What Factors Contribute to the Risk for MS?

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.

Prevalence~350,000 persons in the United States

Sex distribution ~75% female

Age at onsetTypically 20−40 years,

but can present at any age

Ethnic origin Predominantly Caucasian

MS Epidemiology

MS

Immune Dysregulation

Genetic Predisposition Environmental Factors

Graphic courtesy of Suhayl Dhib-Jalbut, MD.

Multiple SclerosisAn Immunogenetic Disease

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 Genetic Basis of MS

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

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

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.

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)

Reprinted from Kurtzke JF. Acta Neurol Scandinav. 1980;62:65-80, with permission from Blackwell Synergy.

Latitude gradient for UVB is strikingly similar = indirect evidence for vitamin D hypothesis

≥30 per 100,000 population5–25 per 100,000 population<5 per 100,000 population

Worldwide Prevalence of MS

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.

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

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

Pathophysiology of MS

• Acute Inflammation Relapses

• Neuronal Degeneration Disability

Pathophysiology of MS

1. Dhib-Jalbut S. Neurology. 2007;68:S13-S21. 2. Viglietta V, et al. J Exp Med. 2004;199:971-979.

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

IFN-, IL-12, TNFIL-4, IL-10, TGFß

InflammatoryAnti-inflammatory

IFN-, IL-12, TNF

IL-4, IL-10,TGFßInflammatory

Anti-inflammatory

Normal

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TH1 TH2

TH1

TH2

Cytokine Imbalance in MS

Graphic courtesy of Suhayl Dhib-Jalbut, MD.

1. Uccelli A, et al. Trends Immunol. 2005;26:254-259.

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

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

1. Trapp BD, et al. 1. Trapp BD, et al. N Engl J Med.N Engl J Med. 1998;338:278-285. 2. Trapp BD. 1998;338:278-285. 2. Trapp BD. Neuroscientist.Neuroscientist. 1999;5:48-57. 1999;5:48-57.

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?

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