Epstein–Barr virus as a leading cause of multiple sclerosis: mechanisms and implications

Abstract

Epidemiological studies have provided compelling evidence that multiple sclerosis (MS) is a rare complication of infection with the Epstein-Barr virus (EBV), a herpesvirus that infects more than 90% of the global population. This link was long suspected because the risk of MS increases markedly after infectious mononucleosis (symptomatic primary EBV infection) and with high titres of antibodies to specific EBV antigens. However, it was not until 2022 that a longitudinal study demonstrated that MS risk is minimal in individuals who are not infected with EBV and that it increases over 30-fold following EBV infection. Over the past few years, a number of studies have provided clues on the underlying mechanisms, which might help us to develop more targeted treatments for MS. In this Review, we discuss the evidence linking EBV to the development of MS and the mechanisms by which the virus is thought to cause the disease. Furthermore, we discuss implications for the treatment and prevention of MS, including the use of antivirals and vaccines. Nature Reviews Neurology Review articleof these findings and how they could lead to the development of EBV-targeted MS treatments and preventative vaccines. EBV infectionEBV is a double-stranded DNA virus belonging to the herpesvirus family and was the first virus shown to cause cancer in humans. This discovery was made in the 1960s when virus particles were found in cultured cells from rapidly growing tumours around the jawbones of children from specific regions of Africa 21,22 . Since then, EBV has been detected in all parts of the world, infecting more than 90% of the population, mostly during the first two decades of life 23 . The virus is transmitted primarily by saliva and infects B cells in the oral cavity, either directly or via EBV-infected oropharyngeal epithelial cells 24 . After infection, the virus establishes latency, wherein the expression of viral proteins is markedly lowered in comparison with active infection, thereby reducing recognition of infected B cells by cytotoxic T cells 24 . EBV can exhibit different types of latency; in the more restrictive patterns, only proteins essential for EBV are expressed, including Epstein-Barr nuclear antigen 1 (EBNA1), which is needed for viral genome maintenance 25 .EBV persists in B cells for life, where it can intermittently reactivate, enabling transmission of the virus to a new host. Primary infection during early childhood is usually asymptomatic but up to 75% of individuals who are first infected during adolescence or adulthood develop IM 26 . As an oncogenic virus, EBV is known to cause several types of malignancies, including B cell lymphomas (for example, Burkitt lymphoma and Hodgkin lymphoma), T cell and natural killer cell lymphoproliferative disorders, and epithelial malignancies (for example, nasopharyngeal carcinoma and gastric cancer). In addition, EBV has been linked to diseases that are thought to have an autoimmune component such as systemic lupus erythematosus, Sjögren syndrome and MS 27,28 .

Risk of a first clinical diagnosis of central nervous system demyelination in relation to human herpesviruses in the context of Epstein–Barr virus

“…The increased risk associated with higher EBNA IgG persisted after adjustment for any of the viral markers in this study but was possibly enhanced by the presence of HHV-6-DNA. There is compelling evidence that EBV infection is a risk factor/necessary cause of MS [31], most recently coming from a nested case-control study within a large US military cohort study [1]. Among the proposed mechanisms for the link between EBV infection/serology and MS is the "dual virus hypothesis" [32], whereby HHV-6A activates EBV latent in B cells in the CNS [33] either directly or via activation of a human endogenous retrovirus [32,33], to induce CNS inflammation and demyelination.…”

A novel approach to identify cross-identity peptides between Epstein-Barr virus and central nervous system proteins in Guillain-Barré syndrome and multiple sclerosis

“…It is likely that the epitope spreading mechanism initiates a cascade of self-reactivity years before the onset of clinical symptoms (45). A previous EBV infection likely triggers multiple sclerosis, but its role in disease progression is poorly understood (46,47).…”

The Role of Viral Infections in the Onset of Autoimmune Diseases

“…The strongest evidence for virus-induced MS is documented for EBV. Several different mechanisms have been proposed for how EBV infection can trigger MS, including molecular mimicry and altered immune responses that lead to persistent EBV infections [ 171 ]. EBV can persistently infect B cells lifelong, from where the virus can intermittently reactivate.…”