CNS-specific Th1 and Th17 encephalitogenic T cells develop in MS patients. Recent studies have indicated that naturally occurring Th17 (n-Th17) cells develop in the thymus and migrate into the peripheral lymphoid organs and gut. Interestingly, autoreactive T cells differentiate into Th17 cells at a higher rate than non-autoreactive T cells. Although n-Th17 cells are not pathogenic, IL-23 can convert n-Th17 cells into GM-CSF-producing pathogenic Th17 cells. To investigate how CNS-specific T cells spontaneously differentiate into encephalitogenic T cells, we have recently generated transgenic (Tg) mice that express MS-associated HLA-DR2a genes and a myelin basic protein (MBP)-specific T-cell receptor (TCR) isolated from an MS patient. Interestingly, 3A6 TCR Tg mice develop spontaneous experimental autoimmune encephalomyelitis (EAE), and GM-CSF-producing Th17 and Th1 cells were predominantly detected in the mesenteric lymph nodes, colon, and CNS during the development of spontaneous EAE. Since IL-23 is produced in the gut in response to commensal bacteria, the gut is a potential source of IL-23, and MBP-specific T cells may migrate into the gut, differentiate into encephalitogenic T cells upon exposure to IL-23, and subsequently induce the development of spontaneous EAE. We will examine this possibility.Recent studies have also indicated that commensal bacteria not only shape intestinal immunity but also affect the development of autoimmune diseases outside of the gut. Interestingly, commensal bacteria can initiate the development of spontaneous autoimmune arthritis in an animal model but suppress the development of autoimmune diabetes in NOD mice. Therefore, the effects that commensal bacteria have on an autoimmune disease appear to be dependent on the autoimmune disease. It is still unknown how commensal bacteria affect the initiation of spontaneous EAE. Since MBP-TCR Tg CD4 T cells expand in the colon and differentiate into Th1 and Th17 effector cells during the development of spontaneous EAE, we hypothesize that commensal bacteria play an essential role in the development of encephalitogenic T cells in the gut and that the balance between pathogenic T cell-inducing and regulatory T cell-inducing commensal bacteria controls the development of the EAE-inducing encephalitogenic T cells in the gut. Since segmented filamentous bacteria (SFB) and Bacteroides fagilitis promote the development of Th17 cells and Foxp3 regulatory T cells, respectively, we will create germ-free 3A6 Tg mice and investigate the effects of these commensal bacteria on the initiation of the development of encephalitogenic T cells in this study. Although the effects of commensal bacteria on ongoing EAE have been studied, the pathogenic role of commensal bacteria in the initiation of CNS autoimmunity has not been investigated. This study will provide new insight into the effects of gut immunity on the initiation of CNS autoimmune diseases and the etiological role of commensal bacteria in MS.
|Effective start/end date||9/1/12 → 8/31/15|
- Congressionally Directed Medical Research Programs (CDMRP)