A segment of a group presentation reflecting upon some of the genetic components that may contribute to Multiple Sclerosis pathogenesis. IL2Rα and IL7Rα were the two genes of focus. (This presentation was originally done for Semester 2 , 2008)

1. Investigating Multiple Sclerosis

2. An Introduction Multiple Sclerosis (MS) is the most prevalent autoimmune disease among young people, affecting between 2 and 150 people per 100,000. It is a condition that attacks and destroys myelin, an insulating substance that aids neural transmission in the Central Nervous System (CNS).

4. Both environmental and genetic factors contribute to the vulnerability and pathogenesis of the disease and its suggested triggers of exacerbation include physical injury, bacterial or viral infections, stressful life events, and genetic susceptibility.

5. Considerable research suggests an inflammatory cycleWinquist, R.J, Kwong, A, Ramachandran, R, Jain, J (2007). The Complex Etiology of Multiple Sclerosis. Biochemical Pharmacology74:1321-1329.

6. Genetic insights into Multiple Sclerosis Pathogenesis Aaron Sparshott

7. An Introduction The pathogenesis of MS is the result of complex interactions between genes and the environment. ~50% of MS cases can be explained by the heritable component. Certain human leukocyte antigen (HLA) factors belonging to the major histocompatibility complex (MHC) on chromosome 6 were shown in the 1970s to have strong associations with MS and other autoimmune diseases (e.g. diabetes). To date HLA Factors have shown the strongest correlations to MS pathogenesis Genetic MS susceptibility however is not limited to one gene, but is rather the sum of a number of variant genes exerting small contributory effects.

9. IL2Rα (2)

10. IL7Rα

11. CBLB

12. DBC1

13. CD58

14. KLRB1

15. PDE4B

16. ALK

17. FAM69α (2)

18. KIAA0350

19. RPL5

20. ANKRD15

21. EV15 (2)Level of significance of genetic region with MS susceptibility HAFLER ET AL. (2007) Risk Alleles for Multiple Sclerosis Identified by a Genomewide Study. N Engl J Med. 357(9):851-62. * International Multiple Sclerosis Genetics Consortium

22. Non-HLA Genes A number of other gene loci on chromosome1p22 have also shown links to MS pathogenesis. The discovery of new linked genes opens new avenues for pharmacological targets and therapeutic strategies. Both cytokines are of central importance in promoting the growth and differentiation of T and B cells.

23. IL2Rα’s Role in pathogenesis Proposed Mechanism Regulatory T cells are crucial for the maintenance of immunological tolerance. SNPs in IL2Rα cause a loss in regulatory T cell function, thus limiting the body’s ability to control auto-reactive T cells that have escaped the process of negative selection in the thymus. T cells which subsequently assist in the autoimmune reaction. Pharmacological Targets & Therapeutic Strategies In support of this association stage 2 trials of Daclizumab (Zenapax®) a monoclonal antibody targeting the IL2Rα chain have shown clinical efficacy.

24. Importance of Genetic Research Current Research Refined the knowledge of MS pathogenesis Provided supporting evidence for the scientific community’s consensus that MS is an autoimmune inflammatory disorder Led to the development of new pharmacological targets and therapeutic strategies for MS. Future Research Biomarkers for early diagnosis Preventative strategies Treatments and therapies designed specifically for the individual