What is Multiple Sclerosis (MS)? Autoimmune disease Affects 2.3 million people in the world 3 Types Relapsing-remmitting Primary-progressive Secondary-progressive Chronic

What is the epidemiology of MS? Onset Geographic distribution Population studies Genetic factors

What are the possible risk factors? Infections Age Genetic Factors DR15 haplotype Autoimmune diseases Race Climate

How are myelin autoreactive T-cells activated? Myelin-reactive T-cells Myelin basic protein (MBP) T-cell activation Autoantigens Molecular mimicry Immune cell recruitment CD8 + cells B cells Granulocytes Monocytes Mast cells

How do T-cells migrate across the BBB? Activated T-cells cross the BBB by: Cytokines TNF-α and IFN-γ Adhesion molecules LFA-1 and VLA-4 Proteases Matrix metalloproteinases (MMPs)

What happens once across the BBB? Reactivation of CD4 + cells Proinflammatory cytokines Microglial and astrocyte activation Myelin phagocytosis Humoral response B cell co-stimulation of CTLs Demyelination Type II hypersensitivity CTL apoptosis Reactive species /discovery-of-a-treatment-to-block-the-progression-of- multiple-sclerosis-neuroinnovations.jpg

What causes neuronal degeneration? MS lesions Active lesions Inactive, chronic lesions Remyelination Immune mechanisms cause: Oligodendrocyte damage Injury and loss of axon Gliosis

Overview of MS mechanisms

What are the symptoms of MS? Early symptoms Daily effects Age range Characteristics of symptoms

What are the possible triggers of MS? Epstein-Barr Virus Smoking Vitamin-D deficiency

How is MS treated? There is no cure for MS Treatments MS attacks Modify Progression Beta interferons Glutiramer acetate (Copaxone) Signs and symptoms mer_acetate

References Hemmer B, Archelos JJ, and Hartung HP New concepts in the immunopathogenesis of multiple sclerosis. Nature Reviews 3; Ponzio, M. & Brichetto, G. Workers with disability: the case of multiple sclerosis. (2015). Neurological Sciences. 36: 1835 – Sospedra, M & Martin, R. Molecular mimicry in multiple sclerosis. (2006). Journal of Autoimmunity. 39: Lassmann, H Mechanisms of multiple sclerosis. Drug Discovery Today: Disease Mechanisms 2; Lysandropoulos, A. & Havrdova, E. ‘Hidden’ factors influencing quality of life in patients with multiple sclerosis. (2015). European Journal of Neurology. 22: O’Gorman, C. & Lucas, R. Environmental Risk Factors for Multiple Sclerosis: A Review with a Focus on Molecular Mechanisms. (2012). International Journal of Molecular Sciences. 13: 11718– Smitth KJ and McDonald WI The pathophysiology of multiple sclerosis: the mechanisms underlying the reduction of symptoms and natural history of the disease. The Royal Society;

Questions?

Study Questions 1.Why is Epstein-Barr virus a possible trigger for MS? A. Epstein-Barr virus has an epitope similar to basic myelin protein activating an immune response against myelin B. Epstein-Barr virus activates B-cells which cause a humoral response that attacks the myelin sheath C. Epstein-Barr virus directly attacks the myelin sheath D. Epstein-Barr virus is attacked by the immune system causing necrosis that damages the myelin sheath 2. How do Beta interferon treatments work to modify progression of MS? (Circle all that apply) A. Acts as a decoy, diverting an autoimmune response against myelin B. Balances the expression of pro and anti—inflammatory agents in the brain C. Reduces the number of inflammatory cells that cross the blood brain barrier D. Binds to the outside of the myelin sheath and acts a barrier to CTL 3. In regards to geographic distribution, where would the highest prevalence rates of MS be found and what is the likely explanation? A. Japan; large fishing market B. Brazil; large amounts of pollution from the water C. Great Britain; low levels of vitamin D D. indigenous people of equatorial Africa; high levels of vitamin D

Study Questions 4. The clear cause of MS remains unknown, though _______ may be important factors? A. Ethnicity, diet, and antibiotic resistance B. Climate, blood pressure, and genetics C. Emotional health, childhood habits, and age D. Environment, viruses, and genetics 5. A. What are two ways the T cells are activated? B. Once activated, how do these immune cells cross the blood brain barrier? C. Explain how resident brain immune cells contribute to the immune attack on myelin