Oligodendrocyte Dysfunction to Immune Pathology in Multiple Sclerosis: A Conspiracy of Herpesviruses?

Multiple sclerosis is an immune-driven neurological disease that affect myelinated axons in the central nervous system. However, the trigger of the (dysregulated) immune reactions is not56 known. According to Wilkin’s primary lesion theory, myelin-reactive T cells present in the immune repertoire respond to myelin antigens that are released from idiopathic lesions within the central nervous system. However, neither the cause of the primary lesion, nor the cause of the immune hyper-reactivity are known. We investigated whether these unknown activation signals may be relayed by common herpesviruses. The results highlight human herpesvirus-6A as a potential trigger of primary lesions due to its proven capacity to cause oligodendrogliopathy, cytomegalovirus as a trigger for the formation of effector memory cytotoxic T cells with proven capacity to induce multiple sclerosis pathology in a non-human primate MS model and Epstein Barr Virus due to its capacity to render B cells capable to effectively present a critical myelin antigen to these effector memory cytotoxic T cells. These results lead us to propose the novel paradigm that the immunopathogenesis of multiple sclerosis results from a conspiracy of common herpesviruses.