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What Factors Contribute to the Risk for MS?

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

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What Factors Contribute to the Risk for MS?

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  1. What Factors Contribute to the Risk for MS?

  2. 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.

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

  4. 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.

  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. 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.

  8. 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.

  9. 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.

  10. 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

  11. Pathophysiology of MS

  12. Pathophysiology of MS • Acute Inflammation Relapses • Neuronal Degeneration Disability

  13. 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.

  14. 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.

  15. 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.

  16. 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

  17. 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.

  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

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