High antibody levels against human herpesvirus-6A interact with lifestyle factors in multiple sclerosis development

Abstract

Background:

Infection with human herpesvirus 6A (HHV-6A) has been suggested to increase multiple sclerosis (MS) risk. However, potential interactions between HHV-6A and environmental/lifestyle risk factors for MS have not previously been studied.

Methods:

We used two Swedish population-based case-control studies comprising 5993 cases and 5995 controls. Using logistic regression models, subjects with different HHV-6A antibody levels, environmental exposures, and lifestyle habits were compared regarding MS risk, by calculating odds ratios (ORs) with 95% confidence intervals (CIs). Potential interactions between high HHV-6A antibody levels and common environmental exposures and lifestyle factors were evaluated on the additive scale.

Results:

High HHV-6A antibody levels were associated with increased risk of developing MS (OR = 1.5, 95% CI = 1.4–1.6). Regarding MS risk, significant interactions were observed between high HHV-6A antibody levels and both smoking (attributable proportion (AP) = 0.2, 95% CI = 0.1–0.3), low ultraviolet radiation (UVR) exposure (AP = 0.3, 95% CI = 0.1–0.4), and low vitamin D levels (AP = 0.3, 95% CI = 0.0–0.6).

Conclusion:

High HHV-6A antibody levels are associated with increased MS risk and act synergistically with common environmental/lifestyle risk factors for MS. Further research is needed to investigate potential mechanisms underlying the interactions presented in this study.

Keywords

Multiple sclerosis human herpesvirus 6A environmental risk factors interaction

Get full access to this article

View all access options for this article.

References

Browne

Chandraratna

Angood

, et al. Atlas of multiple sclerosis 2013: A growing global problem with widespread inequity. Neurology 2014; 83: 1022–1024.

Fogdell-Hahn

Ligers

Grønning

, et al. Multiple sclerosis: A modifying influence of HLA class I genes in an HLA class II associated autoimmune disease. Tissue Antigen 2000; 55(2): 140–148.

Olsson

Barcellos

Alfredsson

Interactions between genetic, lifestyle and environmental risk factors for multiple sclerosis. Nat Rev Neurol 2017; 13(1): 25–36.

Sundqvist

Sundstrom

Linden

, et al. Lack of replication of interaction between EBNA1 IgG and smoking in risk for multiple sclerosis. Neurology 2012; 79: 1363–1368.

Hedström

Olsson

Alfredsson

High body mass index before age 20 is associated with increased risk for multiple sclerosis in both men and women. Mult Scler 2012; 18(9): 1334–1336.

Bjørnevik

Riise

Bostrom

, et al. Negative interaction between smoking and EBV in the risk of multiple sclerosis: The EnvIMS study. Mult Scler 2017; 23(7): 1018–1024.

Strausbaugh

Caserta

Mock

, et al. Human herpesvirus 6. Clin Infect Dis 2001; 33: 829–833.

Hall

Caserta

Schnabel

, et al. Persistence of human herpesvirus 6 according to site and variant: Possible greater neurotropism of variant A. Clin Infect Dis 1998; 26(1): 132–137.

Akhyani

Berti

Brennan

, et al. Tissue distribution and variant characterization of human herpesvirus (HHV)-6: Increased prevalence of HHV-6A in patients with multiple sclerosis. J Infect Dis 2000; 182(5): 1321–1325.

10.

Engdahl

Gustafsson

Huang

, et al. Increased serological response against human herpesvirus 6A is associated with risk for multiple sclerosis. Front Immunol 2019; 10: 2715.

11.

Hillert

Stawiarz

The Swedish MS registry: Clinical support tool and scientific resource. Acta Neurol Scand 2015; 132(199): 11–19.

12.

Polman

Reingold

Banwell

, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011; 69(2): 292–302.

13.

Waterboer

Sehr

Michael

, et al. Multiplex human papillomavirus serology based on in situ-purified glutathione s-transferase fusion proteins. Clin Chem 2005; 51(10): 1845–1853.

14.

Michels

Becker

Suciu

, et al. Multiplex bead-based measurement of humoral immune responses against tumor-associated antigens in stage II melanoma patients of the EORTC18961 trial. Oncoimmunology 2018; 7: e1428157.

15.

Hedström

Huang

Michel

, et al. High levels of Epstein–Barr virus nuclear antigen-1-specific antibodies and infectious mononucleosis act both independently and synergistically to increase multiple sclerosis risk. Front Neurol 2019; 10: 1368.

16.

Patsopoulos

Baranzini

Santaniello

, et al. The Multiple Sclerosis Genomic Map: Role of peripheral immune cells and resident microglia in susceptibility. Biorxiv 2017; 365: eaav7188.

17.

Dilthey

Leslie

Moutsianas

, et al. Multi-population classical HLA type imputation. PLoS Comput Biol 2013; 9(2): e1002877.

18.

Rothman

Greenland

Lash

TL.

Modern epidemiology. 3rd ed. Philadelphia, PA: Wolters Kluwer, 2008.

19.

VanderWeele

TJ.

Sufficient cause interactions and statistical interactions. Epidemiology 2009; 20(1): 6–13.

20.

Cuomo

Angeloni

Zompetta

, et al. Human herpesvirus 6 variant A, but not variant B, infects EBV-positive B lymphoid cells, activating the latent EBV genome through a BZLF-1-dependent mechanism. AIDS Res Hum Retroviruses 1995; 11: 1241–1245.

21.

Tao

Simpson

Jr Taylor

, et al. Association between human herpesvirus & human endogenous retrovirus and MS onset & progression. J Neurol Sci 2017; 372: 239–249.

22.

Nielsen

Pedersen

Rostgaard

, et al. Correlations between Epstein–Barr virus antibody levels and risk factors for multiple sclerosis in healthy individuals. Mult Scler 2007; 13(3): 420–423.

23.

Xiong

, et al. An epidemiological and molecular study of the relationship between smoking, risk of nasopharyngeal carcinoma, and Epstein–Barr virus activation. J Natl Cancer Inst 2012; 104: 1396–1410.

24.

Qiu

Liang

Liu

, et al. Impacts of cigarette smoking on immune responsiveness: Up and down or upside down? Oncotarget 2017; 8: 268–284.

25.

Simon

van der Mei

Munger

, et al. Combined effects of smoking, anti-EBNA antibodies, and HLA-DRB1*1501 on multiple sclerosis risk. Neurology 2010; 74: 1365–1371.

26.

Salzer

Stenlund

Sundström

The interaction between smoking and Epstein–Barr virus as multiple sclerosis risk factors may depend on age. Mult Scler 2014; 20(6): 747–750.

27.

Prasad

Sajja

Park

, et al. Impact of cigarette smoke extract and hyperglycemic conditions on blood-brain barrier endothelial cells. Fluids Barriers CNS 2015; 12: 18.

28.

Aranow

Vitamin D and the immune system. J Investig Med 2011; 59: 881–886.

29.

von Essen

Kongsbak

Schjerling

, et al. Vitamin D controls T cell antigen receptor signaling and activation of human T cells. Nat Immunol 2010; 11(4): 344–349.

30.

Munger

Levin

Hollis

, et al. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA 2006; 296: 2832–2838.

31.

Maghzi

Ataei

Khorvash

, et al. Association between acute infectious mononucleosis and vitamin D deficiency. Viral Immunol 2016; 29(7): 398–400.

32.

Salzer

Nystrom

Hallmans

, et al. Epstein–Barr virus antibodies and vitamin D in prospective multiple sclerosis biobank samples. Mult Scler 2013; 19(12): 1587–1591.

33.

Rolf

Muris

Mathias

, et al. Exploring the effect of vitamin D3 supplementation on the anti-EBV antibody response in relapsing-remitting multiple sclerosis. Mult Scler 2018; 24: 1280–1287.

34.

Ohl

Tenbrock

Kipp

Oxidative stress in multiple sclerosis: Central and peripheral mode of action. Exp Neurol 2016; 277: 58–67.

35.

Wimalawansa

SJ.

Vitamin D deficiency: Effects on oxidative stress, epigenetics, gene regulation, and aging. Biology 2019; 8: 30.

36.

Lassoued

Ben Ameur

Ayadi

, et al. Epstein–Barr virus induces an oxidative stress during the early stages of infection in B lymphocytes, epithelial, and lymphoblastoid cell lines. Mol Cell Biochem 2008; 313(1–2): 179–186.

37.

Sebastiano

Chastel

de Thoisy

, et al. Oxidative stress favours herpes virus infection in vertebrates: A meta-analysis. Curr Zool 2016; 62(4): 325–332.

38.

Cohen

JI.

Vaccine development for Epstein–Barr virus. Adv Exp Med Biol 2018; 1045: 477–493.

39.

Cruz-Munoz

Fuentes-Panana

EM.

Beta and gamma human herpesviruses: Agonistic and antagonistic interactions with the host immune system. Front Microbiol 2017; 8: 2521.

40.

Tobacco: The public health agency of Sweden, 2019, http://www.folkhalsomyndigheten.se/the-public-health-agency-of-sweden/living-conditions-and-lifestyle/alcohol-narcotics-doping-tobacco-and-gambling/tobacco/

41.

DeLorenze

Munger

Lennette

, et al. Epstein–Barr virus and multiple sclerosis: Evidence of association from a prospective study with long-term follow-up. Arch Neurol 2006; 63(6): 839–844.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.12 MB