B cells promote inflammatory T cell responses during the initiation of central nervous system autoimmune disease

Thesis (Ph.D.)--University of Washington, 2013Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) mediated by autoreactive T cells specific for myelin proteins. A recent development in MS treatment is the discovery that B cell depletion with Rituximab reduced the numbers of lesions and new relapses in MS patients. The role of B cells has been studied in the animal model of MS, experimental autoimmune encephalomyelitis (EAE), but results from these studies have been variable and contradictory, and the contribution of B cells to CNS autoimmune disease is still unclear. We examined the role of B cells in C3H mice and found that both C3HeB/Fej and C3H.SW μMT mice had a reduced incidence of EAE, suggesting an important role for B cells in the initiation of disease. B cells were the predominant MHC class II+ cells in the healthy CNS and were able to secrete cytokines, indicating that they could be influencing T cell responses before inflammation is initiated. Myelin-specific T cells were able to migrate to the CNS in the absence of B cells, but were unable to initiate immune responses. The ability of the early infiltrating T cells to secrete cytokines and initiate the recruitment of additional T cells to the CNS from the periphery before onset of EAE was defective in B cell deficient mice. Recruitment of T cells from the periphery constituted the majority of the increase in T cell number in the CNS of wildtype mice prior to onset. In vitro, B cells preferentially reactivated effector Th1 cells and not Th17 cells in the absence of IL-1β. Induction of EAE with Th1- or Th17-skewed cells led to reduced numbers of IFN-γ- and IL-17-producing cells in the brains of B cell deficient mice after onset of EAE. However, there was a greater effect on the numbers of IFN-γ-producing cells, and in B cell deficient recipients of Th1-skewed cells, the localization of inflammation changed to permit inflammation in the brain. These studies indicate that B cells are important for T cell responses in the initiation of CNS autoimmunity, and can influence the localization of inflammation in EAE