Elsevier

Journal of Neuroimmunology

Volume 330, 15 May 2019, Pages 90-95
Journal of Neuroimmunology

Perfluorinated substances, risk factors for multiple sclerosis and cellular immune activation

https://doi.org/10.1016/j.jneuroim.2019.03.002Get rights and content

Highlights

  • PFAS exposure is not an environmental risk factor for multiple sclerosis.

  • Patients with multiple sclerosis have lower serum-PFOS than healthy controls.

  • Lower frequencies of circulating MAIT-like cells in healthy controls who smokes.

Abstract

Perfluorinated alkylated substances (PFASs) have immunomodulatory effects but the impact on multiple sclerosis (MS) and cellular immune functions is only sparsely described. In the present study, we found lower concentrations of the long chain PFAS perfluorooctane sulfonic acid (PFOS) in MS than in healthy controls (HC). In HC, we did not detect associations between PFOS concentrations and immune phenotypes. Analyzing the impact of known MS risk factors on cellular immune functions, we found that smoking and Epstein–Barr nuclear antigen 1 antibodies were associated with distinct circulating immune cell changes. In summary, current background PFAS exposure is not an important risk factor for MS.

Introduction

Perfluorinated alkylated substances (PFASs) are synthetic chemical compounds produced since the 1950s. PFASs are substances with long carbon chains with fluorine atoms replacing the hydrogen atoms. Carbon‑fluorine bindings are very stable, and biodegradation of PFASs is extremely slow (Li et al., 2018). Much focus has been on the “long-chain” PFASs as the toxicity and accumulation in the environment seems to increase with the length of the carbon chains. PFASs have been used as surfactants in a wide range of consumer products due to their combined hydrophilic and hydrophobic properties and has for the last two decades been investigated for their potential harmful effects in humans (Buck et al., 2011). Human exposure to PFASs stem from inhaled particles and from contaminated food products and drinking water due to a lack of environmental degradation (ATSDR, 2018).

In humans, PFASs are only slowly eliminated, and serum half-lives of up to 5.4 years are reported (Li et al., 2018, Stahl et al., 2011). PFASs bind to serum proteins and accumulate in kidneys, liver and blood (Jian et al., 2018). Mostly shorter chain PFASs are found to be excreted in urine whereas long-chain PFASs are suggested to be excreted through breast milk and blood (Fromme et al., 2009; Lorber et al., 2015; Wong et al., 2014). Reported health effects from PFASs includes several studies suggesting an immunosuppressive or immunotoxic effect of PFASs (DeWitt et al., 2019; Grandjean et al., 2017a; Stein et al., 2016).

Multiple sclerosis (MS) is an immune-mediated disease in the central nervous system (CNS). The disease is driven by autoimmune cells recruited from the periphery causing disease upon entry to the CNS (Compston and Coles, 2008; Sospedra and Martin, 2016). Genetic and environmental factors are believed to be main contributors to the etiology of MS. Some of the strongest risk factors reported are female sex, smoking, low vitamin D, Epstein-Barr virus (EBV) infection, and carrying the HLA-DRB1*15:01 risk gene (Belbasis et al., 2015; Duan et al., 2014; Handel et al., 2011; The International Multiple Sclerosis Genetics and The Wellcome Trust Case Control, 2011).

One study has reported a slightly increased occurrence of MS at highly elevated exposures to perfluorooctanoic acid (PFOA), but the association between serum-PFOA concentrations and MS was not statistically significant (Steenland et al., 2013). However, the serum concentration obtained may not have reflected the pathogenic exposure. To our knowledge, effects of PFASs on MS risk factors and circulating immune cell characteristics are poorly known.

Accordingly, we aimed to investigate if serum-PFAS concentrations are associated with MS and to further examine the impact of PFASs and known MS risk factors on the relative distribution and activation of circulating immune cells.

Section snippets

Study population

Serum concentrations of PFASs were measured in 86 out of 100 healthy controls (HC) from whom we had collected blood samples and obtained data on immune cell frequencies and activation in a previous study (Ammitzboll et al., 2017) and 76 patients of whom 67 were diagnosed with relapsing-remitting MS (RRMS), and 9 with a clinically isolated syndrome (CIS). All patients were untreated at the time of blood sampling. From the RRMS patient cohort, 51 patients were newly diagnosed and untreated and 16

Results

One hundred HC and 76 patients with RRMS or CIS were included in the study. Demographics are shown in Table 1. From 86 HC and from all 76 patients, we obtained serum concentrations of six long-chain PFASs: the per fluorinated alkylated sulfonic acids perfluorohexane sulfonic acid (PFHxS) (C6), perfluoroheptane sulfonic acid (PFHpS) (C7) and perfluorooctane sulfonic acid (PFOS) (C8); and the perfluoroalkyl carboxylic acids perfluorooctanoic acid (PFOA) (C7), perfluoro nonanoic acid (PFNA) (C8)

Discussion

With the present study, we show novel data on the cross-sectional relationship between PFAS exposure and RRMS and conclude that RRMS is associated with lower serum concentrations of PFOS compared with HC, whereas we found no difference for the other PFASs studied after adjustment for relevant confounding factors.

Being one of the largest PFAS, PFOS is poorly eliminated from the human body. Consequently, the health problems associated with PFOS exposure, as compared with other PFASs, have

Conflict-of-interest disclosure

C.A., L.B. H.B·S and P.G. report no financial conflicts of interest. E.R.P. has served on scientific advisory board for Teva and received support for congress participation from Roche. A.B.O. has served on scientific advisory boards for Biogen Idec, Novartis and Sanofi Genzyme; has received research support from Novartis and Biogen Idec; has received speaker honoraria from Biogen Idec, Novartis and TEVA; and has received support for congress participation from, Merck, TEVA, Biogen, Roche,

Funding source

This study was supported by the Danish Multiple Sclerosis Society (R308A19240). P.G. is supported by the STEEP Superfund Center (P42ES027706) from the National Institute of Environmental Health Sciences (NIH).

References (47)

  • D.J. Benjamin et al.

    Redefine statistical significance

    Nat. Hum. Behav.

    (2018)
  • R.C. Buck et al.

    Perfluoroalkyl and polyfluoroalkyl substances in the environment: terminology, classification, and origins

    Integr. Environ. Assess. Manag.

    (2011)
  • V. Cunill et al.

    Relapsing-remitting multiple sclerosis is characterized by a T follicular cell pro-inflammatory shift, reverted by Dimethyl Fumarate treatment

    Front. Immunol

    (2018)
  • W. Dankers et al.

    Vitamin D in autoimmunity: molecular mechanisms and therapeutic potential

    Front. Immunol.

    (2016)
  • J.C. DeWitt et al.

    Exposure to per-fluoroalkyl and polyfluoroalkyl substances leads to immunotoxicity: epidemiological and toxicological evidence

    J. Expo. Sci. Environ. Epidemiol

    (2019)
  • X. Fan et al.

    Follicular helper CD4+ T cells in human neuroautoimmune diseases and their animal models

    Mediat. Inflamm.

    (2015)
  • M. Filippi et al.

    Multiple sclerosis

    Nat. Rev. Disease Prim

    (2018)
  • J.M. Fletcher et al.

    CD39<sup>+</sup>Foxp3<sup>+</sup> regulatory T cells suppress pathogenic Th17 cells and are impaired in multiple sclerosis

    J. Immunol.

    (2009)
  • G. Ghalamfarsa et al.

    IL-21 and IL-21 receptor in the immunopathogenesis of multiple sclerosis

    J. Immunotoxicol.

    (2016)
  • P. Grandjean et al.

    Serum vaccine antibody concentrations in children exposed to perfluorinated compounds

    Jama.

    (2012)
  • P. Grandjean et al.

    Serum vaccine antibody concentrations in adolescents exposed to perfluorinated compounds

    Environ. Health Perspect.

    (2017)
  • P. Grandjean et al.

    Estimated exposures to perfluorinated compounds in infancy predict attenuated vaccine antibody concentrations at age 5-years

    J. Immunotoxicol.

    (2017)
  • A.E. Handel et al.

    Smoking and multiple sclerosis: an updated meta-analysis

    PLoS One

    (2011)
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