Causality of Sex-Driven Dimorphism in a Relapsing-Remitting Murine Disease Model of Multiple Sclerosis



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Multiple sclerosis (MS) is the most common neurodegenerative autoimmune disorder that affects young adults. Autoimmune disorders display sexual dimorphic characteristics in disease susceptibility and progression to females over males. MS is characterized by the destruction of myelin sheaths that cover axons, disrupting neuronal activity and causing neurological deficits. Relapsing-Remitting Multiple Sclerosis (RRMS) is the most common progression of MS. RRMS disease progression begins with an acute onset of neuroinflammatory events followed by periods of remyelination followed by periods of demyelination. RRMS displays sexual dimorphic characteristics that favor females over males approaching a 4:1 ratio. Disruption of the blood brain barrier (BBB) allowing for leukocyte entry and chronic inflammation is considered the primary cause of MS pathogenesis. A disease-modifying molecule, sphingosine 1-phosphate receptor 2 (S1PR2), has shown to disrupt BBB integrity. This receptor has an increased expression in the female cerebellum, a disease susceptible region, compared to males. The underlying cause of the overproduction of S1PR2 has yet to be discovered.Treatment with an S1PR2 antagonist, JTE-013, has previously shown to lower clinical scores of disease severity in a commonly used murine model for MS, experimental autoimmune encephalomyelitis (EAE). Phenotypic analysis of inflammatory leukocyte infiltrates found in disease regions of the CNS is needed to further understand the effects of S1PR2 antagonism. This project was completed with contributions from Robyn Klein, Lauren Vollmer, Sindhu Manivasagam, and Jessica Williams from the Washington University at St. Louis, Infectious Diseases.