by Alessia Dolcetti

Multiple sclerosis (MS) is an autoimmune disordercharacterized by axon demyelination in the central nervous system (CNS). While the exact cause of MS is unknown, genetic and environmental risk factors have been identified[1] . Most risk-conferring genes are involved in immunity, vitamin Dmetabolism, and neuronal repair[2] . Environmental factors appear to affect individuals with a genetic susceptibility, and are believed to act long before the first clinical manifestations of the disease. The primary non-genetic factors associated with MS risk are vitamin D deficiency, viral infection, and cigarette smoking. As researchers continue to study the interplay between genetic and environmental factors in the development of MS, it may be possible to develop more effective strategies for the prevention and treatment of this debilitating disorder.

1.1 Risk-conferring genes

Epidemiological studies have identified a genetic component to MS susceptibility [3] .The disease tends to aggregate in families, with first degree relatives at 10 to 25 times greater risk than the general population. Genome wide association (GWA) studies have discovered a number of susceptibility loci, most of which have only a small impact on disease risk.

1.1a Immunity

As MS is widely believed to be an autoimmune disease, it is not surprising
Figure 1. Human leukocyte antigen (HLA) genes on chromosome 6. Adapted from "Expert Reviews in Molecular Medicine: http://www.expertreviews.org/"

that many susceptibility loci have important roles in immune processes. The human leukocyte antigen(HLA) genes on chromosome 6 have the most robust associations with MS (Figure 1)[4] . The first risk-conferring loci to be identified were HLA-A3 and -B7, which encode MHC class I proteins. Since then, the class II genes HLA-DR2, -DR3, -DQA1, -DPB1, -DRB1, and -DQB1 have also been found to influence MS susceptibility. The immune system uses MHC proteins to distinguish foreign invaders from host proteins. The disruption of pathways involved in self-recognition may lead to autoimmunity in MS patients.

Other loci involved in immunity have more modest associations with MS [5] . They include the interleukin-2-receptor-α (IL2RA), interleukin-7-receptor-α (IL7RA), and cluster of differentiation 58 (CD58) genes, all of which regulate T cell activity. Additional susceptibility loci are the interferon regulatory factor 5 (IRF5) and interferon regulatory factor 8 (IRF8) genes, which are involved in the synthesis and release of antimicrobial proteins.

1.1b Vitamin D metabolism

Numerous epidemiological studies have associated vitamin D deficiency with increased risk of MS [6] . This result is consistent with the discovery of an MS susceptibility gene that is involved in vitamin D metabolism [7] . CYP27B1, which encodes the enzyme 25-hydroxyvitamin D-1 alpha hydroxylase, was first identified as a potential risk-conferring gene by a GWA study. The link was tentative, however, because the marker single nucleotide polymorphism (SNP) was associated with an additional 24 genes. The association was later confirmed by a study that genotyped three CYP27B1 variants in 3,046 parent-affected child trios. A significant heterozygous association was identified for the variant involving an arginine to histidine amino acid change (R389H). Genotyping over 12,500 individuals with MS for other nonsynonymous CYP27B1 mutations allowed four additional variants to be identified. When the frequency of all 5 variants in MS patients was compared to controls, the results were highly significant. The discovery of a risk-conferring gene involved in vitamin D synthesis supports the putative role of vitamin D deficiency in MS pathogenesis.

1.1c Neuronal repair

Two genes that are thought to confer MS risk are involved in neuronal repair processes. The first to be identified was the kinesin family member 1b (KIF1b) gene, which encodes a motor protein that mediates the transport of mitochondria and synaptic vesicles[8] . In zebrafish, KIF1b has been shown to be required for the localization of myelin mRNA to the processes of oligodendrocytes (Figure 2). Moreover, knocking out KIF1b causes neurodegeneration in mice [9] . The glypican proteoglycan 5 (GPC5) gene is a second potential susceptibility locus[10] . It encodes a heparan sulphate proteoglycan that regulates cell growth and proliferation. Disrupting the functions of KIF1b and GPC5 may increase MS susceptibility by impairing normal neuronal regeneration processes.

Figure 2. Myelin mRNA is localized to cell bodies and myelinating processes in control zebrafish (left) but only to cell bodies when KIF1b is knocked out (right).

1.2 Environmental factors

Like most diseases, MS appears to involve a complex interplay of genetic and environmental factors. Vitamin D deficiency, viral infection, and cigarette smoking are the primary non-genetic factors that are thought to influence MS risk.

1.2a Vitamin D deficiency

There is considerable evidence to suggest that vitamin D deficiency confers MS susceptibility[11] . The main factors influencing vitamin D status are sun exposure and diet. Ultraviolet (UV) radiation is necessary for the conversion of 7-dehydrocholesterol in the skin to previtamin D, which spontaneously isomerizes to the bioactive form of vitamin D. Dietary sources of vitamin D include supplements, fortified foods, and fish oils.

Figure 3. World map showing MS prevalence estimates from a meta-analysis of 321 peer-reviewed studies.
Figure 3. World map showing MS prevalence estimates from a meta-analysis of 321 peer-reviewed studies.

Figure 4. MS incidence and month of birth.
Figure 4. MS incidence and month of birth.

The effect of sun exposure on MS risk has been extensively studied. Disease susceptibility increases with distance from the equator, a variable that is inversely correlated with sunlight intensity (Figure 3) [12] . It also appears that prenatal sun exposure may be important, as MS occurs more frequently in individuals born in May than in November (Figure 4) [13] . This hypothesis is consistent with animal experiments that have shown gestational vitamin D deprivation to impair fetal brain development. Another study associated reduced MS risk with increased actinic damage, a consequence of excessive sun exposure [14] . Because UV light is required for vitamin D synthesis, these results support a model implicating vitamin D deficiency in MS pathogenesis.

Like sun exposure, dietary intake of vitamin D has been associated with MS susceptibility. A case-control study in Norway found MS incidence to be significantly lower in individuals who consumed fish (a vitamin D-rich food) one to three times a week [15] than in controls. Because Norway is far from the equator, the participants in the study would have derived most of their vitamin D from dietary sources. This finding is consistent with the results of a prospective study of 200,000 women in the United States whose vitamin D intake was monitored every four years for a maximum of 30 years [16] . Not only was vitamin D intake inversely correlated with disease risk, but women who consumed 400 IU of supplements per day had a 41% lower incidence of MS than non-users. If vitamin D deficiency truly does increase MS risk, the use of dietary supplements could be an effective method of prevention.

Although the effect of vitamin D on MS risk is not well understood, the molecule is thought to prevent the development of autoimmunity in genetically susceptible individuals [17] . Vitamin D inhibits the release of cytokines by dendritic cells, potentially suppressing the proliferation of autoreactive T cells. There are also vitamin D receptors on T cell membranes, indicating that direct inhibition of lymphocytes may be important. The recent identification of a vitamin D response element in the promoter region of HLA- DRB1 suggests a compelling new role for the molecule in preventing disease onset [18] . Of all the MHC class II loci, HLA- DRB1 has the strongest association with MS. Upregulating the expression of its gene product has been proposed to increase the likelihood that autoreactive T cells are deleted in the thymus. With continued research on the role of vitamin D in MS, it may be possible to better characterize its effect on disease susceptibility.

1.2b Viral Infection

A number of infectious agents have been proposed to trigger the onset of MS. Pathogens that have received the most attention are the Epstein-Barr, human herpes, and varicella-zosterviruses [19] .

Epstein-Barr virus (EBV)
Of the infectious agents that have been studied, EBV has the strongest link to MS susceptibility[20] . The virus is common in developed nations, with approximately 50% of people infected during childhood. Although EBV infection is us
Figure 5. Presence of anti-EBV antibodies in MS patients and healthy controls.
Figure 5. Presence of anti-EBV antibodies in MS patients and healthy controls.
ually benign in children, it may lead to a symptomatic infectious mononucleosis(IM) in adults. This condition is associated with a range of symptoms, including fever and a massive proliferation of T lymphocytes. A meta-analysis of data from 18 clinical studies reported a 2.17 increase in MS risk in individuals with a history of IM[21] . An epidemiological study also identified a significant association between EBV and MS, with 99.5% of MS patients and 94.2% of healthy controls seropositive for the virus [22] . In a related report, antibodies responsive to EBV peptides produced during active viral replication were found to be elevated in the sera of MS patients (Figure 5) [23] . The mechanism underlying the relationship between EBV infection and MS risk remains unclear [24] . It is possible that molecular mimicry causes T cells to recognize self-antigens, thus initiating the development of autoimmunity. An alternative hypothesis suggests that EBV immortalizes autoreactive B cells by imitating immune cell signalling.

Human herpes virus (HHV)
Although infection by HHV has not yet been associated with the development of MS, the virus has several characteristics that suggest it may be involved in disease onset[25] . HHV, which infects oligodendrocytes and microglia, frequently establishes latency in the CNS. It is also known to cause other disorders of the CNS, including encephalitis and epilepsy. Furthermore, there is compelling evidence to suggest that the virus’s U24 protein plays a role in triggering autoimmunity[26] . Myelin basic protein (MBP), which appears to be the main target of autoreactive immune cells in MS (Figure 6), shares considerable sequence similarity with U24. T cells that cross react with MBP and U24 have been detected at a significantly higher concentration in the blood of MS patients than controls. Despite the lack of epidemiological data to support an association between HHV and MS, it appears that the virus may still be involved in disease pathogenesis.
Figure 6. (a) Actively demyelinating axons stained for MBP (red) and axons (green). Arrowheads indicate regions of demyelination. (b) Schematic summary of the demyelination process. Adapted from: Trapp BD, Nave KA. Multiple sclerosis: an immune or neurodegenerative disorder? Annual Review of Neuroscience (2008) 31: 247-269.

Varicella-zoster virus (VZV)
A tentative role has been proposed for VZV in the development of MS[27] . The virus infects the peripheral and central nervous systems, and typically develops latency in the dorsal ganglia. The concentration of VZV in the leukocytes and cerebrospinal fluid of MS patients has been reported to increase during relapses. A meta-analysis of data from 40 studies, however, did not support an association between VZV infection and increased MS risk[28] . Because the results are inconclusive, it is unclear whether VZV is involved in the onset of MS.

1.2c Cigarette smoking

Epidemiological studies have found the incidence of MS to be mildly elevated in smokers. A meta-analysis of data on 3,052 MS cases and 457,619 controls reported smokers to have an increased risk ratio of 1.48[29] . The effect of cigarette smoking on MS susceptibility, however, is not well understood. It has been suggested that components of cigarette smoke affecting neuronal survival and immune function may be important. Nicotine does not appear to be the primary molecule involved, since the use of tobacco snuff has not been found to confer MS risk[30] . Nitric oxidehas been identified as a more interesting candidate because of its demyelinating properties. Smoking is known to be involved in the onset of other autoimmune disorders (e.g. systemic lupus erythematosus), and is currently considered to play a very minor role in MS susceptibility.

1.3 Demographic factors

Figure 7. Ratio of female to male MS cases in Canada by year of birth.
The two major demographic factors that influence MS susceptibility are sex and ethnicity. The identification of groups who are at increased risk has helped to inform hypotheses about genetic and environmental factors that may be involved in MS pathogenesis.

It is well-established that MS is more common in females than in males. In Canada, the ratio of female to male MS cases is currently estimated to be 3.2:1[31] . Hormonal factors and sex-linked genes are thought to underlie the higher incidence of MS in females. The sex ratio has increased over the past few decades, with a greater proportion of women affected (Figure 7). Although this trend has been attributed to environmental changes, the exact cause is unknown.

Ethnic background is another demographic factor that influences MS susceptibility. North American, African American, Puerto Rican, and Japanese[32] populations have a reduced risk of developing MS, and the disease is almost completely absent from Chinese and Filipino populations. Genetic factors are believed to explain the variable incidence of MS in different ethnic groups.

1.4 Conclusions

MS is a neurodegenerative disorder with a complex etiology that involves both genetic and environmental factors. Although many potential risk factors have been identified, the exact origins of MS are not well understood. Continued research is needed to better characterize the events leading to the onset of this debilitating disease.

1.5 See also

1.6 References

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