Clinical Study Title:
Epstein-Barr Virus, Cytomegalovirus, and Multiple Sclerosis Susceptibility: A Multiethnic Study

Clinical Study Abstract:
OBJECTIVE: To determine whether Epstein-Barr virus (EBV) or cytomegalovirus (CMV) seropositivity is associated with multiple sclerosis (MS) in blacks and Hispanics and to what extent measures of the hygiene hypothesis or breastfeeding could explain these findings. EBV and CMV have been associated with MS risk in whites, and the timing and frequency of both viruses vary by factors implicated in the hygiene hypothesis.

METHODS: Incident cases of MS or its precursor, clinically isolated syndrome (CIS), and matched controls (blacks, 111 cases/128 controls; Hispanics, 173/187; whites, 235/256) were recruited from the membership of Kaiser Permanente Southern California. Logistic regression models accounted for HLA-DRB1*1501 status, smoking, socioeconomic status, age, sex, genetic ancestry, and country of birth.

RESULTS: Epstein-Barr nuclear antigen-1 (EBNA-1) seropositivity was independently associated with an increased odds of MS/CIS in all 3 racial/ethnic groups (p < 0.001 for blacks and whites, p = 0.02 for Hispanics). In contrast, CMV seropositivity was associated with a lower risk of MS/CIS in Hispanics (p = 0.004) but not in blacks (p = 0.95) or whites (p = 0.96). Being born in a low/middle-income country was associated with a lower risk of MS in Hispanics (p = 0.02) but not after accounting for EBNA-1 seropositivity. Accounting for breastfeeding did not diminish the association between CMV and MS in Hispanics.

CONCLUSIONS: The consistency of EBNA-1 seropositivity with MS across racial/ethnic groups and between studies points to a strong biological link between EBV infection and MS risk. The association between past CMV infection and MS risk supports the broader hygiene hypothesis, but the inconsistency of this association across racial/ethnic groups implies noncausal associations.

Reference:
Langer-Gould A, Wu J, Lucas R, et al. Epstein-Barr virus, cytomegalovirus, and multiple sclerosis susceptibility: a multiethnic study. Neurology. 2017;89(13):1330-1337.

The connection between EBV and MS has been recognized for a long time. Some experts have even suggested that EBV may be the cause of MS, but I think that the evidence for this is meager, and, so, it is probably not the case. It does appear, however, that EBV infection is 1 of several emerging risk factors that can put someone at a higher risk for developing this syndrome of MS. Notice that I use the word syndrome, and that is because I am not convinced that MS is a single disease. So, there is a link, but we are not clear on the significance of this link. We know, for example, that the enormous majority—more than 90%—of adults with MS in the Western world also are positive for EBV antibodies.

This study by Langer-Gould and colleagues examined whether EBV seropositivity is a risk factor across various ethnic groups. Researchers concluded that, indeed, the presence of EBNA seropositivity was associated with an increased risk for MS or CIS in the 3 racial ethnic groups they studied (ie, whites, Hispanics, blacks). They also looked at CMV seropositivity, which has not traditionally been regarded as a risk factor for MS, and they found that it was linked to a lower risk for MS, but only in the Hispanic population. The implications of this particular finding are unclear. Thus, this study highlights the consistency of the link between EBV (a B-cell tropic virus) and increased risk for developing MS.

There has been recent independent immunological work that suggests how EBV infection may play a role in the presentation of antigens that might establish MS. To wit, researchers have found that EBV infection seems to empower human B cells for autoimmunity by facilitating cross-presentation of disease-relevant epitopes to CD8⁺ T cells. This is all work that is attempting to identify the role that EBV infection might be playing with respect to MS, and I think that the whole story remains to be told. It is important to recognize that we are identifying a growing number of risk factors that increase the risk not only of developing MS, but also, in many cases, of experiencing greater disease severity.