Multiple Sclerosis: A Disease of the Central Nervous System

1. Multiple Sclerosis:A Disease of the Central Nervous System Presented By: John Campiche & Danielle Pfaff

2. Worldwide Distribution of MS

3. Multiple Sclerosis: Epidemiology • MS is increasing in occurrence as you travel further north from the equator. • Epidemiological studies indicate Populations: • North of the 37th parallel: 110-140 cases/ 100,000. • South of 37th parallel: 57-78 cases/ 100,000. • Female to male ratio is 3: 1. • Diagnosed between ages 20 and 40.

4. What is MS? • Chronic inflammatory disease of the central nervous system (CNS). • It’s an autoimmune disease that attacks the myelin of the CNS • The antigen that stimulates the autoimmune response is not known • Symptoms affect mainly brain, spinal cord and optic nerves • Progression is dynamic • Variable symptoms ranging from mild numbness to severe paralysis or loss of vision • http://www.youtube.com/watch?v=qgySDmRRzxY

5. MS Is An Inflammatory Demyelinating Disease of the CNS

6. MS Pathogenesis & Pathophysiology • APC with classII MHC displays autoAg, which is recognized by self-reactive Thcell • Thcell activates & differentiates into Th1 or Th2 subset. • Th1 cells and their released cytokines TNFα & IFNγ directly/indirectly attack myelin. • Th2 cells differentiate into B cells that form autoAbs that trigger ADCC or complement mediated attack of myelin.

7. MS Pathogenesis & Pathophysiology • Activated Th1 cells go through the “Local Acute Inflammatory Response” (Ch. 13) to cross the BBB & attack the myelin sheath . • AutoAb’s are signalled by microglial/Th1 cell interaction.

8. Oligodendrocyte

9. Multiple Sclerosis Subtypes(Coyle P, 2002; adapted from Lublin F, et al Neurology 1996)

10. MS Plaques On histological sections: * Black areas are demylination sites * MS affects white matter & grey matter * Slides show plaques within the grey matter & if an MS plaque extends into the grey matter, there is an increased likelihood of cognitive deficits.

11. Genetic predisposition Infectious agent Environmental factors Abnormal immunologic response MS Underlying Factors of MS

12. MS: Genetics Average Person in the US has 1/1000 chance of developing MS. 1° relatives of a person affiliated with MS have 1/50-1/100 chance in development. Identical twin of a person affiliated with MS has 1/3 chance in development. There is no identified locus (loci) associated with MS.

13. Can a virus predispose someone to MS? • Protein Theory • Patient at young age is exposed to some agent, e.g. a virus or bacteria & immune system responds by fighting agent. There are other proteins on the agent that look identical to proteins located on myelin. • Since body is accustomed to attacking agents with this identical protein it then begins to attack endogenous myelin as an autoimmune process. • Example: Epstein Barr virus (EBV) a.k.a. Human herpesvirus-4 (HHV-4) causes mononucleosis (Mono). • Patients first contract the herpes virus. • Immune system recognizes protein on EBV (also present on myelin) “mistaken” protein results an autoimmune response. • Whenever an increase in EBV load, immune system is stimulated and MS attack results. • This theory is the most accepted hypothesis in current research. Though the protein on myelin causing the cross-reactivity is not known.

14. Environmental Causes Environmental causes have been suggested but no environmental factor is clearly a direct cause of MS. People who migrate from a low incidence area to a high incidence area before the age of 15 years have a high risk of developing MS. After 15 years of age, migration does not affect the risk of developing MS.

15. Is there a Positive Correlation Between Vitamin D & MS? • Studies investigate a correlation between vitamin D and MS in Tasmanian children and noted that these children have one third the prevalence of MS. • Vitamin D acts as an immunosuppressant because lymphocytes have vitamin D receptors on their membranes that when activated by vitamin D, it will then suppress the immune response. • It was hypothesized that the increased exposure to the sun (ages < 15) increased vitamin D and may suggest reason to lower rates of MS closer to the equator.

16. MS Treatments • There are three groups of drugs: • Interferons – proteins; β1A-interferon has been demonstrated to slow the disability progression of the disease. Ex: Rebif. • Glatimer acetate – myelin basic protein. It was thought that treatment with this would actually create an MS-like response because it would be seen as foreign resulting in an immune response against the myelin. In fact, the opposite is true. It works somewhat like an allergy shot and “desensitizes” the immune system. • • Natalizumab – monoclonal antibody; n-natalizumab has been demonstrated to slow disability progression of the disease. Natalizumab blocks the adhesion of immune cells to the endothelial cells in the brain and prevents the immune cells from crossing the BBB. • Note: that these treatments are NOT cures, but do impact “the disability progression”. • Bottom Line: With treatment, inflammation in the brain can be significantly decreased and have a significant impact in function of MS patients.