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A variety of putative models have been proposed to explain the course of disease. The preeminent mechanisms are suggested to be based on autoimmunity, including via viral epitope mimicry, although difficulties with a classical autoimmunity model for MS have been described. One prior idea that incorporates consideration of viral\u2013self-cross-reactivity is that reactivated HHV-6A virus might induce subsequent reactivation of another virus, EBV, in a relay, resulting in a cascade of downstream consequences. Here, an alternative model for MS is proposed. This posits a viral reactivation relay in which EBV reactivation in the brain precedes HHV-6A reactivation in oligodendrocytes and neurons. At this juncture, relapsing\u2013remitting MS (RRMS) can ensue to generate characteristic lesions, dominated by outbreaks of viral reactivation and CD8+T-cell-mediated cytotoxicity and inflammation. Additionally, self-targeting antibodies can be raised to mark the onset of progressive MS in a subset of patients. This model harmonises a plethora of prior evidence from diverse fields. It is suggested that future studies should challenge this new model for MS and that it provides direction for future approaches to prevention and therapy.<\/jats:p>","DOI":"10.1007\/s10238-025-01666-3","type":"journal-article","created":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T09:34:28Z","timestamp":1746178468000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A unifying model for multiple sclerosis"],"prefix":"10.1007","volume":"25","author":[{"given":"Daniel Jonathan","family":"Park","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,30]]},"reference":[{"key":"1666_CR1","doi-asserted-by":"crossref","first-page":"a028936","DOI":"10.1101\/cshperspect.a028936","volume":"8","author":"LH Multiple","year":"2018","unstructured":"Multiple LH, Pathology S. Multiple sclerosis pathology. 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