Multiple sclerosis (MS), a progressive disease that affects 2.8 million people worldwide and for which there is no definitive cure, is likely caused by infection with the Epstein-Barr virus (EBV), according to a study led by Harvard T.H. Chan School of Public Health researchers.
Their findings will be published online in Science on January 13, 2022.
“The hypothesis that EBV causes MS has been investigated by our group and others for several years, but this is the first study providing compelling evidence of causality,” said Alberto Ascherio, professor of epidemiology and nutrition at Harvard Chan School and senior author of the study.
“This is a big step because it suggests that most MS cases could be prevented by stopping EBV infection, and that targeting EBV could lead to the discovery of a cure for MS.”
MS is a chronic inflammatory disease of the central nervous system that attacks the myelin sheaths protecting neurons in the brain and spinal cord. Its cause is not known, yet one of the top suspects is EBV, a herpes virus that can cause infectious mononucleosis and establishes a latent, lifelong infection of the host.
Establishing a causal relationship between the virus and the disease has been difficult because EBV infects approximately 95% of adults, MS is a relatively rare disease, and the onset of MS symptoms begins about ten years after EBV infection.
To determine the connection between EBV and MS, the researchers conducted a study among more than 10 million young adults on active duty in the U.S. military and identified 955 who were diagnosed with MS during their period of service.
The team analyzed serum samples taken biennially by the military and determined the soldiers’ EBV status at time of first sample and the relationship between EBV infection and MS onset during the period of active duty. In this cohort, the risk of MS increased 32-fold after infection with EBV but was unchanged after infection with other viruses.
Serum levels of neurofilament light chain, a biomarker of the nerve degeneration typical in MS, increased only after EBV infection. The findings cannot be explained by any known risk factor for MS and suggest EBV as the leading cause of MS.
Ascherio says that the delay between EBV infection and the onset of MS may be partially due the disease’s symptoms being undetected during the earliest stages and partially due to the evolving relationship between EBV and the host’s immune system, which is repeatedly stimulated whenever latent virus reactivates.
“Currently there is no way to effectively prevent or treat EBV infection, but an EBV vaccine or targeting the virus with EBV-specific antiviral drugs could ultimately prevent or cure MS,” said Ascherio.
Other Harvard Chan School researchers who contributed to this study include Kjetil Bjornevik, Marianna Cortese, Michael Mina, and Kassandra Munger.
Multiple sclerosis (MS) is a disease of the central nervous system characterized by inflammation, blood-brain barrier breakdown, demyelination, lesion formation and axonal damage. The clinical course of relapsing-remitting MS is marked by recurring exacerbations, which are followed by either complete or partial recovery (Reich et al., 2018).
Over time, the majority of relapsing-remitting MS (RRMS) patients enter a progressive disease course in which there is gradual worsening of clinical disability with or without superimposed relapses, and eventually become secondary-progressive MS (SPMS) (Lublin, 2014).
A small portion of patients diagnosed as primary-progressive MS (PPMS) experience an early and continuous accumulation of physical disability without any superimposed acute relapses. Although MS risk is associated with environmental, neuroimmune, and genetic factors, the exact causative factor for MS is not known. The environmental risk factors most consistently linked MS risk are infection with Epstein-Barr virus (EBV), sun exposure/vitamin D deficiency, and smoking.
EBV or ubiquitous human herpesvirus 4 usually persists asymptomatically in immune-competent and healthy individuals (Figure 1) (Lucas et al., 2011). In the United States, approximately 50% of 6–8 years old children and 90% of 18–19 years old adults exhibit evidence of prior EBV exposure (Balfour et al., 2013). EBV infects B cells and epithelial cells (Lucas et al., 2011). The persistence of EBV in B cells in a latent state is chronic and lifelong.
Primary EBV infection occurs mainly in children of young age and is generally asymptomatic. However, when EBV infection occurs in adolescent/early adulthood it is more often accompanied by clinically overt symptoms, manifested as infectious mononucleosis (IM) in 30–40% of infected individuals (Sokal et al., 2007). Exposure to EBV can be assessed in the clinical setting using anti-EBV antibody panels and by measuring viral load (Centers for Disease Control and Prevention, 2018).
The occurrence of IgG antibodies against EBV early antigen (anti-EA IgG) is a biomarker of active EBV infection (Centers for Disease Control and Prevention, 2018). Anti-EA IgG induction is generally transient: it appears during the acute phase of infections and becomes undetectable 3–6 months after infection. However, anti-EA IgG can persist for years in 20% of the EBV infected patients (Centers for Disease Control and Prevention, 2018).
Anti-EBV nuclear antigen-1 (anti-EBNA-1) antibodies appear 2–4 months after infection and persist for the remainder of the host’s life. Similar to anti-EA IgG, seropositivity for anti-EBV Viral Capsid Antigen (anti-VCA) IgM occurs early in EBV infection and disappears after 4–6 months. Anti-VCA IgG appears in the acute phase of EBV infection, peaks at 2–4 weeks, declines slightly and persists for the remainder of the host’s life. Individuals seronegative for VCA are considered susceptible to infectious mononucleosis (Centers for Disease Control and Prevention, 2018).
The initial report of association between infectious mononucleosis occurrence and the subsequent development of MS have been corroborated by multiple meta-analysis (Martyn et al., 1993; Thacker et al., 2006; Handel et al., 2010). Interestingly, the prevalence of both infectious mononucleosis and MS demonstrates a co-localizing and uneven geographical distribution that may be explained by the hygiene hypothesis (Ascherio et al., 2012).
According to the hygiene hypothesis, the relative lack of early exposure to common pathogens during childhood in areas of with high levels of sanitation and hygiene may increase the risk for aberrant immune responses and autoimmune diseases if they are exposed to infectious triggers such as EBV later during adolescence and adulthood (Table 1) (Ascherio and Munger, 2007).
Memory B-cells play an important role in MS pathogenesis possibly because they are reservoirs for EBV latency and are also antigen-presenting cells, which activate auto-aggressive T-cells against the myelin proteins (Greenfield and Hauser, 2018). Several MS-associated risk alleles responsible for the regulation of B-cell functions, such as antigen presentation and immune-regulation, have been identified (Smets et al., 2018).
In the brain of MS patients, B-cells aggregate within the subarachnoid space into lymphoid-like structures, a process that is guided by the expression of lymphoid-homing chemokines (Franciotta et al., 2008). These lymphoid structures, termed tertiary lymphoid follicles, were isolated from post-mortem MS brains and comprised of EBV-infected B-cells that express genes related to their growth, differentiation, pathogen recognition, and enhanced T-cell activation (Magliozzi et al., 2007; Serafini et al., 2007, 2010; Veroni et al., 2018).
Tertiary lymphoid follicles can be potential sites for perpetual and independent lymphocyte activation after the primary autoimmune initiation (Parker Harp et al., 2015). Intrathecal administration of anti-CD20 (a marker for B-cell lineage) in murine experimental autoimmune encephalomyelitis (EAE) model effectively depletes B-cells within the meningeal lymphoid follicles located near MS lesions (Lehmann-Horn et al., 2014).
Although most of the disease-modifying therapies currently approved for MS were initially believed to act mainly on T-cells, later investigations showed additional effects on the B-cell population (Baker et al., 2017). The assessment of leptomeningeal contrast enhancement on post-contrast 3D fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) allows the visualization of leptomeningeal inflammation in tertiary lymphoid follicles in vivo, and potentially monitors their associations with disease progression (Absinta et al., 2015).
This review evaluates the role of EBV in MS from both clinical and imaging point of view, explores the effects of disease-modifying therapies that might be targeting EBV, and discusses other emerging virus candidates that may be potentially involved in MS pathogenesis. The search strategy is shown in Table 2.
More information: Kjetil Bjornevik et al, Longitudinal analysis reveals high prevalence of Epstein-Barr Virus associated with multiple sclerosis. , Science (2022). DOI: 10.1126/science.abj8222. www.science.org/doi/10.1126/science.abj8222
William Robinson et al, Epstein-Barr virus and multiple sclerosis, Science (2022). DOI: 10.1126/science.abm7930. www.science.org/doi/10.1126/science.abm7930