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What Factors Contribute to the Risk for MS?. MS Epidemiology.

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Ms epidemiology l.jpg
MS Epidemiology

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.


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Multiple SclerosisAn Immunogenetic Disease

Environmental Factors

Genetic Predisposition

Immune Dysregulation

MS

Graphic courtesy of Suhayl Dhib-Jalbut, MD.


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Evidence for Genetic Basis of MS

50

45

40

35

Approximate Probability of Developing MS

30

25%

25

20

15

5%

10

3%

2%

5

1%

0.1%

0.1%

0

Identical

Fraternal

Sibling

Parent or

First

Spouse

No

Twin

Twin

Half-

Cousin

Family

Sibling

Member

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.


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Evidence for Environmental Basis of MS

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


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Multiple Sclerosis What Are the Environmental Factors?

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


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Evidence for EBV

Indirect evidence

Late EBV infection is associated with MS

Symptomatic mononucleosis is associated with MS

Direct evidence

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.


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Worldwide Prevalence of MS

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.


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Direct Evidence for Vitamin D

>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.


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Risk Factors for MSSummary

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



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Pathophysiology of MS

  • Acute Inflammation Relapses

  • Neuronal Degeneration Disability


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Immune Dysregulation in MST Cells

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.


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Cytokine Imbalance in MS

TH1

TH2

Normal

Inflammatory

Anti-inflammatory

IFN-g, IL-12, TNF

IL-4, IL-10, TGFß

TH2

MS

Anti-inflammatory

TH1

IL-4, IL-10,TGFß

Inflammatory

IFN-g, IL-12, TNF

Graphic courtesy of Suhayl Dhib-Jalbut, MD.


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Immune Dysregulation in MSB Cells

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.


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Immune Dysregulation in MSOther Involved Cells

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

Monocytes

Secrete IL-6 (promotes B cell growth) and IL-2 (aids differentiation of Th1 cells)

Macrophages

Phagocytic activity may contribute to demyelination

Microglia

Specialized macrophages in the CNS, also may contribute to T cell activation


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Neurodegeneration

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.


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Conclusions

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


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