Multiple sclerosis (MS) is one of the most common neurological disorders and is one of the causes of non-trauma in young adults in many countries1. It is a chronic and progressive disease of the central nervous system, which can infrequently affect the peripheral nerves and may lead to associated symptoms and complications2,3. The pathogenesis of this disease is not fully understood. The activation of immune mechanisms against myelin antigen appears to be involved in the development of the disease, which can be due to genetic, environmental and immunological factors4,5,6. Usually, the first manifestations of the disease appear in patients aged 20 to 40 years old with symptoms such as anxiety, weakness, imbalance, visual impairment, and mental changes such as depression, disappointment, and reduced ability to resolve problems7,8,9. There are more than 400,000 people in North America, around 500,000 people in Europe, and 2.5 million people worldwide affected by the disease10.

MS is seen in both recurrent and progressive forms (primary or secondary) and is divided into primary and secondary progression based on the course of the disease and the occurrence of symptoms in the form of an attack-recovering type with a prevalence of about 70%11,12. An important symptom of the disease is the presence of plaque in the brain or the spinal cord, which includes a demyelination region along with the relative preservation of axons that vary in acute and chronic stages13. Despite the advances in medical science in recent years, there is currently no definitive and eradicating treatment for MS. Most of the existing treatments reduce the symptoms or slow the progression of disease. Therefore, rapid detection and diagnosis of disease and control during this time, can prevent severe complications and uncontrollable progress14. Considering the migration pattern of people around the world, one of the notable features of the global distribution of MS is that, with increasing latitude in the north and south of the equator, the probability of occurrence of the MS also increases several times, which indicates not only genetic factors play an important role but environmental factors can also affect the disease15,16. The present review was conducted to evaluate recent evidence on the potential environmental risk factors involved in the incidence of MS.

This review was conducted using the keywords of "multiple sclerosis," "factors", and "risk factors" through searching in the scientific databases of PubMed, Scopus, and Web of Science, focusing on articles published over the recent years. Unrelated sources and articles were removed. Assessing the related papers showed that in general, MS is recognized as an autoimmune disease in the background of genetic factors caused by uncertain environmental factors. Epidemiological effects based on race, gender and geographical location are strongly linked to the frequency, characteristics, severity and progression of the disease 17. Different environmental factors play a role in the pathogenesis and progression of MS. Some of the most important ones are discussed in the following.

Vitamin D is a hormone that is made up of two forms of D2 and D3 (D3 forms with sunlight in the skin)1. Recent epidemiological studies have shown that the association between low vitamin D levels and increased probability of MS is likely to be due to the anti-inflammatory effects of vitamin D and its potential effects on cytokine levels18,19. Many studies show the effect of vitamin D on growth and maturation of immune cells such as macrophages, dendritic cells, T cells and B cells20. Since sun exposure induces vitamin D3 synthesis from the skin21, it is assumed that exposure to the sun in early childhood is associated with a reduction in the risk of MS19. Studies have indicated that vitamin D is also essential in improving regulatory function for autoimmune disease control22,23.

Although the most important factor in the occurrence of MS is genetics, environmental factors play an important role in the development of the disease as well as its recurrence. Among the environmental factors, infectious agents can also have a potential for pathogenesis24. There are different assumptions about which infectious agents, and how they are involved in the process of occurrence and progression of the disease. In studies that were carried out, different microorganisms involving in the incidence and development of MS include Human Type-6 herpesvirus, Human Type-4 herpesvirus, Chlamydia pneumonia, torque teno virus, and Epstein-Barr viruses (EBV)23,25. Meanwhile, EBV is important in the development of this disease. EBV is a double strain DNA virus of the family of herpes viruses, and 90% of the general population in the first decade of life is likely to be infected. The virus remains in memory cells permanently26, and can cause infectious mononucleosis in case of severe contamination.

Although the mechanism for the participation of other infections in the incidence of MS is still unclear, in the case of EBV, it is believed that the exposure to the infection may increase the risk of MS14. Various hypotheses about the function mechanism of this virus have been proposed, including the excessive activation of B and T lymphocytes during infectious mononucleosis, stimulation of B lymphocytes, cross-reactivity of viral antigens with myelin antigens, etc. Besides, EBV-infected cells in the white and gray matter of MS patients may induce T cell lymphocyte responses that ultimately damage the surrounding tissues26. Research has shown that the risk of MS in people with infectious mononucleosis is 2-3 times higher27. It has also been stated that the prevalence of MS patients not infected with EBV is less than 0.01%28.

Accordingly, although this virus is not the main cause of MS, it is necessary to develop disease progression. Recent studies have shown that antibodies against bacterial antigens, such as Acinetobacter and Pseudomonas aeruginosa, is significantly increased in MS29. These bacterial antigens are likely to interact with the myelin peptides30, causing the immune system to attack and demyelinate nerve cells.

Although many studies point to the role of cigarette smoking in the incidence of MS, there is still insufficient evidence for its definite role in the incidence of MS29. Smoking may be responsible for the recurrence of MS. A study conducted on American women showed that the incidence of MS in smokers is 60% higher than non-smokers and increases the likelihood of its occurrence in people who are exposed to smoke30. Cigarette compounds, such as nicotine and tobacco, cause this problem in the immune system. Researchers have shown that nicotine increases blood flow in the cerebral capillaries and increases the penetration of the solution into the blood brain barrier, and ultimate leakage from the blood brain barrier is suggested to be a factor in the development of MS31,32. Another possibility is that some compounds in cigarettes may have direct toxic effects on the central nervous system and cause myelin loss of neurons33. Studies have shown that antibodies against chlamydia pneumoniae are more common in smokers than non-smokers34. Therefore, cigarette smoking is considered as a factor in increasing the duration and severity of respiratory infections, which may lead to infection-induced MS35. Literature has shown that smoking can decrease the activity of indole amine 2,3-dioxygenase, increase the activity of the renin-angiotensin system and the levels of some of the cytokines, which can accelerate the course of MS disease and exacerbate its symptoms36. Based on studies that have been conducted to study the effect of smoking on the risk of incidence and developing MS, there was no relationship between the risk of MS and early stages of smoking, however, 10 years after the cessation of smoking, the risk decreases37.

Other environmental factors that can increase the risk of MS include personal diets, which can directly or indirectly affect cellular elements26. Several studies have been done to show that a diet based on high fat, cholesterol, sugars, and salt can exacerbate or increase the incidence of MS38. It is the fact that excessive fat intake causes obesity and increases the body mass index. It has been reported that there is a direct correlation between the body mass index and the risk of MS, specially in young ages39. Sodium intake is also associated with obesity and changes in body fat compositions, which plays a role in the incidence of MS40. However, unlike exposure to sunlight, vitamin D and infection, diet is not important due to the lack of evidence, but is important for the progression of the disease29.

MS is a central nervous system disease that affects many people in the world, especially young women, with the mechanism of myelin loss in different parts of the nervous system. Yet, the underlying cause of MS is not clear3. Genetic and environmental factors are likely to contribute to the disease. A study of MS in Canada showed that the incidence of MS in women was significantly higher than men, which probably depends on the rate of change in the environment and the interaction of the gene with the environment41. This difference is reported to be 3 to 1 in some studies, which indicates the role of environmental factors, hormonal differences, and in particular, the different geographical conditions and environments in the incidence of MS42.

In this paper, we outline the risk factors for MS pathogenesis, such as vitamin D, exposure to sunlight, infection, cigarette, diet, and possible mechanisms for the emergence of MS. In different studies, while introducing cigarettes as a factor in preventing MS43, smoking has been identified as a factor in the accelerated process of MS and its symptoms36. We have mentioned the impact of infection on MS with various bacterial and viral pathogens, especially the EBV virus, which can be essential to contribute to the pathogenesis of this disease23,25,29. It is worth noting that some studies also referred to the effects of parasites on the onset of the disease and its impact on the process16. Other infectious agents, as an environmental factor, can be associated with fungal infections. HLA-DRB1 allele, which is the most important genetic risk factor for MS, is associated with fungal infections. Many cytokines and markers involved in fungal infection such as interleukin 17, chitotriosidase and antibodies against fungus are also involved in MS disease and can be pathogenic44. In relation to the diet, the conducted experiments prevented people with MS from a high-fat diet, high in cholesterol, sugar, and sodium, to prevent the exacerbation of disease symptoms38. Therefore, due to the importance of these factors in MS disease, the control of them by prevention and/or care is potentially useful to prevent the disease, and also because of the progression of MS, these measures to prevent the rapid progression of the disease and exacerbate its symptoms are essential.

Due to the progression of MS, today, there are many different treatments for MS patients that can prevent the exacerbation of the symptoms and progression. The primary goal of MS treatment is to reduce the rate of relapse and reduce the progression of the disease. Many studies on the natural history of MS have shown that MS can occur in two stages. The first stage is associated with a relative inflammation, which varies from time to time and until the benign disease disability it will take. The second stage and phase of the disease last for several years until the disease progresses in a uniform period. Research has shown that the first phase of the disease is likely to be better suited to start treatment and is best effective45.

Since B lymphocytes play an essential role in the pathogenesis of MS, the first line of treatment for MS disease is the use of ocrelizumab, which unlike the old drugs targeting T cells, targets significant cause of the pathogenesis of the disease that attacks and destroys CD20⁺ B lymphocytes46. Ocrelizumab is superior to interferon beta in preventing recurrence of the disease, which is used in the treatment of advanced primary MS47,46.

EBV: Epstein-Barr virus

MS: Multiple sclerosis

The authors declare that they have no conflicts of interest.

SMMH contributed in study design. HN and SMMH searched and summarized the data. SMMH, AAK, PS and AAA reviewed and edited the first draft. All authors reviewed, commented and approved the final draft.

Brownlee W.J. Hardy T.A. Fazekas F. Miller D.H. Diagnosis of multiple sclerosis: progress and challenges Lancet 2017 389 10076 1336 46 0140-6736 10.1016/S0140-6736(16)30959-X 27889190 Hojati S. Zarghami A. Yousefzad T. Hojati S. Baes M. Epidemiological Features of 263 Patients with Multiple Sclerosis Residing in ‎Babol, Iran J Babol Univ Med Sci 2016 18 1 52 6 1561-4107 Patsopoulos N. Baranzini S.E. Santaniello A. Shoostari P. Cotsapas C. Wong G. The Multiple Sclerosis Genomic Map: role of peripheral immune cells and resident microglia in susceptibility bioRxiv 2017 143933 Milo R. Kahana E. Multiple sclerosis: geoepidemiology, genetics and the environment Autoimmun Rev 2010 9 5 387 94 1568-9972 10.1016/j.autrev.2009.11.010 19932200 Lemus H.N. Warrington A.E. Rodriguez M. Multiple sclerosis: mechanisms of disease and strategies for myelin and axonal repair Neurol Clin 2018 36 1 1 11 0733-8619 10.1016/j.ncl.2017.08.002 29157392 Hojjati S.M. Zarghami A. Hojjati S.A. Baes M. Optic neuritis, the most common initial presenting manifestation of multiple sclerosis in northern Iran Caspian J Intern Med 2015 6 3 151 5 2008-6164 26644882 Colasanti A. Guo Q. Giannetti P. Wall M.B. Newbould R.D. Bishop C. Hippocampal neuroinflammation, functional connectivity, and depressive symptoms in multiple sclerosis Biol Psychiatry 2016 80 1 62 72 0006-3223 10.1016/j.biopsych.2015.11.022 26809249 van Munster C.E. Jonkman L.E. Weinstein H.C. Uitdehaag B.M. Geurts J.J. Gray matter damage in multiple sclerosis: impact on clinical symptoms Neuroscience 2015 303 446 61 0306-4522 10.1016/j.neuroscience.2015.07.006 26164500 Hojjati S.M. Hojjati S.A. Baes M. Bijani A. Relation between EDSS and monosymptomatic or polysymptomatic onset in clinical manifestations of multiple sclerosis in Babol, northern Iran Caspian J Intern Med 2014 5 1 5 8 2008-6164 24490005 Leray E. Moreau T. Fromont A. Edan G. Epidemiology of multiple sclerosis Rev Neurol (Paris) 2016 172 1 3 13 0035-3787 10.1016/j.neurol.2015.10.006 26718593 Ghasemi N. Razavi S. Nikzad E. Multiple Sclerosis: Pathogenesis, Symptoms, Diagnoses and Cell-Based Therapy Cell J 2017 19 1 1 10 2228-5806 28367411 Dutta R. Trapp B.D. Relapsing and progressive forms of multiple sclerosis: insights from pathology Curr Opin Neurol 2014 27 3 271 8 1350-7540 10.1097/WCO.0000000000000094 24722325 Filippi M. Rocca M.A. Ciccarelli O. De Stefano N. Evangelou N. Kappos L. Study Group MAGNIMS MRI criteria for the diagnosis of multiple sclerosis: MAGNIMS consensus guidelines Lancet Neurol 2016 15 3 292 303 1474-4422 10.1016/S1474-4422(15)00393-2 26822746 Garg N. Smith T.W. An update on immunopathogenesis, diagnosis, and treatment of multiple sclerosis Brain Behav 2015 5 9 e00362 2162-3279 10.1002/brb3.362 26445701 Munger K.L. Levin L.I. Hollis B.W. Howard N.S. Ascherio A. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis JAMA 2006 296 23 2832 8 0098-7484 10.1001/jama.296.23.2832 17179460 Correale J. Gaitán M.I. Multiple sclerosis and environmental factors: the role of vitamin D, parasites, and Epstein-Barr virus infection Acta Neurol Scand 2015 132 199 46 55 0001-6314 10.1111/ane.12431 26046559 Kurtzke J.F. Epidemiology and etiology of multiple sclerosis Phys Med Rehabil Clin N Am 2005 16 2 327 49 1047-9651 10.1016/j.pmr.2005.01.013 15893675 Ascherio A. Munger K.L. Epidemiology of multiple sclerosis: from risk factors to prevention\textemdashan update Semin Neurol 2016 36 2 103 14 0271-8235 10.1055/s-0036-1579693 27116717 Kulie T. Groff A. Redmer J. Hounshell J. Schrager S. Vitamin D: an evidence-based review J Am Board Fam Med 2009 22 6 698 706 1557-2625 10.3122/jabfm.2009.06.090037 19897699 Szodoray P. Nakken B. Gaal J. Jonsson R. Szegedi A. Zold E. The complex role of vitamin D in autoimmune diseases Scand J Immunol 2008 68 3 261 9 0300-9475 10.1111/j.1365-3083.2008.02127.x 18510590 Hayes C.E. Vitamin D: a natural inhibitor of multiple sclerosis Proc Nutr Soc 2000 59 4 531 5 0029-6651 10.1017/S0029665100000768 11115787 Kang S.W. Kim S.H. Lee N. Lee W.W. Hwang K.A. Shin M.S. 1,25-Dihyroxyvitamin D3 promotes FOXP3 expression via binding to vitamin D response elements in its conserved noncoding sequence region J Immunol 2012 188 11 5276 82 0022-1767 10.4049/jimmunol.1101211 22529297 Grytten N. Aarseth J.H. Lunde H.M. Myhr K.M. A 60-year follow-up of the incidence and prevalence of multiple sclerosis in Hordaland County, Western Norway J Neurol Neurosurg Psychiatry 2016 87 1 100 5 1468-330X 25714916 Belbasis L. Bellou V. Evangelou E. Ioannidis J.P. Tzoulaki I. Environmental risk factors and multiple sclerosis: an umbrella review of systematic reviews and meta-analyses Lancet Neurol 2015 14 3 263 73 1474-4422 10.1016/S1474-4422(14)70267-4 25662901 Sibley W.A. Bamford C.R. Clark K. Clinical viral infections and multiple sclerosis Lancet 1985 1 8441 1313 5 0140-6736 10.1016/S0140-6736(85)92801-6 2860501 Correale J. Farez M.F. Gaitán M.I. Environmental factors influencing multiple sclerosis in Latin America Mult Scler J Exp Transl Clin 2017 3 2 2055217317715049 2055-2173 10.1177/2055217317715049 28638627 Thacker E.L. Mirzaei F. Ascherio A. Infectious mononucleosis and risk for multiple sclerosis: a meta-analysis Ann Neurol 2006 59 3 499 503 0364-5134 10.1002/ana.20820 16502434 Dobson R. Kuhle J. Middeldorp J. Giovannoni G. Epstein-Barr-negative MS: a true phenomenon? Neurol Neuroimmunol Neuroinflamm 2017 4 2 e318 2332-7812 10.1212/NXI.0000000000000318 28203615 Hughes L.E. Smith P.A. Bonell S. Natt R.S. Wilson C. Rashid T. Cross-reactivity between related sequences found in Acinetobacter sp., Pseudomonas aeruginosa, myelin basic protein and myelin oligodendrocyte glycoprotein in multiple sclerosis J Neuroimmunol 2003 144 1-2 105 15 0165-5728 10.1016/S0165-5728(03)00274-1 14597104 Hernán M.A. Olek M.J. Ascherio A. Cigarette smoking and incidence of multiple sclerosis Am J Epidemiol 2001 154 1 69 74 0002-9262 10.1093/aje/154.1.69 11427406 Olsson T. Barcellos L.F. Alfredsson L. Interactions between genetic, lifestyle and environmental risk factors for multiple sclerosis Nat Rev Neurol 2017 13 1 25 36 1759-4758 10.1038/nrneurol.2016.187 27934854 Weston M. Constantinescu C.S. What role does tobacco smoking play in multiple sclerosis disability and mortality? A review of the evidence Neurodegener Dis Manag 2015 5 1 19 25 1758-2024 10.2217/nmt.14.45 25711451 Marabita F. Almgren M. Sjöholm L.K. Kular L. Liu Y. James T. Smoking induces DNA methylation changes in Multiple Sclerosis patients with exposure-response relationship Sci Rep 2017 7 1 14589 2045-2322 10.1038/s41598-017-14788-w 29109506 Kumar S. Smith-Norowitz T.A. Kohlhoff S. Apfalter P. Roblin P. Kutlin A. Exposure to cigarette smoke and Chlamydia pneumoniae infection in mice: Effect on infectious burden, systemic dissemination and cytokine responses: A pilot study J Immunotoxicol 2016 13 1 77 83 1547-691X 10.3109/1547691X.2015.1006346 25640695 Ramanujam R. Hedström A.K. Manouchehrinia A. Alfredsson L. Olsson T. Bottai M. Effect of smoking cessation on multiple sclerosis prognosis JAMA Neurol 2015 72 10 1117 23 2168-6149 10.1001/jamaneurol.2015.1788 26348720 Correale J. Farez M.F. Smoking worsens multiple sclerosis prognosis: two different pathways are involved J Neuroimmunol 2015 281 23 34 0165-5728 10.1016/j.jneuroim.2015.03.006 25867464 Hedström A.K. Hillert J. Olsson T. Alfredsson L. Smoking and multiple sclerosis susceptibility Eur J Epidemiol 2013 28 11 867 74 0393-2990 10.1007/s10654-013-9853-4 24146047 Riccio P. Rossano R. Nutrition facts in multiple sclerosis ASN Neuro 2015 7 1 1759091414568185 1759-0914 10.1177/1759091414568185 25694551 Hedström A.K. 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 1352-4585 10.1177/1352458512436596 22328681 Farez M.F. Fiol M.P. Gaitán M.I. Quintana F.J. Correale J. Sodium intake is associated with increased disease activity in multiple sclerosis J Neurol Neurosurg Psychiatry 2015 86 1 26 31 0022-3050 10.1136/jnnp-2014-307928 25168393 Orton S.M. Ramagopalan S.V. Brocklebank D. Herrera B.M. Dyment D.A. Yee I.M. Effect of immigration on multiple sclerosis sex ratio in Canada: the Canadian Collaborative Study J Neurol Neurosurg Psychiatry 2010 81 1 31 6 0022-3050 10.1136/jnnp.2008.162784 19710047 Mielcarz D.W. Kasper L.H. The gut microbiome in multiple sclerosis Curr Treat Options Neurol 2015 17 4 344 1092-8480 10.1007/s11940-015-0344-7 25843302 Hedström A.K. Olsson T. Alfredsson L. Smoking is a major preventable risk factor for multiple sclerosis Mult Scler 2016 22 8 1021 6 1352-4585 10.1177/1352458515609794 26459151 Benito-León J. Laurence M. The role of fungi in the etiology of multiple sclerosis Front Neurol 2017 8 535 1664-2295 10.3389/fneur.2017.00535 29085329 Stangel M. Penner I.K. Kallmann B.A. Lukas C. Kieseier B.C. Towards the implementation of `no evidence of disease activity' in multiple sclerosis treatment: the multiple sclerosis decision model Ther Adv Neurol Disorder 2015 8 1 3 13 1756-2856 10.1177/1756285614560733 25584069 Hauser S.L. Bar-Or A. Comi G. Giovannoni G. Hartung H.P. Hemmer B. I OPERA Clinical Investigators OPERA II Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis N Engl J Med 2017 376 3 221 34 0028-4793 10.1056/NEJMoa1601277 28002679 Annibali V. Mechelli R. Romano S. Buscarinu M.C. Fornasiero A. Umeton R. IFN-β and multiple sclerosis: from etiology to therapy and back Cytokine Growth Factor Rev 2015 26 2 221 8 1359-6101 10.1016/j.cytogfr.2014.10.010 25466632