SciELO - Scientific Electronic Library Online

 
vol.72 issue11Promising treatments for neuropathic painAnterior temporal white matter lesions in adult-form myotonic dystrophy type 1 author indexsubject indexarticles search
Home Pagealphabetic serial listing  

Services on Demand

Journal

Article

Indicators

Related links

Share


Arquivos de Neuro-Psiquiatria

Print version ISSN 0004-282X

Arq. Neuro-Psiquiatr. vol.72 no.11 São Paulo Nov. 2014

http://dx.doi.org/10.1590/0004-282X20140159 

Views and Reviews

Modifiable environmental factors in multiple sclerosis

Fatores ambientais modificáveis na esclerose múltipla

Yara Dadalti Fragoso

1Departamento de Neurologia, Faculdade de Medicina, Universidade Metropolitana de Santos, Santos SP, Brazil

ABSTRACT

Potential environmental modifiable factors involved in multiple sclerosis (MS) include low adherence to treatment, smoking, obesity, low levels of liposoluble vitamins A and D, high consumption of salt, and a sedentary lifestyle. Chronic tobacco use, obesity, sedentarism and insufficient levels of these vitamins all contribute to maintenance of a proinflammatory state. It is unlikely that there will be noticeable improvement in the inflammatory condition of MS if stopping smoking, reducing weight, exercising, increasing vitamin levels are done in an isolated and erratic manner. Modification of each and every one of these environmental risk factors is likely to be an important approach in the management of MS. The present review presents the arguments for an association between these hazardous modifiable factors and the chronic inflammatory state observed in MS.

Key words: multiple sclerosis; smoking; obesity; vitamin D; vitamin A; exercise

RESUMO

Potenciais fatores ambientais modificáveis envolvidos na esclerose múltipla (EM) incluem baixa adesão ao tratamento, tabagismo, obesidade, baixos níveis das vitaminas lipossolúveis A e D, e um estilo de vida sedentário. O uso crônico de tabaco, obesidade, sedentarismo e níveis insuficientes destas vitaminas podem todos contribuir para a manutenção de um estado pró-inflamatório. É pouco provável que haja melhora notável na condição inflamatória da EM se a cessação do tabagismo, a redução de peso, exercícios e maiores níveis de vitaminas forem obtidos isoladamente e de maneira errática. A modificação de cada um destes fatores de risco ambientais poderá ser importante parte do manejo eficaz da EM. A presente revisão apresenta argumentos para uma associação entre os fatores modificáveis nocivos e o estado inflamatório crônico observado na EM.

Palavras-Chave: esclerose múltipla; tabagismo; obesidade, vitamina D; vitamina A; exercícios

Evidence for the inflammatory pathogenic basis of multiple sclerosis (MS) is overwhelming. This chronic neurological disease is characterized by demyelination, multifocal inflammation, reactive gliosis and axonal/neuron loss1.

The most effective treatments for MS are immunosuppressive in nature and may, for example, include monoclonal antibodies such as natalizumab [NTZ], daclizumab [DCL], and alemtuzumab [ATZ]. Patients with MS who do not respond to immunomodulatory drugs (first-line therapy) receive immunosuppressive drugs (second-line therapy), which have the risk of potentially fatal adverse events. The monoclonal antibodies recommended for MS treatment may have to be withdrawn after a certain period of use, due to intolerance of side effects. At this time, MS may reactivate with severe inflammatory reactions2.

It is possible that, with a specific approach to modifiable factors, the use of more aggressive treatment may not be necessary and the patient might thrive on immunomodulatory drugs that have less severe side effects. However, when the patient presents an aggressive form of MS and/or does not respond to immunomodulatory drugs3, the immediate reaction is to progress to immunosuppression4.

Perhaps it is time to consider the modifiable factors in MS when treating a patient. It goes without saying that adequate adherence to treatment needs to have been confirmed before the patient is given second-line therapy with potentially more serious, and even fatal, side effects. Through quitting smoking, losing weight, exercising and maintaining proper serum levels of vitamins A and D, the patient may respond better to all pharmacological treatments. It is, after all, the environmental factors that perpetuate the inflammatory state in MS and, for unknown reasons, these factors are frequently ignored. A summary of the potentially modifiable factors in presented in Table.

Table Summary of the effects of modifiable environmental factors in multiple sclerosis (MS). Simple changes in lifestyle are capable of altering the pro-inflammatory state of MS, inducing favorable shifts towards homeostasis and an anti-inflammatory state. 

Smoking obesity Induces apoptosis, leads to the release of both inflammatory cytokines and matrix metalloproteinases Promotes of inflammation due to an anergic state of Treg cells
Vitamin A Promotes homeostasis between Th1, Th2, Th17, Tregs, B cells and dendritic cells
Vitamin D Suppresses TNFα, IL-12 and inducible NO synthase, induces Th2 cells and IL-10 expression
Exercise Reduces plasma levels of interferon gamma and IL-17
Low salt diet, omega-3 and probiotics Reduces induction of Th17 lymphocytes

Smoking

Cigarette smoking increases the risk of developing autoimmune diseases and leads to worse disease evolution for patients suffering from immunological diseases5. The relative risk of developing MS among smokers is almost twice that of never-smokers5,6. Cigarette smoke is capable of increasing the expression of Fas on B and CD4 T lymphocyte cell surfaces7. Fas (CD95) is a pro-apoptotic transmembrane protein that also induces release of inflammatory cytokines by macrophages8. In addition, cigarette smoking leads to release of matrix metalloproteinases9 and affects immunological homeostasis10,11.

Patients with MS who smoke have a more severe disease course and a faster disability progression rate12,13. Furthermore, smokers run a risk of developing antibodies against natalizumab that is almost three times higher than that of non-smokers14. A recent meta-analysis has shown that, independently of the type of study, smoking is associated to MS15. An interesting and recent study points out that smoking is associated to MS only for certain genotypes, characterizing a situation where environmental and genetic factors interact16.

Passive smoking also increases the risk of developing MS17 and it is advisable that patients with MS should not be exposed to environments with tobacco smoke.

Obesity

Individuals who were overweight or obese during childhood or adolescence have twice the risk of developing MS in adulthood18,19,20. In fact, other autoimmune diseases are also more common in individuals who are above the proper weight21. Exposure to the so-called "Western diet", which includes high fat and cholesterol, high protein, high sugar, and excess salt intake, promotes obesity, metabolic syndrome, cardiovascular disease and autoimmune diseases22.

White adipose tissue is not an inert tissue devoted solely to energy storage. Adipocytes can be regarded as part of an endocrine organ that releases several proinflammatory mediators, such as tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), leptin and C-reactive protein23. A small number of adipocytes have anti-inflammatory properties and release the beneficial protein adiponectin24. In the presence of obesity, production and/or secretion of these factors may be dysfunctional, leading to obesity-related disorders, including autoimmune diseases.

One key player in the immunological tolerance response that can be affected by obesity is regulatory T cells (Tregs). These are forkhead box P3 (FOXP3)+ T cells that have pivotal importance in the mechanisms controlling immunological homeostasis and function25. Leptin, one of the inflammatory cytokines released by adipocytes, can affect the function of Tregs26. Administration of an anti-leptin antibody has been found to succeed in reversing the anergic status of Tregs in vitro, enabling them to proliferate in response to anti-CD3 and anti-CD28 stimulation27. In vivo, a significant inverse correlation is observed between the number of Foxp3 Treg cells and body weight and plasma leptin levels28. Leptin has also been found to promote Th17 inflammatory responses in normal human CD4(+) T cells and in mice, both in vitro and in vivo29,30. Leptin is also a major contributor to vascular damage in obesity-related cardiovascular diseases, which are not the subject of the present review31. However, it is clear that cardio and cerebrovascular complications in a patient with MS represent an extra burden on the patient, the family and society.

Vitamin A

Retinoic acid (RA), the active metabolite of vitamin A, modulates the functional balance between Th1, Th2, Th17, Tregs, B cells and dendritic cells32. RA plays a major role both in increasing tolerance and in decreasing inflammation, and RA synthesis may be manipulated by the complex cross-talk among cells during infection and inflammation33.

Specific receptors for RA, namely RXRγ, can promote remyelination by acting on oligodendrocytic precursor cells34. It has long been known that RA suppresses development of autoimmune experimental encephalitis (EAE) in rats35 in association with increased IL-4 levels in the animal34.

Although studies on vitamin A supplementation are at a nascent stage, it is reasonable to maintain normal retinol values in the plasma of patients with MS. Intake of foods that are rich in carotenoids and retinyl esters, which are both precursors of retinol, must be encouraged. Serum levels of retinol should be assessed in the same manner in which vitamin D metabolites are now regularly assessed in patients with MS. It is important to highlight that no supplementation with vitamin A has ever been tested or proven effective for the treatment of MS and excess vitamin A can be fatal.

Vitamin D

Over the last decades, studies on vitamin D, immune-mediated diseases, cancer and bone metabolism have shown that homeostasis of vitamin D is crucial.

Vitamin D is almost immediately hydrolyzed in the liver by 25-hydroxylase to 25-hydroxyvitamin D (25(OH)D). This circulating metabolite of vitamin D best reflects the vitamin D status of the patient, but 25(OH)D can be further hydrolyzed to 1,25-dihydroxyvitamin D (1,25(OH)2D) or calcitriol. This is the biologically active metabolite of vitamin D36.

Vitamin D is a hormone with important immunological roles. IL-10 expression is induced by 1,25(OH)2D in different cells of the immune system. Vitamin D has a direct effect on naive CD4(+) T cells, leading to development of Th2 cells37. Macrophages conditioned with 1,25(OH)2D3 potently suppressed the expression of pro-inflammatory parameters such as TNFα, IL-12 and inducible NO synthase (iNOS)38,39.

Low serum levels of 25-hydroxyvitamin D (25[OH]-D) were found to correlate with MS activation and progression over five years in a large population of individuals presenting a first demyelinating episode40. This finding was independent of treatment with interferon beta. Vitamin D3 add-on treatment to interferon beta reduced the activity of MS in relation to patients treated only with interferon beta, as assessed by magnetic resonance imaging40,41. On the other hand, there are also very sound studies showing that vitamin D has a disputable relation to MS42,43.

Even if an association between MS and vitamin D is considered to exist, the correct manner in which to proceed with supplementation, if necessary, remains a matter to be clarified in the future44. However, it is advisable that patients with MS should maintain normal serum levels of vitamin D, and be encouraged to eat foods that are sources of this vitamin. Moderate sun exposure at early hours of the day is also essential if vitamin D levels are to be corrected.

It is important to observe that 1,25(OH)2D and RA have synergistic effects on the regulation of T cells, in particular Th1745. To give supplements of one vitamin and not the other may negatively influence their effects on Th17 cell-related immune diseases32,33. It is, therefore, likely that vitamin D supplementation will be less effective in patients with MS whose levels of vitamin A are insufficient. In fact, dietary intake of all vitamins should be encouraged rather than supplementation with pills.

It is also of importance to emphasize that high doses of vitamin D are hazardous and should not be used, especially because there is no scientific evidence of its efficacy.

Exercise

Exercise in MS is more than rehabilitation. It is a form of treatment that does not lead to adverse events and can be quite inexpensive. Several types of exercises have been studied, and aerobic training, endurance exercises, exercise classes, aquatic exercises and yoga have all been shown to be beneficial in relation to several aspects of the disease, including fatigue, depression and disability46. Exercise induces favorable changes in T cells by reducing plasma levels of interferon gamma and IL-1747. Secondary benefits from regular physical activities include somatic-affective improvement in mood48. In fact, exercise and physical activity may have beneficial effects on depression symptoms that are comparable to those of antidepressant treatments49.

Low salt diet, omega-3 and probiotics

High salt (sodium chloride) diet has been shown to boost the induction of Th17 lymphocytes both in animal models and in humans50,51. The Th17 cells generated under high-salt diet appear to be highly pathogenic and related to pro-inflammatory cytokines. Although still an experimental observation that needs epidemiological confirmation, it is important to alert the patients about this potentially hazardous factor.

A diet rich in omega-3 unsaturated fatty acids, polyphenols and probiotics has been described to influence the development and character of regulatory T lymphocytes, or T regs52,53.

Alcohol

A dose-dependent association between alcohol consumption and the risk of developing MS has been shown recently54. Patients with MS seem to have a tendency to misuse alcohol, but only very few studies have been carried out on the subject55. At least in vitro, ethanol can induce a cytokine profile consistent with a Th17 regulatory phenotype56. A further complication of the long-term alcohol consumption in patients is, obviously, the cognitive alterations induce both by ethanol and MS.

DISCUSSION

The pathogenic inflammatory aspects of MS are of major importance regarding treatment. The presently approved treatments are all anti-inflammatory and have variable efficacy, which generally speaking, is positively associated with the severity of side effects. To declare that a patient is not responsive to a particular treatment implies that all possible ways of controlling the inflammation have been taken into consideration. Modifiable factors could be specifically discussed with the patient during routine consultations. Although most patients seem to be willing to receive high doses of vitamin D (even megadoses, without any scientific evidence for their use), not too many patients seem to be willing to stop smoking, drinking, starting with exercise and weight loss programs. In fact, there are reports clearly showing that patients are willing to run the risk of life-endangering side effects from immunosuppressive drugs for MS in order to continue with the treatment57,58. Furthermore, thousands of patients with MS worldwide were found to be willing to submit themselves to a vascular surgical procedure to treat their MS for which there was no scientific basis59. The evidence arising from these events therefore begs the following questions: Should modifiable factors be so difficult to modify, given that the methods are inexpensive and safe? Are we doing enough to resist the introduction of immunosuppressive treatment for patients with MS?

Introduction of a diet rich in vitamins A and D can contribute towards weight loss. Exercise will be beneficial both for the disease and for weight management. With a healthier lifestyle, better nutrient intake and regular exercise, the patient is likely to be less resistant to stopping smoking and drinking. It is perhaps time to consider more than just supplementation of vitamin D for patients with MS60,61. In fact, single supplementation of vitamin D (often at high doses or even megadoses) may alter the delicate immunological homeostasis that occurs between vitamin D and vitamin A33. Other life style habits, such as chronic caffeine ingestion, may also be related to the development of MS and further research into other modifiable factors is urgently needed. The criteria for therapeutic failure of a treatment are clearly related to inflammation and its lack of control, e.g., relapses and lesions in the brain and spinal cord62. Thus, if a patient does not respond well to a given treatment, perhaps we should ask ourselves whether everything that could be done to decrease inflammation has indeed been done. At the same time, in our daily practice, we should encourage all patients to modify the factors that prolong their exposure to inflammatory cytokines since the very beginning of the disease. In time, perhaps we will see that our future rate of non-responders may not the same we have now.

References

. Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med. 2000;343(13):938-52. http://dx.doi.org/10.1056/nejm200009283431307 [ Links ]

. Fragoso YD, Arruda NM, Arruda WO, Brooks JBB, Correa EC, Damasceno A et al. We know how to prescribe natalizumab for multiple sclerosis, but do we know how to withdraw it? Expert Rev Neurother. 2014;14(2):127-30. http://dx.doi.org/10.1586/14737175.2014.874947 [ Links ]

. McGraw CA, Lublin FD. Interferon beta and glatiramer acetate therapy. Neurotherapeutics. 2013;10(1):2-18. http://dx.doi.org/10.1007/s13311-012-0163-4 [ Links ]

. Rieckmann P. Concepts of induction and escalation therapy in multiple sclerosis. J Neurol Sci. 2009;277 Suppl 1:S42-5. http://dx.doi.org/10.1007/s13311-012-0163-4 [ Links ]

. Costenbader KH, Karlson EW. Cigarette smoking and autoimmune disease: what can we learn from epidemiology? Lupus. 2006;15(11):737-45. http://dx.doi.org/10.1177/0961203306069344 [ Links ]

. Maghzi AH, Etemadifar M, Heshmat-Ghahdarijani K, Moradi V, Nonhal S, Ghorbani A et al. Cigarette smoking and the risk of multiple sclerosis: a sibling case-control study in Isfahan, Iran. Neuroepidemiology. 2011;37(3-4):238-42. http://dx.doi.org/10.1159/000332765 [ Links ]

. Bijl M, Horst G, Limburg PC, Kallenberg CG. Effects of smoking on activation markers, Fas expression and apoptosis of peripheral blood lymphocytes. Eur J Clin Invest. 2001;31(6):550-3. http://dx.doi.org/10.1046/j.1365-2362.2001.00842.x [ Links ]

. Wang F, Lu Z, Hawkes M, Yang H, Kain KC, Liles WC. Fas (CD95) induces rapid, TLR4/IRAK4-dependent release of pro-inflammatory HMGB1 from macrophages. J Inflamm (Lond). 2010;7(1):30. http://dx.doi.org/10.1186/1476-9255-7-30 [ Links ]

. Seagrave J, Barr EB, March TH, Nikula KJ. Effects of cigarette smoke exposure and cessation on inflammatory cells and matrix metalloproteinase activity in mice. Exp Lung Res. 2004;30(1):1-15. http://dx.doi.org/10.1080/01902140490252858 [ Links ]

. Moszczyński P, Żabiński Z, Moszczyński P Jr, Rutowski J, Słowińskia S, Tabarowski Z. Immunological findings in cigarette smokers. Toxicol Lett. 2001;118(3):121-7. http://dx.doi.org/10.1016/s0378-4274(00)00270-8 [ Links ]

. Robbins CS, Dawe DE, Goncharova SI, Pouladi MA, Drannik AG, Swirski FK et al. Cigarette smoke decreases pulmonary dendritic cells and impacts antiviral immune responsiveness. Am J Respir Cell Mol Biol. 2004;30(2):202-11. http://dx.doi.org/10.1165/rcmb.2003-0259oc [ Links ]

. Manouchehrinia A, Tench CR, Maxted J, Bibani RH, Britton J, Constantinescu CS. Tobacco smoking and disability progression in multiple sclerosis: United Kingdom cohort study. Brain. 2013;136(Pt 7):2298-304. http://dx.doi.org/10.1093/brain/awt139 [ Links ]

. Roudbari SA, Ansar MM, Yousefzad A. Smoking as a risk factor for development of secondary progressive multiple sclerosis: A study in IRAN, Guilan. J Neurol Sci. 2013;330(1-2):52-5. http://dx.doi.org/10.1016/j.jns.2013.04.003 [ Links ]

. Hedström A, Alfredsson L, Lundkvist Ryner M, Fogdell-Hahn A, Hillert J, Olsson T. Smokers run increased risk of developing anti-natalizumab antibodies. Mult Scler. 2013;20(8):1081-5. http://dx.doi.org/10.1177/1352458513515086 [ Links ]

. O'Gorman C, Broadley SA. Smoking and multiple sclerosis: evidence for latitudinal and temporal variation. J Neurol. 2014;261(9)1677-83. http://dx.doi.org/10.1007/s00415-014-7397-5 [ Links ]

. Briggs FB, Acuna B, Shen L, Ramsay P, Quach H, Bernstein A et al. Smoking and risk of multiple sclerosis: evidence of modification by NAT1 variants. Epidemiology. 2014;25(4):605-14. http://dx.doi.org/10.1097/ede.0000000000000089 [ Links ]

. Hedström AK, Bäärnhielm M, Olsson T, Alfredsson L. Exposure to environmental tobacco smoke is associated with increased risk for multiple sclerosis. Mult Scler. 2011;17(7):788-93. http://dx.doi.org/10.1177/1352458511399610 [ Links ]

. Munger KL, Chitnis T, Ascherio A. Body size and risk of MS in two cohorts of US women. Neurology. 2009;73(19):1543-50. http://dx.doi.org/10.1212/wnl.0b013e3181c0d6e0 [ Links ]

. Munger K, Bentzen J, Laursen B, Stenager E, Koch-Henrisken N, Sørensen TI et al. Childhood body mass index and multiple sclerosis risk: a long-term cohort study. Mult Scler, 2013;19(10):1323-9. http://dx.doi.org/10.1177/1352458513483889 [ Links ]

. Hedström AK, Olsson T, Alfredsson L. 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):1334-6. http://dx.doi.org/10.1177/1352458512436596 [ Links ]

. Harpsøe MC, Basit S, Andersson M, Nielsen NM, Frisch M, Wohlfahrt J et al. Body mass index and risk of autoimmune diseases: a study within the Danish National Birth Cohort. Int J Epidemiol. 2014;43(3):843-55. http://dx.doi.org/10.1093/ije/dyu045 [ Links ]

. Manzel A, Muller DN, Hafler DA, Erdman SE, Linker RA, Kleinewietfeld M. Role of "western diet" in inflammatory autoimmune diseases. Curr Allergy Asthma Rep. 2014;14(1):404. http://dx.doi.org/10.1007/s11882-013-0404-6 [ Links ]

. Fietta P, Delsante G. Focus on adipokines. Theor Biol Forum. 2013;106(1-2):103-29. [ Links ]

. Ouchi N, Ohashi K, Shibata R, Murohara T. Adipocytokines and obesity -linked disorders. Nagoya J Med Sci. 2012;74(1-2):19-30. [ Links ]

. Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008;133(5):775-87. http://dx.doi.org/10.1016/j.cell.2008.05.009 [ Links ]

. Zeng H, Chi H. The interplay between regulatory T cells and metabolism in immune regulation. Oncoimmunology. 2013;2(11):e26586. http://dx.doi.org/10.4161/onci.26586 [ Links ]

. De Rosa V, Procaccini C, Calì G, Pirozzi G, Fontana S, Zappacosta S et al. A key role of leptin in the control of regulatory T cell proliferation. Immunity. 2007;26(2):241-55. http://dx.doi.org/10.1016/j.immuni.2007.01.011 [ Links ]

. Wagner NM, Brandhorst G, Czepluch F, Lankeit M, Eberl C, Herzberg S et al. Circulating regulatory T cells are reduced in obesity and may identify subjects at increased metabolic and cardiovascular risk. Obesity (Silver Spring). 2013;21(3):461-8. http://dx.doi.org/10.1002/oby.20087 [ Links ]

. Deng J, Liu Y, Yang M, Wang Z, Zhang M, Wang X et al. Leptin exacerbates collagen-induced arthritis via enhancement of Th17 cell response. Arthritis Rheum. 2012;64(11):3564-73. http://dx.doi.org/10.1002/art.34637 [ Links ]

. Yu Y, Liu Y, Shi FD, Zou H, Matarese G, La Cava A. Cutting edge: Leptin-induced RORγt expression in CD4+ T cells promotes Th17 responses in systemic lupus erythematosus. J Immunol. 2013;190(7):3054-8. http://dx.doi.org/10.4049/jimmunol.1203275 [ Links ]

. Pucino V, De Rosa V, Procaccini C, Matarese G. Regulatory T cells, leptin and angiogenesis. Chem Immunol Allergy. 2014;99:155-69. http://dx.doi.org/10.1159/000353557 [ Links ]

. Fragoso YD, Stoney PN, McCaffery PJ. The evidence for a beneficial role of vitamin A in multiple sclerosis. CNS Drugs. 2014;28(4):291-9. http://dx.doi.org/10.1007/s40263-014-0148-4 [ Links ]

. Hall JA, Grainger JR, Spencer SP, Belkaid Y. The role of retinoic acid in tolerance and immunity. Immunity. 2011;35(1):13-22. http://dx.doi.org/10.1016/j.immuni.2011.07.002 [ Links ]

. Huang JK, Jarjour AA, Nait Oumesmar B, Kerninon C, Williams A, Krezel W, et al. Retinoid X receptor gamma signaling accelerates CNS remyelination. Nat Neurosci. 2011;14(1):45-53. http://dx.doi.org/10.1038/nn.2702 [ Links ]

. Massacesi L, Castigli E, Vergelli M, Olivotto J, Abbamondi AL, Sarlo F et al. Immunosuppressive activity of 13-cis-retinoic acid and prevention of experimental autoimmune encephalomyelitis in rats. J Clin Invest. 1991;88(4):1331-7. http://dx.doi.org/10.1172/JCI115438 [ Links ]

. Racke MK, Burnett D, Pak SH, Albert PS, Cannella B, Raine CS et al. Retinoid treatment of experimental allergic encephalomyelitis. IL-4 production correlates with improved disease course. J Immunol. 1995;154(1):450-8. [ Links ]

. Smolders J, Damoiseaux J, Menheere P, Hupperts R. Vitamin D as an immune modulator in multiple sclerosis, a review. J Neuroimmunol. 2008;194(1-2):7-17. http://dx.doi.org/10.1016/j.jneuroim.2007.11.014 [ Links ]

. Boonstra A, Barrat FJ, Crain C, Heath VL, Savelkoul HF, O’Garra A. 1α, 25-dihydroxyvitamin d3 has a direct effect on naive CD4(+) T cells to enhance the development of Th2 cells. J. Immunol. 2001;167(9):4974-80. http://dx.doi.org/10.4049/jimmunol.167.9.4974 [ Links ]

. Korf H, Wenes M, Stijelmans B, Takiishi T, Robert S, Miani M et al. 1,25-Dihydroxyvitamin D3 curtails the inflammatory and T cell stimulatory capacity of macrophages through an IL-10-dependent mechanism. Immunobiology. 2012;217(12):1292-300. http://dx.doi.org/10.1016/j.imbio.2012.07.018 [ Links ]

. Ascherio A, Munger KL, White R, Köchert K, Simon KC, Polman CH, et al. Vitamin D as an early predictor of multiple sclerosis activity and progression. JAMA Neurol. 2014;71(3):306-14. http://dx.doi.org/10.1001/jamaneurol.2013.5993 [ Links ]

. Soilu-Hänninen M, Aivo J, Lindström BM, Elovaara I, Sumelahti ML, Färkkilä M et al. A randomised, double blind, placebo controlled trial with vitamin D3 as an add-on treatment to interferon β-1b in patients with multiple sclerosis. J Neurol Neurosurg Psychiatr. 2012;83(5):565-71. http://dx.doi.org/10.1136/jnnp-2011-301876 [ Links ]

. Antico A, Tampoia M, Tozzoli R, Bizzaro N. Can supplementation with vitamin D reduce the risk or modify the course of autoimmune diseases? A systematic review of the literature. Autoimmun Rev. 2012;12(2):127-36. http://dx.doi.org/10.1016/j.autrev.2012.07.007 [ Links ]

. Theodoratou E, Tzoulaki I, Zgaga L, Ioannidis JP. Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials. BMJ. 2014;348:g2035. http://dx.doi.org/10.1136/bmj.g2035 [ Links ]

. Simon KC, Munger KL, Ascherio A. Vitamin D and multiple sclerosis: epidemiology, immunology, and genetics. Curr Opin Neurol. 2012;25(3):246-51. http://dx.doi.org/10.1097/WCO.0b013e3283533a7e [ Links ]

. Ikeda U, Wakita D, Ohkuri T, Chamoto K, Kitamura H, Iwakura Y et al. 1alpha,25-Dihydroxyvitamin D3 and all-trans retinoic acid synergistically inhibit the differentiation and expansion of Th17 cells. Immunol Lett. 2010;134(1):7-16. http://dx.doi.org/10.1016/j.imlet.2010.07.002 [ Links ]

. Sá MJ. Exercise therapy and multiple sclerosis : a systematic review. J Neurol. 2013;261(9)1651-61. http://dx.doi.org/10.1007/s00415-013-7183-9 [ Links ]

. Golzari Z, Shabkhiz F, Soudi S, Kordi MR, Hashemi SM. Combined exercise training reduces IFN-γ and IL-17 levels in the plasma and the supernatant of peripheral blood mononuclear cells in women with multiple sclerosis. Int Immunopharmacol. 2010;10(11):1415-9. http://dx.doi.org/10.1016/j.intimp.2010.08.008 [ Links ]

. Swank C, Thompson M, Medley A. Aerobic exercise in people with multiple sclerosis: its feasibility and secondary benefits. Int J MS Care. 2013;15(3):138-45. http://dx.doi.org/10.7224/1537-2073.2012-037 [ Links ]

. Dinas PC, Koutedakis Y, Flouris AD. Effects of exercise and physical activity on depression. Ir J Med Sci. 2011;180(2):319-25. http://dx.doi.org/10.1007/s11845-010-0633-9 [ Links ]

. Kleinewietfeld M, Manzel A, Titze J, Kvazan H, Yosef N, Linker RA et al. Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature. 2013;496(7446):518-22. http://dx.doi.org/10.1038/nature11868 [ Links ]

. Wu C, Yosef N, Thalhamer T, Zhu C, Xiao S, Kishi Y et al. Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1. Nature. 2013;496(7446):513-7. http://dx.doi.org/10.1038/nature11984 [ Links ]

. Issazadeh-Navikas S, Teimer R, Bockermann R. Influence of dietary components on regulatory T cells. Mol Med. 2012;18(1):95-110. http://dx.doi.org/10.2119/molmed.2011.00311 [ Links ]

. Kim W, Lee H. Advances in nutritional research on regulatory T-cells. Nutrients. 2013;5(11):4305-15. http://dx.doi.org/10.3390/nu5114305 [ Links ]

. Hedström AK, Hillert J, Olsson T, Alfredsson L. Alcohol as a modifiable lifestyle factor affecting multiple sclerosis risk. JAMA Neurol. 2014;71(3):300-5. http://dx.doi.org/10.1001/jamaneurol.2013.5858 [ Links ]

. Beier M, D'Orio V, Spat J, Shuman M, Foley FW. Alcohol and substance use in multiple sclerosis. J Neurol Sci. 2014;338(1-2):122-7. http://dx.doi.org/10.1016/j.jns.2013.12.029 [ Links ]

. Freysdottir J, Sigurpalsson MB, Omarsdottir S, Olafsdottir ES, Vikingsson A, Hardardottir I. Ethanol extract from birch bark (Betula pubescens) suppresses human dendritic cell mediated Th1 responses and directs it towards a Th17 regulatory response in vitro. Immunol Lett. 2011;136(1):90-6. http://dx.doi.org/10.1016/j.imlet.2010.12.009 [ Links ]

. Kachuck NJ. When neurologist and patient disagree on reasonable risk: new challenges in prescribing for patients with multiple sclerosis. Neuropsychiatr Dis Treat. 2011;7:197-208. http://dx.doi.org/10.2147/NDT.S17522 [ Links ]

. Heesen C, Kleiter I, Nguyen F, Schäffler N, Kwasper J, Köpke S, et al. Risk perception in natalizumab-treated multiple sclerosis patients and their neurologists. Mult Scler. 2010;16(12):1507-12. http://dx.doi.org/10.1177/1352458510379819 [ Links ]

. Valdueza JM, Doepp F, Schreiber SJ, Oosten BW, Schmierer K, Paul F et al. What went wrong? The flawed concept of cerebrospinal venous insufficiency. J Cereb Blood Flow Metab. 2013;33(5):657-68. http://dx.doi.org/10.1038/jcbfm.2013.31 [ Links ]

. Pekmezovic T, Drulovic J, Milenkovic M, Jarebinski M, Stojsavljevic N, Mesaros S et al. Lifestyle factors and multiple sclerosis: a case-control study in Belgrade. Neuroepidemiology. 2006;27(4):212-6. http://dx.doi.org/10.1159/000096853 [ Links ]

. Salzer J, Biström M, Sundström P. Vitamin D and multiple sclerosis: where do we go from here? Expert Rev Neurother. 2014;14(1):9-18. http://dx.doi.org/10.1586/14737175.2014.864952 [ Links ]

. Graber JJ, Dhib-Jalbut S. Biomarkers of disease activity in multiple sclerosis. J Neurol Sci. 2011;305(1-2):1-10. http://dx.doi.org/10.1016/j.jns.2011.03.026 [ Links ]

Received: June 18, 2014; Revised: August 16, 2014; Accepted: September 04, 2014

Correspondence: Yara Dadalti Fragoso; Departamento de Neurologia, Faculdade de Medicina, Universidade Metropolitana de Santos; Rua da Constituicao 374, 11015-470 Santos SP, Brasil; E-mail: yara@bsnet.com.br

Conflict of interest: There is no conflict of interest to declare.

Creative Commons License This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.