1. Multiple Sclerosis
Teresa Kuhns

2. MS is a neurodegenerative AI disease that affects the brain and spinal cord
~250, ,000 affected in U.S.1
6 Characterized by
Demyelination of axons
Oligodendrocytes in CNS
Plaque formation
Motor weakness
Sensory impairments
Above:
Right: Zivadinov R, Bakshi R. Role of Magnetic Resonance Imaging in the Diagnosis and Prognosis of Multiple Sclerosis.

3. Most common symptoms of MS involve decreased motor and sensory functions 2,6
Picture adapted from multiplesclerosis.net

4. Four key types of MS 1,2
Picture from

5. Dominant theory for MS pathogenesis 1
Activation of immune cells
Molecular mimicry
Blood-brain barrier breakdown
Inflammatory response
Resulting myelin degradation
inflammatory cytokines, proteases, free radicals, and nitric acid
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Picture from

6. Viruses such as EBV mimic myelin sheath proteins (e.g. MBP) 1,2
Myelin basic protein (MBP)
Proteolipid protein (PLP)
Many similar molecules
Epstein-Barr Virus (EBV)
Etc.
Picture from
Human MBP: V V H F F K N I V
EBV: V Y H F V K K H V
(from book)

7. The impact of the blood brain barrier breakdown in MS5
BBB – separates CNS from systemic circulation
Junctional proteins affected by inflammation
Leukocyte extravasation
Further breakdown once compromised
Matrix metalloproteinases
ROS
Inflammatory cytokines
Top picture from
Bottom picture from Dr. Spilatro’s “Components of the Immune System” slide

8. Experiments with mice 4
EAE – experimental autoimmune encephalomyelitis
CD4+ T-cell mediated
Mice injected with MBP specific peptide
Develop EAE
T-cells clones isolated & injected into another mouse
Mice expression MBP-specific TCR 1
Under pathogen free conditions = no phenotype
Under non-sterile conditions = mice developed EAE
Picture from

9. Epidemiology 3,2 EBV Vitamin D 6,2 Influences Cigarette smoking
Transcription rate
Apoptosis
Immune cell differentiation
Transmigration via BBB
Amount of pro-inflammatory cytokines like TNF and IL-1
Cigarette smoking
Obesity
Picture from

10. Treatment depends on the type of MS 2
Acute relapses
Corticosteroids
Chronic symptoms
Various medication depending on symptom
Modify course of disease
Immunosuppressant medication
BBB breakdown
2 goals
Slow progression
Improve quality of life
Only temporary solution

11. References
1 Demetriou MD Multiple Sclerosis, Genetics, and Autoimmunity. . In: Olek MJ. Editor. Multiple Sclerosis: Etiology, Diagnosis, and New Treatment Strategies. Totowa (NJ): Humana Press Inc.; p Faguy K Multiple Sclerosis: an update. Radiologic Technology 87(5): Hagan KA, Munger KL, Ascherio A, Grodstein F Epidemiology of Major Neurodegenerative Diseases in Women: Contribution of the Nurses’ Health Study. American Journal of Public Health 106(9): McCarthy DP, Richards MH, Miller SD Mouse Models of Multiple Sclerosis: Experimental autoimmune encephalomyelitis and Theiler’s virus-induced demyelinating disease. Methods of Molecular Biology 900: Ortiz GG, Pacheco-Moises FP, Macias-Islas MA, Flores-Alvarado LJ, Mireles-Ramirez MA, Conzalez- Renovato ED, Hernandez VE, Sanchez-Lopez AL, Alatorre-Jimenez MA Role of the Blood-Brain Barrier in Multiple Sclerosis. Archives of Medical Research 45(8): Sundstrom P, Salzer J Vitamin D and multiple sclerosis – from epidemiology to prevention. Acta Neurologica Scandinavica 132: Van den Noort S Signs and Symptoms of Multiple Sclerosis. In: Olek MJ. Editor. Multiple Sclerosis: Etiology, Diagnosis, and New Treatment Strategies. Totowa (NJ): Humana Press Inc.; p

12. Questions?

13. 1. All of the following may contribute to the blood-brain barrier breakdown, EXCEPT A. Degradation of proteins that form tight junctions between epithelial cells B. Metabolic processes that release peroxides and superoxide C. Changes in gene expression that allows for interaction between leukocytes and epithelial cells D. Activated pericytes releasing metalloproteinases that breakdown astrocytes 2. Which of the following is NOT necessary for the pathogenesis of MS? A. Activation of B-cells and T-cells by the Epstein Barr Virus B. Release of chemokines that propagate inflammatory response C. Breakdown of the separation between CSF and systemic circulation D. Degradation of oligodendrocytes 3. All of the following demonstrate the role of vitamin D in MS, EXCEPT A. Vitamin D helps regulate gene expression B. Vitamin D increases the amount of Treg cells C. An overabundance of vitamin D increases the rate of migration through the blood-brain barrier D. Cytokines like IL-1 and TNF are decreased in the presence of vitamin D 4. Which cell is least likely to contribute to the pathology of MS? A. Oligodendrocytes B. Microglial cells C. CTLs D. Neutrophils

14. 5. MS patients are at risk of acquiring progressive multifocal leukoencephalopathy (PML), a disease caused by the John Cunningham virus (JCV), which many people carry in a latent form. When activated, JCV attacks the brain. A. Why do you think people with MS are at a higher risk for PML than normal individuals with JCV? B. One treatment for MS is Natalizumab, which blocks the function of an integrin that assists cells traversing epithelial layers. However, in 2005, Natalizumab was temporarily withdrawn from the market because it increased the risk of PML when combined with other therapies. C. Looking at the name Natalizumab, what type of immunotherapy is this? D. How might Natalizumab help to control MS, and why might it have increased the risk of acquiring PML?