Adaptive natural killer cell response to cytomegalovirus and disability progression in multiple sclerosis

Mult Scler. 2016 May;22(6):741-52. doi: 10.1177/1352458515601215. Epub 2015 Sep 11.


Background: Human cytomegalovirus (HCMV) causes a highly prevalent infection which may have a multifaceted impact on chronic inflammatory disorders. However, its potential influence in multiple sclerosis (MS) remains controversial. The HCMV-host interaction may induce an adaptive reconfiguration of the natural killer (NK) cell compartment, whose hallmark is a persistent expansion of peripheral NKG2C+ NK-cells.

Objective: The purpose of this study was to evaluate whether the HCMV-driven NKG2C+ NK-cell expansion is related to the MS clinical course.

Methods: Multicentre analysis of NKG2C expression and genotype according to HCMV serostatus and time of assignment of irreversible disability scores in 246 MS patients prospectively followed up in our institutions.

Results: NKG2C expression was unrelated to disease-modifying drugs, remained stable under steady-state conditions, and was higher in HCMV(+) NKG2C(+/+) homozygous individuals. NKG2C+ NK-cell expansion in HCMV(+) patients, as compared to HCMV(+) or HCMV(-) patients with lower NKG2C+ NK-cells proportions, conferred a lower risk of progression in Cox regression analysis (Expanded Disability Status Scale (EDSS)>3.0, hazard ratio (HR)=0.33, 95% confidence interval (CI) 0.15-0.71, p=0.005; EDSS>5.5, HR=0.23, 95% CI 0.07-0.74, p=0.014). Neither HCMV serostatus nor NKG2C genotype appeared to be related to disability progression.

Conclusions: HCMV may exert a beneficial influence on MS, decreasing the risk of disability progression in those patients displaying a virus-driven NKG2C+ NK-cell expansion.

Keywords: Cytomegalovirus; NKG2C; disability progression; herpesvirus; multiple sclerosis; natural killer cells.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity / immunology
  • Adult
  • Antibodies, Viral / blood
  • Cytomegalovirus / immunology*
  • Cytomegalovirus Infections / immunology*
  • Disease Progression
  • Female
  • Follow-Up Studies
  • Humans
  • Killer Cells, Natural / immunology*
  • Male
  • Middle Aged
  • Multiple Sclerosis* / immunology
  • Multiple Sclerosis* / metabolism
  • Multiple Sclerosis* / physiopathology
  • NK Cell Lectin-Like Receptor Subfamily C / metabolism*


  • Antibodies, Viral
  • KLRC2 protein, human
  • NK Cell Lectin-Like Receptor Subfamily C