| Experimental allergic encephalomyelitis (EAE) is the rodent model of Multiple Sclerosis (MS). Although many studies have focused on the contribution of autoreactive T cells, other cell types also play significant roles in the inflammation and nerve damage associated with these diseases. Previous studies using mast cell deficient mice have demonstrated a significant role for mast cells in contributing to disease severity, however it remains unclear how mast cells are exerting their potent effects. In these studies we sought to determine how mast cells are activated, the location of mast cell influence, and a mechanism of mast cell action during this disease.; Cross-linking of Fc receptors on the mast cell surface is a well-studied mechanism of mast cell activation. Using a bone marrow mast cell reconstitution model, we found that mast cells deficient in FcγRIII exhibited an attenuated disease course comparable to W/Wv controls. Mast cells deficient in the inhibitory receptor FcRIIB, contributed to an exacerbation in later phases of disease. From this study, we conclude that both activating and inhibitory Fc receptors on mast cells contribute to disease pathogenesis.; To determine where mast cells are exerting their effects during disease, we performed a kinetic study of BMMC reconstitution. Surprisingly, we were unable to detect mast cells in the CNS of reconstituted mice, despite an EAE disease course equivalent to wild type mice. However, there appeared to be an inverse correlation between the number of mast cells in the spleen and EAE disease severity. These data suggest that mast cells may be acting outside the CNS, perhaps in the generation of the auto-reactive T cell response.; Finally, T cell responses were characterized in mast cell-deficient mice (W/Wv) and their wild type (WT) littermates during EAE. Kinetic analyses demonstrate CD4+ T cell activation and T cell trafficking into the brain are delayed in W/Wv mice. Adoptive transfer of encephalitogenic W/Wv T cells into WT mice confirms a role for mast cell mediated activation of T cells, while transfer of WT cells into W/Wv recipients demonstrates the importance of the mast cell microenvironment in determining disease severity. These findings provide evidence of a new and more complex role for mast cells in EAE that will likely extend to other adaptive immune responses. |
