Epstein-Barr virus infection and vitamin D deficiency are both "causal" for multiple sclerosis (MS) - could the common denominator be their effects on hepcidin levels?

Multiple sclerosis (MS) is a neurological disorder characterized by damage to the myelin sheaths surrounding axons in the central nervous system, causing decreased axonal signal transmission and disability in people with MS. Epstein-Barr virus (EBV) infection and vitamin D deficiency have been put forward as causal factors for the development of MS, but their effects have not been conclusively linked to the disruption of myelin maintenance. Interestingly, both EBV infection and vitamin D deficiency increase the levels of hepcidin, an acute-phase peptide hormone that inhibits iron absorption. The current understanding of iron dysregulation in MS is that iron accumulates in deep gray matter brain structures which leads to disability progression. However, recent studies have revealed that the apparent iron influx may be an artefact of disease-related brain atrophy, and that iron is in contrast depleted in the deep gray matter in MS, which could cause iron deficiency in oligodendrocytes (the cells producing myelin), leading to their demise due to a mitochondrial energy deficit, with consequent demyelination. EBV infection, vitamin D deficiency and iron deficiency may converge as causal risk factors for MS. Dismantling the current understanding that iron excess underpins MS would improve testing and optimization of iron parameters and vitamin D as part of clinical management of MS. This review additionally explores the risk factors for lytic reactivation of EBV which is hypothesized to drive MS disease activity. Conversely, ensuring that EBV remains in a latent state by ameliorating these risk factors may prevent MS exacerbations and disease worsening.