Low cytomegalovirus seroprevalence in early multiple sclerosis: a case for the 'hygiene hypothesis'?

Eur J Neurol. 2018 Jul;25(7):925-933. doi: 10.1111/ene.13622. Epub 2018 Apr 15.


Background and purpose: Cytomegalovirus (CMV) infection has recently been associated with a lower multiple sclerosis (MS) susceptibility, although it remains controversial whether it has a protective role or is merely an epiphenomenon related to westernization and early-life viral infections. We aimed to evaluate whether CMV serostatus may differ in patients with early MS as compared with patients with non-early MS, analyzing the putative association of this virus with MS clinical course and humoral immune responses against other herpesviruses.

Methods: Multicentric analysis was undertaken of 310 patients with MS (early MS, disease duration ≤5 years, n = 127) and controls (n = 155), evaluating specific humoral responses to CMV, Epstein-Barr virus and human herpesvirus-6, as well as T-cell and natural killer (NK)-cell immunophenotypes.

Results: Cytomegalovirus seroprevalence in early MS was lower than in non-early MS or controls (P < 0.01), being independently associated with disease duration (odds ratio, 1.04; 95% confidence interval, 1.01-1.08, P < 0.05). CMV+ patients with MS displayed increased proportions of differentiated T-cells (CD27-CD28-, CD57+, LILRB1+) and NKG2C+ NK-cells, which were associated with a lower disability in early MS (P < 0.05). CMV+ patients with early MS had an age-related decline in serum anti-EBNA-1 antibodies (P < 0.01), but no CMV-related differences in anti-human herpesvirus-6 humoral responses.

Conclusions: Low CMV seroprevalence was observed in patients with early MS. Modification of MS risk attributed to CMV might be related to the induction of differentiated T-cell and NK-cell subsets and/or modulation of Epstein-Barr virus-specific immune responses at early stages of the disease.

Keywords: Epstein-Barr virus; cytomegalovirus; herpesvirus; hygiene hypothesis; immunosenescence; multiple sclerosis; natural killer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antibodies, Viral / blood
  • Cytomegalovirus / isolation & purification*
  • Cytomegalovirus Infections / complications*
  • Female
  • Humans
  • Hygiene Hypothesis*
  • Male
  • Middle Aged
  • Multiple Sclerosis / blood
  • Multiple Sclerosis / virology*
  • Seroepidemiologic Studies
  • Young Adult


  • Antibodies, Viral