A Ceramide Theory of Multiple Sclerosis

This paper presents a new theory explaining the pathological mechanisms of multiple sclerosis (MS). MS is triggered by persistently activated immune cells, mainly B cells, as in reactivated Epstein-Barr virus infection. Activated immune cells release cytokines, the main one here being TNFa. A major role of TNFa is to support immune cell motility and tissue penetration, by promoting the breakdown of ceramide products that stabilize membranes (sphingomyelin (SPM) and galactosylceramide (GalCer)), by stimulating membrane breakdown via ceramide 1-phosphate-induced liberation of arachidonic acid, and by promoting the production of sphingosine 1-phosphate, a ceramide product that promotes immune motility. These ceramide products are expressed in endothelial cells, including the blood-brain barrier, and have a large presence in myelin. Thus, excessive cytokine release both allows immune penetration into the brain, and impairs existing myelin sheaths. SPM and GalCer are essential for myelin maintenance but not for its synthesis, explaining the dominant relapsing-remitting nature of the disease. The theory is supported by diverse evidence, and supports modern B cell-based treatment directions.