What Factors Contribute to the Risk for MS?. MS Epidemiology.
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Compston A, et al. McAlpine’s Multiple Sclerosis, 4th ed. Churchill Livingston; 2006. HauserSL, et al. Multiple Sclerosis. In: Fauci AS, et al. Harrison’s Principles of Internal Medicine. Available at: http://www.accessmedicine.com/content.aspx?aID=2906448. Accessed on: February 19, 2010.
Graphic courtesy of Suhayl Dhib-Jalbut, MD.
Approximate Probability of Developing MS
Hauser SL, et al. Multiple Sclerosis. In: Fauci AS, et al, eds. Harrison's Principles of Internal Medicine. Available at: http://www.accessmedicine.com/content.aspx?aID=2906445. Accessed on: February 19, 2010. Willer CJ, et al. Proc Natl Acad Sci U S A. 2003;100:12877-12882.
No evidence of MS prior to 1822 (~ onset of industrial revolution in Europe)
Change in the gender ratio over time
These changes (eg, gender ratio, increasing incidence) took place over ~ 30 years (1–2 generations)—too fast for a genetics cause
Increased incidence of MS in many regions (especially in women)
When individuals migrate before age 15 from a region of high MS prevalence to one of low prevalence (or vice versa), they seem to adopt a prevalence similar to that of the region to which they moved
When they make the same move after age 15, they seem to retain the risk of the region from which they moved
Many environmental factors have been proposed
Two currently popular candidates for involvement in MS pathogenesis are:
Epstein-Barr virus (EBV) infection
Vitamin D deficiency (sunlight exposure)
These are hypotheses—not proven facts!
Either, neither, or both may be correct
Late EBV infection is associated with MS
Symptomatic mononucleosis is associated with MS
10 out of 12 studies found a significantly higher rate of EBV positivity in MS patients than in controls1-12
When data from these 12 trials are combined (N = 4155), EBV positivity is found in 99.5% of MS patients vs 94.2% of controls (P <10-23)
1. Sumaya, 1980. 2. Bray, 1983. 3. Larson, 1984. 4. Sumaya, 1985. 5. Shirodaria, 1987. 6. Munch, 1998. 7. Myhr, 1998. 8. Wagner, 2000. 9. Ascherio, 2001. 10. Sundström, 2004. 11. Haahr, 2004. 12. Ponsonby, 2005.
Latitude gradient for UVB is strikingly similar = indirect evidence for vitamin D hypothesis
≥30 per 100,000 population
5–25 per 100,000 population
<5 per 100,000 population
Reprinted from Kurtzke JF. Acta Neurol Scandinav. 1980;62:65-80, with permission from Blackwell Synergy.
>185,000 women interviewed about their diet: Those in highest quintile of vitamin D consumption had significantly less new-onset MS compared with lowest quintile1
Study of MS patients and controls from Tasmania found significant negative association between total sun exposure during childhood (especially in those 6–10 years old) and adolescence and the subsequent development of MS2,3
Evaluation of stored serum samples from 257 MS patients and 514 matched controls (US Military) showed the risk of MS was significantly decreased in those with increased serum vitamin D3 levels4
1. Munger KL, et al. Neurology. 2004;62:60-65. 2. Van der Mei IA, et al. J Neurol. 2007;254:581-590. 3. Van der Mei IA, et al. BJM. 2003;327:316. 4. Munger KL, et al. JAMA. 2006;296:2832-2838.
MS is caused by a complex interaction of genetic and environmental factors
In someone with an affected identical twin, risk of MS is 25%, suggesting that genetics play a role in susceptibility but are not the complete story
Vitamin D insufficiency and EBV infection have shown possible links to MS
This research is thought-provoking, but these factors have not been definitely proven as causes of MS
T cells normally recognize specific antigens
CD8+ T cells destroy infected cells
CD4+ T cells release cytokines that mediate inflammatory and anti-inflammatory responses
T cells reactive to myelin are found in MS lesions, blood, and cerebrospinal fluid
CD8+ T cells transect axons, induce oligodendrocyte death, promote vascular permeability1
There is a cytokine imbalance in MS, favoring secretion of inflammatory (Th1) cytokines
T cells that normally regulate immune function have reduced activity in MS2
1. Dhib-Jalbut S. Neurology. 2007;68:S13-S21. 2. Viglietta V, et al. J Exp Med. 2004;199:971-979.
IFN-g, IL-12, TNF
IL-4, IL-10, TGFß
IFN-g, IL-12, TNF
Graphic courtesy of Suhayl Dhib-Jalbut, MD.
In some MS patients, ectopic lymphoid follicles have been found in the meninges1
Mechanisms of B cells in MS may include:
Antimyelin antibody production
Antigen presentation to autoreactive T cells
Proinflammatory cytokine production
1. Uccelli A, et al. Trends Immunol. 2005;26:254-259.
Natural killer (NK) cells
May play opposing roles as both regulators and inducers of disease relative to cytokine environment and cell:cell contact
NK cell function may be lost during clinical relapse
Secrete IL-6 (promotes B cell growth) and IL-2 (aids differentiation of Th1 cells)
Phagocytic activity may contribute to demyelination
Specialized macrophages in the CNS, also may contribute to T cell activation
Loss of axons is the main cause of permanent disability in MS
Axonal damage has been shown to occur in acute inflammatory plaques1 and can lead to brain atrophy
Occurs in white and gray matter
May also produce cognitive impairment
Axonal damage could be the result of
Cumulative inflammatory damage over time
A parallel degenerative process related to loss of trophic support or an independent axonal degeneration2
Can effective immune therapy early in MS prevent worsening disability?
1. Trapp BD, et al. N Engl J Med. 1998;338:278-285. 2. Trapp BD. Neuroscientist. 1999;5:48-57.
Pathogenesis of MS involves complex interactions between genetic and environmental factors
Multiple genes are involved
Vitamin D deficiency and EBV infection are 2 candidates
MS incidence has increased over the past 30 years due to a change in environmental exposure
MS pathogenesis involves multiple immune cell types (T cells, B cells, NK cells, others)
Along with chronic inflammation, MS pathogenesis involves axonal loss
Neurodegeneration is the major source of disability in MS