C-kit signaling pathways regulate EAE susceptibility in male SJL mice (P3119)

Abstract

Abstract Females are more susceptible to autoimmune diseases, including multiple sclerosis (MS), a demyelinating disease of the central nervous system. While genetic, hormonal, and immune differences have been implicated, the mechanism for this female bias remains unclear. The animal model of MS, experimental autoimmune encephalomyelitis (EAE), recapitulates many of the features of the human disease; including the significant sex dimorphism. We previously reported that wild type (WT) female SJL mice exhibit more severe disease than their c-kit mutant counterparts and that this phenotype is mast cell dependent. In contrast, male SJL-Kit-W/W-v mice develop significantly more severe EAE than their WT littermates. This c-kit dependent difference in male disease corresponds to a more robust peripheral CD4+ T cell response at day 10 post disease induction. Male SJL-Kit-W/W-v mice demonstrate a higher percentage and number of encephalitogenic GM-CSF producing PLP(139-151)-specific CD4+ T cells when compared to their WT controls. These data indicate that c-kit signaling exerts its protective effects in the periphery by regulating the magnitude and quality of the autoreactive T cell response. This effect is male specific given that the peripheral T cell GM-CSF responses in WT and Kit-W/W-v females are equivalent. Further studies are ongoing to define the cell type that is the target of c-kit signals and the mechanism by which c-kit exerts its disparate effects in male and female SJL mice.