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| == Causes == | | == Causes == |
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| Although many risk factors for multiple sclerosis have been identified, no definitive cause has been found. MS likely occurs as a result of some combination of both environmental and [[genetics|genetic]] factors. Various theories try to combine the known data into plausible explanations. Although most accept an [[autoimmune]] explanation, several theories suggest that MS is an appropriate immune response to one or several underlying conditions (the [[etiology]] could be heterogeneous<ref>{{cite journal |author=Lassmann H |title=Experimental models of multiple sclerosis |journal=Rev. Neurol. (Paris) |volume=163 |issue=6-7 |pages=651-5 |year=2007|pmid=17607184 |doi=}}</ref>). The need for alternative theories is supported by the poor results of present therapies, since autoimmune theory predicted greater success.<ref>
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| {{cite journal
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| | author=Peter Behan and Abhijit Chaudhuri
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| | title=The pathogenesis of multiple sclerosis revisited
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| | journal=J R Coll Physicians Edinb
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| | year=2002 | pages=244–265 | volume=32 |url=http://www.rcpe.ac.uk/publications/articles/journal_32_4/3_pathogenesis_of_MS.pdf}}</ref><ref>{{cite journal |author=Chaudhuri A, Behan P |title=Multiple sclerosis is not an autoimmune disease |journal=Arch. Neurol. |volume=61 |issue=10 |pages=1610–2|year=2004 |pmid=15477520}}</ref><ref>{{cite journal |author=Altmann D |title=Evaluating the evidence for multiple sclerosis as an autoimmune disease |journal=Arch. Neurol. |volume=62 |issue=4 |pages=688; author reply 688-9 |year=2005 |pmid=15824275}}</ref>
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| === Environmental ===
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| The most popular hypothesis is that a [[virus|viral]] infection or [[retrovirus|retroviral]] reactivation primes a susceptible immune system for an abnormal reaction later in life. On a [[molecule|molecular]] level, this might occur if there is a structural similarity between the infectious virus and some component of the central nervous system, leading to eventual confusion in the [[immune system]].
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| Since MS seems to be more common in people who live farther from the equator, another theory proposes that decreased sunlight exposure<ref>{{cite journal |author=van der Mei IA, Ponsonby AL, Dwyer T, ''et al'' |title=Past exposure to sun, skin phenotype, and risk of multiple sclerosis: case-control study |journal=BMJ |volume=327 |issue=7410 |pages=316 |year=2003 |pmid=12907484|doi=10.1136/bmj.327.7410.316}}</ref> and possibly decreased [[vitamin D]] production may help cause MS. This theory is bolstered by recent research into the [[biochemistry]] of vitamin D, which has shown that it is an important immune system regulator. A large, 2006 study by the Harvard School of Public Health, reported evidence of a link between Vitamin D deficiency and the onset of multiple sclerosis.<ref>{{cite journal |author=Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A |title=Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis |journal=JAMA |volume=296 |issue=23 |pages=2832-8 |year=2006 |pmid=17179460|doi=10.1001/jama.296.23.2832}}</ref> Other data comes from a 2007 study which concluded that sun exposure during childhood reduces the risk of suffering MS, while controlling for genetic factors.<ref>[http://www.neurology.org/cgi/content/abstract/69/4/381?etocChildhood sun exposure influences risk of multiple sclerosis in monozygotic twins.] Talat Islam, MBBS, PhD, W. James Gauderman, PhD, Wendy Cozen, DO, MPH and Thomas M. Mack, MD, MPH. ''Neurology'' 2007;69:381-388</ref><ref>[http://news.bbc.co.uk/1/hi/health/6906712.stm Sunshine 'protective' against MS]. BBC News, 28 July 2007, 23:40 </ref>
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| Other theories, noting that MS is less common in children with siblings, suggest that less exposure to illness in childhood leads to an immune system which is not primed to fight infection and is thus more likely to attack the body. One explanation for this would be an imbalance between the Th1 type of [[T helper cell|helper T-cells]], which fight infection, and the Th2 type, which are more active in [[allergy]] and more likely to attack the body.
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| Other theories describe MS as an immune response to a chronic infection. The association of MS with the [[Epstein-Barr virus]] suggests a potential viral contribution in at least some individuals.<ref>{{cite journal |author=Levin LI, Munger KL, Rubertone MV,''et al'' |title=Temporal relationship between elevation of epstein-barr virus antibody titers and initial onset of neurological symptoms in multiple sclerosis |journal=JAMA |volume=293 |issue=20 |pages=2496-500 |year=2005 |pmid=15914750|doi=10.1001/jama.293.20.2496}}</ref> Still others believe that MS may sometimes result from a chronic infection with [[spirochetal]] bacteria, a hypothesis supported by research in which cystic forms were isolated from the cerebrospinal fluid of all MS patients in a small study.<ref>{{cite journal |author=Brorson O, Brorson SH, Henriksen TH, Skogen PR, Schøyen R|title=Association between multiple sclerosis and cystic structures in cerebrospinal fluid |journal=Infection |volume=29 |issue=6|pages=315-9 |year=2001 |pmid=11787831 |doi=}}</ref> When the cysts were cultured, propagating spirochetes emerged. Another bacterium that has been implicated in MS is ''[[Chlamydophila pneumoniae]]''; it or its DNA has been found in the cerebrospinal fluid of MS patients by several research laboratories, with one study finding that the [[oligoclonal bands]] of 14 of the 17 MS patients studied consisted largely of antibodies to Chlamydophila antigens.<ref>{{cite journal |author=Yao SY, Stratton CW, Mitchell WM, Sriram S |title=CSF oligoclonal bands in MS include antibodies against Chlamydophila antigens |journal=Neurology |volume=56|issue=9 |pages=1168-76 |year=2001 |pmid=11342681 |doi=}}</ref>
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| Severe stress may also be a factor—a large study in Denmark found that parents who had lost a child unexpectedly were 50% more likely to develop MS than parents who had not.<ref>{{cite journal | author = Li J, Johansen C, Bronnum-Hansen H, Stenager E, Koch-Henriksen N, Olsen J | title = The risk of multiple sclerosis in bereaved parents: A nationwide cohort study in Denmark. |journal = Neurology | volume = 62 | issue = 5 | pages = 726-9 | year = 2004 | pmid = 15007121}}</ref> [[Tobacco smoking|Smoking]] has also been shown to be an independent risk factor for developing MS.<ref>{{cite journal |author=Franklin GM, Nelson L|title=Environmental risk factors in multiple sclerosis: causes, triggers, and patient autonomy |journal=Neurology |volume=61|issue=8 |pages=1032-4 |year=2003 |pmid=14581658 |doi=}}</ref>
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| === Genetic ===
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| [[Image:HLA complex1.JPG|thumb|left|upright|HLA region of Chromosome 6. Changes in this area increase the probability of suffering MS.]]
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| MS is not considered a [[hereditary]] disease. However, increasing scientific evidence suggests that genetics may play a role in determining a person's susceptibility to MS:
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| Some populations, such as the Roma, Inuit, and Bantus, rarely if ever get MS. The indigenous peoples of the Americas and Asians have very low incidence rates.
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| In the population at large, the chance of developing MS is less than a tenth of one percent. However, if one person in a family has MS, that person's first-degree relatives—parents, children, and siblings—have a one to three percent chance of getting the disease.
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| For identical [[twins]], the likelihood that the second twin may develop MS if the first twin does is about 30%. For fraternal twins (who do not inherit an identical set of genes), the likelihood is closer to that for non-twin siblings, or about 4%. This pattern suggests that, while genetic factors clearly help determine the risk of MS, other factors such as environmental effects or random chance are also involved. The actual correlation may be somewhat higher than reported by these numbers as people with MS lesions remain essentially asymptomatic throughout their lives.
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| Further indications that more than one gene is involved in MS susceptibility comes from studies of families in which more than one member has MS. Several research teams found that people with MS inherit certain regions on individual genes more frequently than people without MS. Of particular interest is the [[human leukocyte antigen]] (HLA) or [[major histocompatibility complex]] region on chromosome 6. HLAs are genetically determined proteins that influence the immune system. However, there are other genes in this region which are not related to the immune system.
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| The HLA patterns of MS patients tend to be different from those of people without the disease. Investigations in northern Europe and America have detected three HLAs that are more prevalent in people with MS than in the general population. Studies of American MS patients have shown that people with MS also tend to exhibit these HLAs in combination—that is, they have more than one of the three HLAs—more frequently than the rest of the population. Furthermore, there is evidence that different combinations of the HLAs may correspond to variations in disease severity and progression.
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| A large study examining 334,923 [[single nucleotide polymorphism]]s (small variations in [[gene]]s) in 931 families showed that apart from HLA-DRA there were two genes in which polymorphisms strongly predicted MS; these were the ''[[IL-2 receptor|IL2RA]]'' (a subunit of the [[Receptor (biochemistry)|receptor]] for [[interleukin 2]]) and the ''[[IL-7 receptor|IL7RA]]'' (''idem'' for [[interleukin 7]]) genes. Mutations in these genes were already known to be associated with [[diabetes mellitus type 1]] and other autoimmune conditions; the findings circumstantially support the notion that MS is an autoimmune disease.<ref>{{cite journal|author= |title=Risk Alleles for Multiple Sclerosis Identified by a Genomewide Study |journal=N Engl J Med |volume= |issue= |pages=|year=2007 |pmid=17660530 |doi=10.1056/NEJMoa073493}}</ref>
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| Studies of families with multiple cases of MS and research comparing proteins expressed in humans with MS to those of mice with EAE suggest that another area related to MS susceptibility may be located on chromosome 5. Other regions on chromosomes 2, 3, 7, 11, 17, 19, and X have also been identified as possibly containing genes involved in the development of MS.
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| These studies strengthen the theory that MS is the result of a number of factors rather than a single gene or other agent. Development of MS is likely to be influenced by the interactions of a number of genes, each of which (individually) has only a modest effect. Additional studies are needed to specifically pinpoint which genes are involved, determine their function, and learn how each gene's interactions with other genes and with the environment make an individual susceptible to MS.
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| ==References== | | ==References== |