Multiple sclerosis (MS) is a debilitating disease of the central nervous system (CNS) characterized by infiltration of autoreactive T lymphocytes and other activated immune cells across the blood brain barrier (BBB) into the CNS. Subsequent nerve demyelination and axonal loss leads to the characteristic decreased motor and sensory functions. In MS, a significant sex dimorphism exists with the prevalence approaching a 3:1 female predominance over males. While genetic, hormonal, and immune response differences have been implicated, the mechanism for this sex dimorphism remains unclear. The animal model of disease, experimental autoimmune encephalomyelitis (EAE), recapitulates many of the features of MS. In SJL mice, the disease presents with ascending paralysis and exhibits a similar female predominance. It has previously been reported that female c-kit mutant (SJL-KitW/W-v ), mast cell deficient mice are less susceptible to relapsing-remitting EAE than their wild type littermates. Further, restoration of mast cell populations to these mice restores a WT-like disease phenotype. Thus, mast cells are important pathogenic contributors to female disease. Surprisingly, in contrast to the less severe disease of female SJL-KitW/W-v mice, male SJL-KitW/W-v mice develop significantly more severe EAE than their WT littermates. These data suggest that either mast cells or other c-kit mediated events are protective in male SJL mice. Several potential mechanisms exist to explain this phenomenon: A) Male mast cells, under the unique hormonal environment, may respond by producing pro-inflammatory mediators in disease. B) Loss of c-kit signaling in DCs could alter the T helper cell response in male mice in disease c) c-kit signals are neuroprotective in males and override the pro-inflammatory effects of c-ckit+ mast cells in EAE. Perhaps most importantly, the disparate phenotypes of the sexes allows for novel insight into the observed sex dimorphism of EAE. We plan to utilize the extensive research completed with female SJL-KitW/W-v mice as a construct to explore male disease.
The specific aims of the proposed study are:
Aim 1 : To identify within what stage of EAE progression c-kit signaling exerts protective in SJL-KitW/W-v male mice.
Aim 2 : To determine which cell types mediate the c-kit mediated protection in EAE SJL-KitW/W-v male mice.
Nearly three times more women are affected by multiple sclerosis (MS) than men and the exact reason for this is unknown. Our studies use an animal model for MS, called EAE, to study how a signaling cascade (c-kit signaling) differentially contributes to male and female disease. We are testing the hypothesis that it does so by affecting T cells, either directly via intrinsic differences or indirectly, through other immune cels.
|Russi, Abigail E; Walker-Caulfield, Margaret E; Brown, Melissa A (2016) Mast cell inflammasome activity in the meninges regulates EAE disease severity. Clin Immunol :|
|Russi, Abigail E; Walker-Caulfield, Margaret E; Ebel, Mark E et al. (2015) Cutting edge: c-Kit signaling differentially regulates type 2 innate lymphoid cell accumulation and susceptibility to central nervous system demyelination in male and female SJL mice. J Immunol 194:5609-13|
|Russi, Abigail E; Brown, Melissa A (2015) The meninges: new therapeutic targets for multiple sclerosis. Transl Res 165:255-69|