Oligodendrocyte Dysfunction to Autoimmune Pathology in Multiple Sclerosis
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The prevailing view for the onset of Multiple Sclerosis is that it is an “outside-in” driven pathology. It's believed that primary infection with Epstein Barr Virus (EBV) in those with a genetic susceptibility to MS, drives the production of auto-reactive B cells that infiltrate the Central Nervous System from the periphery and seed the CNS with EBV. Upon infection of the CNS with EBV, an autoimmune response to the brain from the periphery leads to MS diagnosis and neurodegeneration. We propose an “Inside Out” model of MS genesis where HHV6-A is responsible for the earliest histological findings observed in MS lesions before and during EBV primary infection, EBV primary infection accelerates activation of HHV-6A residual replication, the transactivation of EBV and the development of the Wilkins Lesion where debris from cellular injury induced by HHV6-A replication lead to the development of autoimmune processes to neuronal proteins like myelin, setting a precedent for MS development. Human Herpesvirus 6A (HHV6A) is ubiquitous and undergoes latent and periodic reactivation in the cerebral compartment of young adults. This reactivation may contribute to the development of gliapathy, a dying-back phenomenon characterized by swelling of the inner lamella of the axon, demyelination, apoptosis, or necroptosis of oligodendrocytes (ODC’s) and their precursors as suggested by Theiler’s Murine Encephalomyelitis Virus Infection (TMEV) and Experimental Allergic Encephalomyelitis (EAE) animal models.