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

Abstract

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 disability progression herpesvirus multiple sclerosis natural killer cells NKG2C

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References

Ascherio

Munger

. Environmental risk factors for multiple sclerosis. Part I: The role of infection. Ann Neurol 2007; 61: 288–299.

Brodin

Jojic

Gao

. Variation in the human immune system is largely driven by non-heritable influences. Cell 2015; 160: 37–47.

White

Suzanne

Barton

. Immune modulation during latent herpesvirus infection. Immunol Rev 2012; 245: 189–208.

Pakpoor

Disanto

. Cytomegalovirus and multiple sclerosis risk. J Neurol 2013; 260: 1658–1660.

Sundqvist

Bergström

Daialhosein

. Cytomegalovirus seropositivity is negatively associated with multiple sclerosis. Mult Scler 2014; 20: 165–173.

Waubant

Mowry

Krupp

. Common viruses associated with lower pediatric multiple sclerosis risk. Neurology 2011; 76: 1989–1995.

Vanheusden

Stinissen

‘t Hart

. Cytomegalovirus: A culprit or protector in multiple sclerosis? Trends Mol Med 2015; 21: 16–23.

Biron

Nguyen

Pien

. Natural killer cells in antiviral defense: Function and regulation by innate cytokines. Annu Rev Immunol 1999; 17: 189–220.

Waggoner

Cornberg

Selin

. Natural killer cells act as rheostats modulating antiviral T cells. Nature 2012; 481: 394–398.

10.

Bielekova

Catalfamo

Reichert-Scrivner

. Regulatory CD56 (bright) natural killer cells mediate immunomodulatory effects of IL-2Ralpha-targeted therapy (daclizumab) in multiple sclerosis. Proc Natl Acad Sci U S A 2006; 103: 5941–5946.

11.

Kaur

Trowsdale

Fugger

. Natural killer cells and their receptors in multiple sclerosis. Brain 2013; 136: 2657–2676.

12.

Martínez-Rodríguez

López-Botet

Munteis

. Natural killer cell phenotype and clinical response to interferon-beta therapy in multiple sclerosis. Clin Immunol 2011; 141: 348–356.

13.

López-Botet

Muntasell

Vilches

. The CD94/NKG2C+ NK-cell subset on the edge of innate and adaptive immunity to human cytomegalovirus infection. Semin Immunol 2014; 26: 145–151.

14.

Béziat

Liu

Malmberg

. NK cell responses to cytomegalovirus infection lead to stable imprints in the human KIR repertoire and involve activating KIRs. Blood 2013; 121: 2678–2688.

15.

Della Chiesa

Falco

Podestà

. Phenotypic and functional heterogeneity of human NK cells developing after umbilical cord blood transplantation: A role for human cytomegalovirus? Blood 2012; 119: 399–410.

16.

Foley

Cooley

Verneris

. Cytomegalovirus reactivation after allogeneic transplantation promotes a lasting increase in educated NKG2C+ natural killer cells with potent function. Blood 2012; 119: 2665–2674.

17.

Gumá

Angulo

Vilches

. Imprint of human cytomegalovirus infection on the NK cell receptor repertoire. Blood 2004; 104: 3664–3671.

18.

Hendricks

Balfour

Jr Dunmire

. Cutting edge: NKG2C(hi)CD57+ NK cells respond specifically to acute infection with cytomegalovirus and not Epstein-Barr virus. J Immunol 2014; 192: 4492–4496.

19.

López-Verges

Milush

Schwartz

. Expansion of a unique CD57(+)NKG2Chi natural killer cell subset during acute human cytomegalovirus infection. Proc Natl Acad Sci U S A 2011; 108: 14725–14732.

20.

Muntasell

López-Montañés

Vera

. NKG2C zygosity influences CD94/NKG2C receptor function and the NK-cell compartment redistribution in response to human cytomegalovirus. Eur J Immunol 2013; 43: 3268–3278.

21.

Muntasell

Vilches

Angulo

. Adaptive reconfiguration of the human NK-cell compartment in response to cytomegalovirus: A different perspective of the host-pathogen interaction. Eur J Immunol 2013; 43: 1133–1141.

22.

Noyola

Fortuny

Muntasell

. Influence of congenital human cytomegalovirus infection and the NKG2C genotype on NK-cell subset distribution in children. Eur J Immunol 2012; 42: 3256–3266.

23.

Martínez-Rodríguez

Saez-Borderías

Munteis

. Natural killer receptors distribution in multiple sclerosis: Relation to clinical course and interferon-beta therapy. Clin Immunol 2010; 137: 41–50.

24.

Amato

Portaccio

. Truly benign multiple sclerosis is rare: Let’s stop fooling ourselves–yes. Mult Scler 2012; 18: 13–14.

25.

Lublin

Reingold

Cohen

. Defining the clinical course of multiple sclerosis: The 2013 revisions. Neurology 2014; 83: 278–286.

26.

Moraru

Cañizares

Muntasell

. Assessment of copy-number variation in the NKG2C receptor gene in a single-tube and characterization of a reference cell panel, using standard polymerase chain reaction. Tissue Antigens 2012; 80: 184–187.

27.

De Jager

Rossin

Pyne

. Cytometric profiling in multiple sclerosis uncovers patient population structure and a reduction of CD8low cells. Brain 2008; 131: 1701–1711.

28.

Miyashita

Tsuchiya

Hikami

. Molecular genetic analyses of human NKG2C (KLRC2) gene deletion. Int Immunol 2004; 16: 163–168.

29.

Zeng

Chen

Gupta

. Deletion of the activating NKG2C receptor and a functional polymorphism in its ligand HLA-E in psoriasis susceptibility. Exp Dermatol 2013; 22: 679–681.

30.

Münz

Lünemann

Getts

. Antiviral immune responses: Triggers of or triggered by autoimmunity? Nat Rev Immunol 2009; 9: 246–258.

31.

Lünemann

Tintoré

Messmer

. Elevated Epstein-Barr virus-encoded nuclear antigen-1 immune responses predict conversion to multiple sclerosis. Ann Neurol 2010; 67: 159–169.

32.

Pirko

Cardin

Chen

. CMV infection attenuates the disease course in a murine model of multiple sclerosis. PLoS One 2012; 7: e32767.

33.

Zhang

Yamamura

Kondo

. Regulation of experimental autoimmune encephalomyelitis by natural killer (NK) cells. J Exp Med 1997; 186: 1677–1687.

34.

Hao

Campagnolo

Liu

. Interleukin-2/interleukin-2 antibody therapy induces target organ natural killer cells that inhibit central nervous system inflammation. Ann Neurol 2011; 69: 721–734.

35.

Goodier

White

Darboe

. Rapid NK cell differentiation in a population with near-universal human cytomegalovirus infection is attenuated by NKG2C deletions. Blood 2014; 124: 2213–2222.

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