1. What Factors Contribute to the Risk for MS?

2. Compston A, et al. McAlpine’s Multiple Sclerosis, 4 th ed. Churchill Livingston; 2006. Hauser SL, 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. http://www.accessmedicine.com/content.aspx?aID=2906448 Prevalence ~350,000 persons in the United States Sex distribution~75% female Age at onset Typically 20−40 years, but can present at any age Ethnic originPredominantly Caucasian MS Epidemiology

3. MS Immune Dysregulation Genetic Predisposition Environmental Factors Graphic courtesy of Suhayl Dhib-Jalbut, MD. Multiple Sclerosis An Immunogenetic Disease

4. 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. Approximate Probability of Developing MS 0 5 10 15 20 25 30 35 40 45 50 Identical Twin Fraternal Twin SiblingParent or Half- Sibling First Cousin SpouseNo Family Member 25% 5% 3% 2% 1%0.1% Evidence for Genetic Basis of MS

5. 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

6. 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

7. 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 controls 1-12 –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)

8. 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 population 5–25 per 100,000 population <5 per 100,000 population Worldwide Prevalence of MS

9. 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 quintile 1 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 MS 2,3 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 levels 4

10. Risk Factors for MS Summary 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

11. Pathophysiology of MS

12. Acute Inflammation Relapses Neuronal Degeneration Disability Pathophysiology of MS

13. 1. Dhib-Jalbut S. Neurology. 2007;68:S13-S21. 2. Viglietta V, et al. J Exp Med. 2004;199:971-979. Immune Dysregulation in MS T 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 permeability 1 –There is a cytokine imbalance in MS, favoring secretion of inflammatory (Th1) cytokines –T cells that normally regulate immune function have reduced activity in MS 2

14. IFN- , IL-12, TNF IL-4, IL-10, TGFß InflammatoryAnti-inflammatory IFN- , IL-12, TNF IL-4, IL-10,TGFß Inflammatory Anti-inflammatory Normal MS TH1TH1 TH2TH2 TH1TH1 TH2TH2 Cytokine Imbalance in MS Graphic courtesy of Suhayl Dhib-Jalbut, MD.

15. 1. Uccelli A, et al. Trends Immunol. 2005;26:254-259. Immune Dysregulation in MS B Cells In some MS patients, ectopic lymphoid follicles have been found in the meninges 1 Mechanisms of B cells in MS may include: –Antimyelin antibody production –Antigen presentation to autoreactive T cells –Proinflammatory cytokine production

16. Immune Dysregulation in MS Other 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

17. 1. Trapp BD, et al. N Engl J Med. 1998;338:278-285. 2. Trapp BD. Neuroscientist. 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 plaques 1 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 degeneration 2 Can effective immune therapy early in MS prevent worsening disability?

18. 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