Download Multiple Sclerosis

MULTIPLE
SCLEROSIS
Teresa Kuhns
MS is a neurodegenerative AI disease that
affects the brain and spinal cord
■ ~250,000- 350,000 affected in
U.S.1
■
6 Characterized
by
– Demyelination of axons
■
Above:
http://smccrx.com/newsite/multiplesclerosis/
Right: Zivadinov R, Bakshi R. Role of
Magnetic Resonance Imaging in the
Diagnosis and Prognosis of Multiple
Sclerosis.
Oligodendrocytes in CNS
– Plaque formation
– Motor weakness
– Sensory impairments
Most common symptoms of MS involve
decreased motor and sensory functions 2,6
Picture adapted from multiplesclerosis.net
Four key types of MS 1,2
Picture from http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/neurology/multiple_sclerosis/
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
https://www.youtube.com/watch?v=K
8R5N7ZMlNk
Picture from
http://www.medscape.com
/viewarticle/771891_2
Viruses such as EBV mimic myelin
sheath proteins (e.g. MBP) 1,2
■ Myelin sheath proteins
– Myelin basic protein (MBP)
– Proteolipid protein (PLP)
■ Many similar molecules
– Epstein-Barr Virus (EBV)
– Etc.
Human MBP:
EBV:
VVHFFKNI V
VYHFVKKHV
(from book)
Picture from
http://www.pnas.org/content/10
6/9/3154/F1.expansion.html
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 http://antranik.org/review-of-the-nervous-system/
Bottom picture from Dr. Spilatro’s “Components of the Immune
System” slide
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
– Develop EAE
■ Mice expression MBP-specific TCR 1
– Under pathogen free conditions = no
phenotype
– Under non-sterile conditions = mice
developed EAE
Picture from
http://www.jci.org/articles/view/37079/figure/1
Epidemiology 3,2
■ EBV
■ Vitamin D 6,2
– Influences
■
■
■
■
■
Transcription rate
Apoptosis
Immune cell differentiation
Transmigration via BBB
Amount of pro-inflammatory
cytokines like TNF and IL-1
■ Cigarette smoking
■ Obesity
Picture from
https://www.eemec.med.ed.ac.uk/wi
ki/wikinode.asp?id=11744&wiki=983
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
References
Demetriou MD. 2005. Multiple Sclerosis, Genetics, and Autoimmunity. . In: Olek MJ. Editor. Multiple
Sclerosis: Etiology, Diagnosis, and New Treatment Strategies. Totowa (NJ): Humana Press Inc.; p. 103112.
1
2 Faguy
K. 2016. Multiple Sclerosis: an update. Radiologic Technology 87(5): 529-550.
Hagan KA, Munger KL, Ascherio A, Grodstein F. 2016. Epidemiology of Major Neurodegenerative
Diseases in Women: Contribution of the Nurses’ Health Study. American Journal of Public Health
106(9): 1650-1655.
3
4 McCarthy
DP, Richards MH, Miller SD. 2012. Mouse Models of Multiple Sclerosis: Experimental
autoimmune encephalomyelitis and Theiler’s virus-induced demyelinating disease. Methods of
Molecular Biology 900: 381-401.
Ortiz GG, Pacheco-Moises FP, Macias-Islas MA, Flores-Alvarado LJ, Mireles-Ramirez MA, ConzalezRenovato ED, Hernandez VE, Sanchez-Lopez AL, Alatorre-Jimenez MA. 2014. Role of the Blood-Brain
Barrier in Multiple Sclerosis. Archives of Medical Research 45(8): 687-697.
5
Sundstrom P, Salzer J. 2015. Vitamin D and multiple sclerosis – from epidemiology to prevention. Acta
Neurologica Scandinavica 132: 56-61.
6
Van den Noort S. 2005. Signs and Symptoms of Multiple Sclerosis. In: Olek MJ. Editor. Multiple
Sclerosis: Etiology, Diagnosis, and New Treatment Strategies. Totowa (NJ): Humana Press Inc.; p. 1-14.
7
QUESTIONS?
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
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?