Large serologic study incriminates both EBV and HHV-6A as triggers of multiple sclerosis

Serologic studies have provided very strong evidence that Epstein-Barr virus (EBV) is one trigger for multiple sclerosis (MS) (Bjornevik 2022).  Serologic studies as well as studies of HHV-6A nucleic acid and antigen in the brain of people with MS also have indicated that HHV-6A may also be one trigger of MS (Leibovitch 2018, Komaroff 2021).

 Investigators led by Anna Fogedell-Hahn and Peter Sundström of Umea University, Sweden, performed a serological case-control study of 670 people with MS and 670 matched control subjects; the sera from cases were obtained and banked prior to the development of MS. The samples were analyzed for IgG antibodies against EBV (EBNA-1 trunc, EBNA-1 pep, VCA p18), HHV-6A (IE1A antigen), and HHV-6B (IE1B antigen). Seropositivity was correlated to the risk of developing MS later in life.

With EBV seropositivity, there was a significantly lower risk for MS in the group <20 years old (OR=0.52, 95% CI 0.29-0.94) and a significantly higher risk for older individuals from age 20-40 (OR = 4.6 95% CI 1.7-7.1). The age where seropositivity to EBV switched from conferring a reduced risk to conferring an increased risk was 18.8 years (Figure 1). The results among people older than age 20 remained statistically significant after multivariable adjustment.

Figure 1: Predicted probability of seropositivity by age for cases and controls with 95% confidence interval. Curves estimated using logistic regression - Bistrom 2021

Seropositivity against IE1A was significantly associated with increased MS risk in all three age groups (OR = 2.1 95% CI 1.6-2.7).  In contrast, there was no significant association for risk of MS development with IE1B.

This study confirms previous epidemiological findings that MS is rare in populations where EBV infection occurs at an early age. Statistical tests of whether there was synergy between EBV infection and HHV-6A infection in raising the risk of subsequent MS were equivocal.  No studies were performed of a third possible trigger of MS: endogenous retroviruses and superantigens they can express.

The authors speculate as to the multiple mechanisms by which these two viruses might trigger MS.  Molecular mimicry recently has been postulated for EBV (Lanz 2022).  HHV-6 infects myelin-producing cells (oligodendrocytes) and is a plausible cause of a failure to re-myelinate in demyelinating diseases like MS. The mechanism may be through interference with migration of oligodendrocyte cells (Campbell 2017), or because infection of oligodendrocytes stimulates an attack against autoantigens on the cell surface such as can occur with CMV infection (Naucler 1996).

Read the full article: Bistrom 2021