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Quarterly Medical Review

Environmental factors in multiple sclerosis Vasiliki Pantazou 1, Myriam Schluep 1, Renaud Du Pasquier 1,2

Available online:

1. CHUV, University Hospital of Lausanne, Department of Clinical Neurosciences, Service of Neurology, 1011 Lausanne, Switzerland 2. CHUV, University Hospital of Lausanne, Centre of Research in Clinical Neurosciences, Laboratory of Neuroimmunology, 1011 Lausanne, Switzerland

Correspondence: Renaud Du Pasquier, CHUV, University Hospital of Lausanne, Department of Clinical Neurosciences, Service of Neurology, BH.10.131, 1011 Lausanne, Switzerland. [email protected]

Environmental factors in multiple sclerosis Vasiliki Pantazou et al., Lausanne, Switzerland The auto-immune concept of multiple sclerosis Bryan Nicol et al., Nantes, France Advanced imaging tools to investigate multiple sclerosis pathology Benedetta Bodini et al., Paris, France Update on clinically isolated syndrome Éric Thouvenot, Nîmes, France Update on rehabilitation in multiple sclerosis Cécile Donzé, Lille, France Update on treatments in multiple sclerosis Laure Michel et al., Montreal, Canada Treatment of multiple sclerosis in children and its challenges Sona Narula et al., Philadelphia, United States

Summary Although multiple sclerosis (MS) is recognized as a disorder involving the immune system, the interplay of environmental factors and individual genetic susceptibility seems to influence MS onset and clinical expression, as well as therapeutic responsiveness. Multiple human epidemiological and animal model studies have evaluated the effect of different environmental factors, such as viral infections, vitamin intake, sun exposure, or still dietary and life habits on MS prevalence. Previous Epstein-Barr virus infection, especially if this infection occurs in late childhood, and lack of vitamin D (VitD) currently appear to be the most robust environmental factors for the risk of MS, at least from an epidemiological standpoint. Ultraviolet radiation (UVR) activates VitD production but there are also some elements supporting the fact that insufficient UVR exposure during childhood may represent a VitD-independent risk factor of MS development, as well as negative effect on the clinical and radiological course of MS. Recently, there has been a growing interest in the gut-brain axis, a bidirectional neuro-hormonal communication system between the intestinal microbiota and the central nervous system (CNS). Indeed, components of the intestinal microbiota may be pro-inflammatory, promote the migration of immune cells into the CNS, and thus be a key parameter for the development of autoimmune disorders such as MS. Interestingly most environmental factors seem to play a role during childhood. Thus, if childhood is the most fragile period to develop MS later in life, preventive measures should be applied early in life. For example, adopting a diet enriched in VitD, playing outdoor and avoiding passive smoking would be extremely simple measures of primary prevention for public health strategies. However, these hypotheses need to be confirmed by prospective evaluations, which are obviously difficult to conduct. In addition, it remains to be determined whether and how VitD supplementation in adult life would be useful in alleviating the course of MS, once this disease has already started. A better knowledge of the influence of various environmental stimuli on MS risk and course would certainly allow the development of add-on therapies or measures in parallel to the immunotherapies currently used in MS.


In this issue

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To cite this article: Pantazou V, et al. Environmental factors in multiple sclerosis. Presse Med. (2015), j.lpm.2015.01.001

V. Pantazou, M. Schluep, R. Du Pasquier


ultiple sclerosis (MS) is a chronic inflammatory demyelinating disorder of the central nervous system (CNS), usually starting in individuals aged between 20 and 40 years old. Although the understanding of MS pathogenesis still faces open questions, it is usually considered that MS results from intermingled genetic and environmental factors. Indeed, the basal risk of MS is less than 0.5% in the general population, whereas the incidence for first-degree relatives is 1.9 to 4.7% [1]. Monozygotic twins carry a concordance rate of approximately 34% [1– 3], whereas dizygotic twins of the same gender display a 2.3% concordance rate [4]. Among genetic risk factors, the HLADRB1*1501 allele confers a 3-fold risk for the development of MS and accounts for approximately 50% of the genetic risk of MS [5]. Recent genome-wide association study (GWAS) has identified several MS risk loci outside of the major histocompatibility complex (MHC), but each of these loci only slightly increases individually the risk of MS [6,7]. Overall, the genetic does not account for the whole cause of MS, yet, environmental factors contribute to the risk of the disease. There is a concordance of data suggesting that there are critical ages in terms of MS onset, i.e. gestation, childhood, and especially adolescence. Hereafter, we will review how different vitamins, diet or still microbial factors may influence the onset of MS.

Epstein-Barr virus


A role of infectious agents in triggering MS has been hypothesized first by Pierre Marie, a pupil of Charcot. Since then, many agents have been incriminated, but each time, their role was finally dismissed [8]. There is however one virus, which remains "in the race'': Epstein-Barr virus (EBV) is a g-herpes virus, which has been consistently associated with MS [9]. Sero-epidemiological studies have demonstrated that 100% of adult MS patients are infected with EBV in contrast to 96% of agematched healthy control subjects, and two independent studies found a significantly higher rate of EBV infection (88%) in children with MS as compared to healthy age-matched children (50%) [10,11]. Levin et al. conducted an elegant nested casecontrol study including 305 individuals who have developed MS and 610 matched controls. The time of EBV infection was determined by measuring antibody titers in serial serum samples collected before MS onset, compared to samples collected on matched controls. Ten (3.3%) MS cases and 32 (5.2%) controls were initially EBV negative. All the 10 EBV-negative cases became EBV positive before MS onset, contrasting with only 10 of the 28 controls (exact P value: 0.0008). It can thus be inferred that the risk of MS is extremely low among individuals not infected with EBV, but that this risk increases dramatically upon EBV infection [12]. The risk of developing MS is higher when EBV is acquired as a teenager rather than as a baby. Indeed, as much as the primoinfection with EBV in babies is asymptomatic, in teenagers it is

usually characterized by a painful pharyngitis with intense fatigue, the "kissing disease'' or infectious mononucleosis (IM) [9]. In a meta-analysis including 18 articles, and totalizing 19,390 MS patients and controls, Handel et al. showed that the risk of developing MS after IM was 2.17 times higher than when one contracted EBV asymptomatically (P = 1054!) [13]. The interval between IM and MS is comprised between five to 10 years [9,14,15]. Altogether, these data are consistent with the fact that adolescence is a critical period in terms of immunology related to MS (see also the discussion on vitamin D [VitD]). The risk of MS increases linearly with the increase of anti-Epstein-Barr nuclear antigen-1 (EBNA-1)-specific IgG [16]. Most studies examining the relationship between EBV and MS have been based on serologies. Not only the humoral immune response, but also the cellular one, link EBV with MS. EBNA-1specific CD4+ as well as EBNA-3A- and latent membrane protein-2 (LMP2)-specific CD8+ were detected more often in the blood of MS patients as compared to healthy EBV-infected controls [17–19]. On our side, we could show that there is a strong EBV-specific CD8+ T cell response in the blood and in the cerebrospinal fluid of patients with early MS, but that the intensity of this response decreased with the duration of MS [20,21]. Linking genetic with environmental factors, we have shown that HLA-B*0702-restricted EBVRPP peptides-specific CD8+ T cells exhibited a deficit in cytotoxic granules and pro-inflammatory cytokines, suggesting that the control of EBV might be suboptimal in MS patients bearing the HLAB*0702 allele [22]. Others found similar results demonstrating that CD8+ T cell response against EBV is increased during the active phase of the disease and that EBV infected plasma cells present in inflammatory post-mortem brain tissue are in close vicinity with cytotoxic CD8+ T cells, a phenomenon, which could sustain EBV specific CD8+ T cell activation in the brain [23]. However, by which mechanism would EBV contribute to trigger MS remains enigmatic: molecular mimicry has been called upon, but is difficult to prove beyond sophisticated experimental design [24]. The accumulation of EBV-infected B cells in the meninges of patients with secondary progressive MS, triggering an inflammatory response at the origin of MS has also been evoked [25], but not confirmed by others [26,27]. In conclusion, it is fair to say that there is a clear association between EBV and MS; however whether EBV is instrumental in the immunopathogenesis of MS or only a bystander effect remains to be determined. Adding to the difficulty, EBV does not infect mice, therefore, the experimental autoimmune encephalomyelitis (EAE) model is of no use for this specific line of research. However, authors recently described the onset of neurological relapses occurring spontaneously in a colony of Japanese monkeys. Analyses of their brain revealed plaques looking like MS plaques, and the presence of a g-herpes virus, thus belonging to the same family as EBV, was detected [28].

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To cite this article: Pantazou V, et al. Environmental factors in multiple sclerosis. Presse Med. (2015), j.lpm.2015.01.001

Intestinal microbiota The gut microbiota is a complex microbial ecosystem in the distal bowel whose function is, among others, to defend against pathogen colonization by active production of antimicrobial substances and to limit bacteria penetration by induction of IgA fortifying the intestinal epithelial barrier [29]. The colonization of the human gut starts immediately after birth, reaching an adult-like synthesis by one year of age when 1012 microorganisms co-exist, divided into three major bacterial genus: Bacteroeides, Prevotella and Ruminococcus [30]. Recent studies suggest that microbiota could guide the maturation and function of the brain by a bidirectional neuro-hormonal communication system, known as the gut-brain axis. This axis may affect prenatal and postnatal developmental programming of the brain [31], but also immune functions such as expansion of CD4+ T cells expressing CD39 that promotes the migration of these cells in the CNS [32]. Animal model studies showed that germ-free myelin oligodendrocyte glycoprotein-sensitized-transgenic mice were resistant to the development of EAE [33]. Interestingly, segmented filamentous bacteria colonization restored EAE susceptibility in germ free mice [34], Bifidobacterium animalis reduced the duration of symptoms in rat EAE [35], Lactobacillus casei Shirota suppressed rat EAE [36], thus indicating the differential roles of the isolated germs of microbiota in promoting or decreasing inflammation. Germ free mice were found to have a marked deficit in Th17-like cells [37]. Although evidences are still lacking, there are some data suggesting that gut microbiota may be involved in the onset of human autoimmune diseases such as inflammatory bowel disease, rheumatoid arthritis and type I diabetes mellitus [38], as well as CNS disorders such as MS, depression, anxiety [38], stress [39] and autism [40]. Likely mechanisms consist, among others, in loss of immune tolerance to components of the microbiota and altered epithelial permeability [41]. Supporting this hypothesis, Banati et al. [42] found that a high percentage of MS patients exhibited antibody responses against gastrointestinal antigens, pointing to a possible altered communication between the gut microbiome and the immune system.

Sun exposure and VitD MS prevalence is largely influenced by latitude, and thus sun exposure appears as a potential important determinant. High latitude areas receive less potent ultra-violet radiation (UVR) exposure. Yet, the further one goes away from the equator (North or South), the higher is the incidence of MS [43]. Detailed epidemiological studies in France supported the importance of sun exposure, demonstrating that MS prevalence was significantly higher in areas with lower UVR [44]. Moreover, an analysis of the Swedish pediatric and adolescent population showed a reduced risk of MS associated with summer outdoor activities

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during childhood and adolescence [45]. Yet, the synthesis of VitD is largely dependent on sun exposure, which led researchers to explore the role of VitD in the immunopathogenesis of MS [46]. In Switzerland, 15–17% of the children between 11 to 16 years are deficient in VitD3 [47]. Almost 40% of the children in Lyon [48], Boston [49], and northern Sweden [50] were found to have a VitD deficiency. In the adult population, approximately 50% of the European citizens are found to be deficient in VitD compared to 20% of the USA population [51]. Low levels of VitD were observed in neurological diseases such as Alzheimer's disease, Parkinson's disease, stroke, or in autoimmune diseases like diabetes mellitus, rheumatoid arthritis and disseminated lupus erythematosus, or still in cardiovascular diseases and different tumors such as colon, prostate and breast cancer [52]. In MS, low levels of VitD have also been associated with an increased risk of relapse, a more rapid progression of the disease (reviewed in [53]), and with magnetic resonance imaging (MRI) measures showing increased brain atrophy [54]. VitD most likely acts by modulating the immune response in MS through its biologically most active metabolite, 1,25(OH)2VitD3 or calcitriol, and the nuclear VitD receptor. Animal studies have demonstrated that calcitriol can reduce Th1 lymphocyte response, thus suppressing IFNg, IL2 and TNFa production while promoting Th2 lymphocyte response [55]. In response to calcitriol, T cells exhibit an increased IL10 production, causing a shift of antigen presenting cells and CD4+ T cells to a less inflammatory profile [56]. Accordingly to a recent study, in vitro calcitriolprimed B cells failed to produce CD40, an essential co-stimulatory signal of the molecular synapse, resulting in an inhibition of naïve, but not memory T cell activation [57]. Calcitriol has also been shown to decrease significantly the proinflammatory cytokines produced by CD8+ T cells [58]. Calcitriol suppresses the expression of matrix metalloproteinase 9, a molecule that is overexpressed during MS relapses and that increases the blood-brain barrier (BBB) permeability [2]. Further suggesting that calcitriol decreases the BBB permeability, authors have noted reduced accumulation of aluminium in the CNS of uremic rats that had received VitD, an effect which was attributed to perivascular astrocytes [59]. Complementary data indicate reduced MHC class II immunoreactivity in the CNS after systemic treatment with VitD in rats with EAE [52,60]. Calcitriol levels measured in the cerebrospinal fluid also correlated positively with BBB integrity [52]. These immunomodulatory effects of calcitriol have raised great interest as a putative preventive measure or therapy for Th1-mediated diseases. Multiple studies in the last decade have shown that calcitriol can,

3 A deficiency in VitD is actually defined as serum levels of 25(OH)VitD < 50 nmol/L (20 ng/mL) et VitD insufficiency when serum levels of 25(OH)VitD < 75 nmol/L (30 ng/ mL) [47].


Environmental factors in multiple sclerosis

To cite this article: Pantazou V, et al. Environmental factors in multiple sclerosis. Presse Med. (2015), j.lpm.2015.01.001

V. Pantazou, M. Schluep, R. Du Pasquier


when administered prophylactically alone or in association with interferon-b, either prevent or lead to a less severe form of established EAE [61]. However, it has to be noted that there are some discordant data. Indeed, some authors found that severe VitD deficiency attenuated CNS inflammation in EAE rather than exacerbating it [61]. These findings were corroborated in a model of dietary VitD deficiency, demonstrating that offsprings of VitD deficient gestational EAE mothers had reduced disease severity [62], although the second generation of mice developed more severe EAE. These data raise a crucial question: during which period of life does VitD exercise its immunomodulatory properties? To answer this question, a study in rats directly compared the effects of VitD supplementation during gestation, early life and adulthood. Females were divided into three groups, fed with different diets: diet containing a five-fold increased amount of VitD (10 IU/g), regular diet containing 2 IU/g of VitD, and VitD deprived diet (0 IU/g). Diets were applied throughout gestation and lactation while offsprings received a regular diet after weaning. The authors found that only early life VitD supplementation suppressed EAE. The juvenile/adolescent group displayed less severe neuroinflammation and demyelination while pre- and early post-natal supplementation or deprivation did not affect the course of EAE. There was no significant impact on disease development in adult rats, thus questioning whether VitD supplementation in adult MS patients may have a therapeutic effect [55]. Whether VitD is useful to patients who are already suffering from MS when VitD substitution is started remains an open question. A recent epidemiological study showed that frequent fatty fish intake was associated with a decreased occurrence of MS. Knowing that fatty fish is rich in VitD, this result is in agreement with the beneficial effect of VitD in MS [63]. Somewhat contrasting with these data, a double-blind randomized phase II study performed in adult MS patients deemed VitD supplementation (200 000 IU weekly) as ineffective [64]. James and al. conducted a meta-analysis on the effect of VitD supplementation on the risk of MS relapses in 129 high-dose VitD treated MS patients and 125 controls. No association between high dose VitD treatment and the risk of MS relapses was put into evidence, but the study was limited by several methodological issues [65]. Another recent meta-analysis confirmed that MS patients had lower mean serum levels of 25(OH)VitD than healthy controls [66]. However, a 10 nmol/L increase in serum 25(OH)VitD was associated with a 34% decrease in the risk of pediatric MS, and with a 9 to 12% decrease in adult patients [67]. Measurements in interferon b (IFNb)-1b-treated MS patients with serum 25(OH)VitD concentrations of > 50 nmol/ L demonstrated four times less changes in T2 lesion load on MRI, a twice lower rate of brain atrophy and a lower disability than those with < 50 nmol/L [53]. A six-month placebo double-blind clinical trial testing VitD in MS patients, which compared high dose (6000 IU daily) versus low dose (1000 IU daily) VitD

supplementation, did not find differences on clinical and MRI outcomes between the two groups, despite increased VitD serum levels in MS patients belonging to the high dose group [68]. In another study, combined IFNb-1b and VitD (200 000 IU/ week) significantly reduced contrast enhancing lesions while T2 lesion burden remained practically unchanged [69]. Even if the inverse association between sun exposure and the risk of MS is largely attributed to VitD, authors have suggested that UVR had some VitD-independent effects on MS risk. This connection has been studied meticulously by Lucas et al., who argued that higher recent or lifetime sun exposure and higher serum 25(OH)VitD levels were independently associated with a reduced risk of a first CNS demyelinating event [70]. It is reported that the persistence of systemic UVR-induced immunosuppression is associated with altered dendritic cell function [71]. UVR and VitD independently stimulate T regulatory cells (Tregs) and promote IL-10 secretion, which reduces IL17 levels and dampens Th1 immune function, providing plausible pathways to reduce MS risk [57]. Furthermore, continuous treatment with UVR suppresses clinical manifestations of EAE, an effect which does not seem to be explained by the sole moderate increase in VitD [72]. UVR and especially, ultraviolet B (a subptype of UVR with a wavelength of 280–315 nm) light treatment seems to induce systemic immune regulation and tolerance via the induction of tolerogenic dendritic cells and Tregs [71]. After local activation, these cells go to the spleen where they both mediate immune suppression. Tregs then migrate to the CNS. According to the findings in EAE, UVR treatment alone was sufficient to provoke a rapid immunomodulation, inhibiting EAE. However, this effect was transient and reversible after the end of the treatment [71]. In MS, a recent cross-sectional study including 264 patients, suggests that sun exposure could potentially have direct effects on MRI measures, such as increased grey and white matter volume. This result remained unaffected after correction for VitD levels, EDSS scale, age and gender. T2 lesion burden was not associated with sun exposure [54].

Month of birth Climate and seasonal variations also affect UVR exposure. Month of birth has lately been described as a risk factor for MS. A recent meta-analysis revealed an excessive MS risk in those born in spring and a reduced risk in those born in autumn, ascribing this observation to UV light exposure and maternal VitD levels [73]. By contrast, a cohort study from 15 countries including 110 415 MS patients did not find significant seasonal fluctuations in MS prevalence [74]. Despite its methodological limitations (large confidence intervals upon stratification per month for each quartile of UV fluctuation, exclusion of the months July and January, no known interaction of other epidemiological factors), this study was in agreement with a recent Australian epidemiological research showing that the effect of the month

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To cite this article: Pantazou V, et al. Environmental factors in multiple sclerosis. Presse Med. (2015), j.lpm.2015.01.001 Environmental factors in multiple sclerosis

Vitamin A Even though a beneficial role of vitamin A (VitA) in the prevention of MS has been suspected for more than three decades [76], its implication in the immune system was studied only recently. VitA4 is essential for making rhodopsin, which mediates visual information to the CNS. Moreover, its most important metabolite, the retinoic acid, is implicated in regulatory T cell proliferation by suppressing Th17 differentiation [77], in reducing the production of IFNg and IL-2 directly and in fostering the secretion of IL-10 by Th2 cells [78]. In the EAE model, retinoic acid impairs the antigen presentation capacity of dendritic cells, decreasing the Th1-Th17 immune response. It thus reduces the severity of declared EAE [79]. In accordance with those findings, in vitro studies showed that retinoic acid reduced cell proliferation induced by myelin basic protein in a dose dependent concentration. The effect of VitA seems to be also relevant in human MS. A recent study in relapsing remitting MS patients has demonstrated that VitA supplementation reduced T-cell proliferation [80]. A small Swedish cohort study has measured VitA levels in the blood of pregnant MS patients versus pregnant control women. Given that VitA cannot be assessed directly, retinolbinding protein, a transport molecule for VitA that correlates equimolar to VitA levels, was measured. There was no association between first trimester gestational retinol binding protein levels and MS risk in the offspring, while there was a 55% lower risk of MS in adult MS patients with VitA levels higher than 1.23 mmol/L as compared to adult MS patients with lower levels. These results must be interpreted with caution, considering the small size of the study [47].

Oils and dietary habits Statins, which inhibit cholesterol biosynthesis, seem to have some immunomodulatory and anti-inflammatory effects in humans, acting as a VitD analogue and interacting directly with the VitD receptor, resulting in an activation of Tregs and an inhibition of Th17 differentiation [81]. Based on these findings, a recent 12-month phase II trial evaluated the efficacy of atorvastatin 40 mg/day added to IFNb-1b in relapsing remitting MS. The proportion of patients with new T2 lesions was equal in both

4 According to the World Health Organization (WHO), VitA deficiency is defined as serum levels < 0.70 mmol/L and VitA sufficiency as serum levels < 1.05 mmol/L [76].

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groups, implying the inefficacy of statin treatment in MS. However, these results should be interpreted with caution given the small number of participants [82]. Investigations in EAE suggest that high-salt/high-fat diets lead to a more severe form of EAE [83], whereas the administration of essential oils from Pterodon emarginatus seed blocks EAE development in mice. This seems to be linked with the essential oil immunomodulatory effects and its ability to inhibit CD4+ T lymphocytes, microglial cell activation and expression of pro-inflammatory mediators as well as reducing demyelination and neuronal death through Th1/Th2 modulation [84]. Further research in animal models is needed to determine the role and time frame of dietary habits during gestation, early life or adulthood for influencing MS risk since convincing human data are still missing.

Obesity An association between obesity in childhood and adolescence and increased MS risk has been suggested [85,86]. Potential mechanisms explaining this association are lower levels of calcitriol in overweight people as compared to the general population [87], and a state of chronic, low-grade inflammation driven by adipose tissue macrophages, which undergo a phenotypic switch from an anti-inflammatory Th2 state to a proinflammatory Th1 state [86]. The main molecule produced by adipose tissue is leptin, which predisposes to Th17 bias, promotes T effector cell proliferation and limits Tregs expansion, promoting a Th1 response [88]. Leptin-deficient mice were resistant to EAE, which was reversed by leptin administration, the latter causing a switch from a Th2 to a Th1 response. Also, diet-induced obese mice developed more severe EAE [86]. In a Swedish case control study, subjects with a body mass index exceeding 27 kg/m2 at the age of 20 had a two-fold increased risk of developing MS as compared with normally weighted subjects [85]. Prevention of adolescent obesity might thus lower the risk of developing MS in later life.

Avoid smoking, do not stress and drink a glass of wine Smoking is a risk factor for autoimmune diseases such as rheumatoid arthritis [89], systemic lupus erythematosis and MS [90]. Tobacco smoke contains an estimated concentration of 1017 oxidants per puff and many potent carcinogens and mutagens [91]. However, not all these cigarette components increase the risk of MS. For example, there is no association between Swedish snuff use and MS risk, suggesting that nicotine alone is not a risk factor for MS [92]. Nicotine could even bear some protective anti-inflammatory and immune modulating effects [93]. There are evidences supporting an increased risk of MS with passive tobacco smoke exposure in childhood and adulthood, via lung irritation [94]. A population-based case control French study found that MS incidence was higher in children whose parents smoked at home, indicating that even low doses


of birth did not persist after correcting UVR during the first trimester of pregnancy. Lower average daily levels of ambient UVR during the first trimester predicted a higher risk of MS independently of the month of birth, with an increased risk below a minimal erythemal dose of 20 U (MED; the smallest dose of radiation capable of inducing erythema, thus assessing the skin sensitivity to UVR) [75].


To cite this article: Pantazou V, et al. Environmental factors in multiple sclerosis. Presse Med. (2015), j.lpm.2015.01.001

V. Pantazou, M. Schluep, R. Du Pasquier

of tobacco exposure are sufficient, and that tobacco smoke exposure during childhood seems to be a risk factor for MS [95]. Briggs et al. have proposed that the host genetic variation could contribute to metabolic efficiency of tobacco smoke constituents, and thus to MS risk in smokers. The NAT1rs73688368 genotype was shown to modify the effect of tobacco exposure on disease risk through the overexpression of N-acetyltransferase [91]. Smoking alters epigenetic mechanisms like histone modification, pattern of DNA methylation and miRNA expression, increasing not only the conversion rate of clinical isolated syndrome to MS, but also the deterioration during the course of the disease [96]. As mentioned above, smoking, but not use of moist snuff, increases MS risk, suggesting that it is not the systemic tobacco effect that alters MS risk but lung irritation. Cigarette smoke causes oxidative stress and pro-inflammatory responses in cells of the lung where autoimmune memory cells are present. These cells could proliferate after local stimulation, acquire migratory properties, and reach the CNS triggering MS [90]. In two Swedish population-based case-control studies, a dose-response association between the cumulative dose of smoking and MS risk was observed, whereas both the duration and intensity of smoking contributed independently to the increase of MS risk [90]. In a Norwegian study, the incidence of MS was 1.81 times higher in smokers than in subjects who had never smoked [97]. An Israeli study including 241 MS patients reported a higher incidence of MS in people who had smoked before the age of 15 [98].

Furthermore, a case-control study including 110 442 subjects argued that even smoking less than five cigarettes per day for many years was correlated with a two-fold higher risk of MS [90]. Contrary to other MS risk factors, which seem to have an effect only if the exposure takes place during a specific period in life (gestation, early life or adolescence), smoking increases MS risk regardless of the age of exposure, while its effect is reversible a decade after smoking cessation regardless of the cumulative dose of smoking. As for another culprit in our life habits, a Swedish case-control study reported that alcohol consumption of more than 15 g/day was associated with a lower risk to develop MS [99]. Alcohol, which easily crosses the BBB, exerts anti-inflammatory effects by increasing IL10 levels, decreasing monocyte inflammatory response, and by stimulating the hypothalamus-pituitarygonadal axis, increasing glucocorticoid hormone levels, and decreasing the inflammatory response. In mice, persistent ethanol consumption delays the onset and halts the progression of collagen-induced arthritis by downregulating leukocyte migration and by the upregulation of testosterone secretion. The moderate consumption of alcohol also leads to lower levels of leucocytes in animals. Alcohol seems to have a similar impact on MS, which is also a complex Th1-driven inflammatory disease [99]. Disclosure of interest: the authors declare that they have no conflicts of interest concerning this article.

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To cite this article: Pantazou V, et al. Environmental factors in multiple sclerosis. Presse Med. (2015), j.lpm.2015.01.001 Environmental factors in multiple sclerosis

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To cite this article: Pantazou V, et al. Environmental factors in multiple sclerosis. Presse Med. (2015), j.lpm.2015.01.001

V. Pantazou, M. Schluep, R. Du Pasquier














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tome xx > n8x > xx 2015

Environmental factors in multiple sclerosis.

Although multiple sclerosis (MS) is recognized as a disorder involving the immune system, the interplay of environmental factors and individual geneti...
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