Multiple Sclerosis Flashcards
When do symptoms of MS usually begin?
between 25-50 years old
MS is a central nervous system disorder. What are the common symptoms of MS?
tingling/numbness
problems with balance
poor muscle co-ordination and weakness
changes in vision
fatigue
slurred speech/stuttering
bladder/bowel problems
MS is more common in people further from the equator. What does this suggest about MS?
decreased sunlight exposure and production of vitamin D plays a role in MS risk
MS has periods of symptoms followed by periods without. What are each of these periods known as?
relapse = symptoms
- new symptoms may appear
- can cause permanent damage
remission = symptoms subside
There are 5 different categories of Ms what are they?
Relapsing remitting (RRMS)/benign MS
Primary progressive (PPMS)
Secondary progressive (SPMS)/galloping MS
Progressive relapsing remitting (PRMS)
What is relapsing remitting MS (RRMS)?
symptoms always resolve between attacks
- unpredictable time periods between relapses
80% of patients in this category
What is primary progressive MS (PPMS)?
no remission symptoms get progressively worse
10% of patients in this category
What is Secondary progressive MS (SPMS)?
initial relapsing-remitting (RRMS) turns into continuous progression
65% of patients diagnosed with RRMS transition to SPMS at some point
What is Progressive relapsing remitting MS (PRMS)?
consists of steady neurological decline with periodic relapses
5% of patients in this category
What is myelin?
lipid rich fatty substance
insulated neuronal axons which allow axon potentials to travel quickly
Why is myelin important in MS?
MS is where the immune system attacks and destroys myelin
- chronic autoimmune disorder which results in a demyelination disease
What is the function of oligodendrocytes?
create and maintains myelin sheath
What happens to oligodendrocytes during MS?
they are destroyed through apoptosis
however, oligodendrocytes are responsible for remission of symptoms as they can repair damaged myelin
What is formed as a consequence of the immune system attacking myelin?
scleroses or plaques/lesions (scars)
- these affect the white matter of the central nervous system (CNS)
Depending on the area of scarring occuring different effects occur. What are these areas and the associated functions altered?
near ventricles of cerebellum
- balance and coordination
brainstem
- autonomic features (breathing, heart etc)
basal ganglia
- memories
spinal cord
- tingling and loss of touch
optic nerve
- optic neuritis which affects vision
The loss of myelin causes impaired nervous system transmission. Why does myelin loss change which affects transmission?
without myelin propagation of the axon potential is lost
- saltatory conduction cannot occur
Impaired nervous transmission lead to neurological symptoms. What are these symptoms?
abnormal sensations
vision problems
weakness
What is the role of T cells in MS?
trigger the immune response against myelin
In MRI scans of patients with MS the affected spots are in white matter areas of the brain. What is the affected regions of the brain that can be seen in MRI images?
ventricles of cerebellum
brain stem
basal ganglia
spinal cord
optic nerve
What is the blood brain barrier?
highly selective semipermeable border which separates the circulating blood from the brain
- highly selective due to tight junctions
usually prevents T cells from getting into the CNS
What happens to the blood brain barrier during MS attacks?
there is a loss/alteration of endothelial cell tight junctions
- therefore leaks occur and substances like T cells can enter the brain
Why do T cells attack myelin once they can enter the brain circulation?
T cells are not usually exposed to myelin due to the BBB
- once BBB is lost or altered T cells come in contact with myelin and detects it as ‘non-self’
Which proteins form the tight junction between endothelial cells of the BBB?
occludin
claudin 3/5
JAM
- these proteins are connected to the cytoskeleton
What occurs after T cells come into contact with myelin to lead to myelin being phagocytosed?
- T cells release cytokines
- cytokines increase BBB permeability allowing the entry of B cells and macrophages
- B cells create antibodies against myelin
- macrophages then phagocytose myelin
What happens to BBB during periods of remission?
BBB can regain its integrity
- allowing periods of remission
but T cells then remain trapped
- which leads to relapse
Macrophages and microglia produce high amounts of ROS and nitric oxide (NO). What substances are susceptible to peroxidation by ROS?
lipids and lipoproteins
In demyelination plaques in brain, plasma and CSF of MS patients an increase in lipid peroxidation products was found. What do oxides lipids cause?
further demyelination and damage to axonal membranes
- oxidised lipids mediate inflammatory processes
creates a positive feedback loop as further demyelination results in more peroxidation
How is Na+/Ca2+ ATP exchanger channels in neurons linked to pathophysiology of MS?
due to higher Na concentration in neurons it needs to get rid of it
- ATP exchanger switches from bringing Na into cell to remove Na
- but this causes Ca to accumulate
Ca2+ triggers mito ROS generation
- causes degradation and apoptosis
Macrophages and microglia cause the production of ROS and NO in MS. How does this affect mitochondria in the neurons?
ROS and NO causes swelling and damage to intra-axonal mitochondria
- neurons will then increase mitochondria content in the area of inflammatory damage
- even with an increase of mito damage is still occurring which leads to more damage occurring.
- this causes a lack of ATP for neuronal cells
How does the high concentration of Ca2+ ions in the neuron associate with mitochondria in the neuron?
high Ca2+ triggers increased mito ROS generation
- ROS destructs lipids in neuronal membranes (degrading the neuron)
- also increases mito permeability allowing cytochrome c to be released = apoptosis occurring
How is MS detected using MRI?
gadolinium can be administered intravenously as a contrast agent which can highlight active plaques by making them bright white spots
- lesions can appear and disappear when remission occurs
How is MS detected through the cerebrospinal fluid?
through a lumbar puncture presence of oligoclonal bands (OCBs) and compare to if they are present in the blood serum.
Why are oligoclonal bands used as a testing marker in cerebrospinal fluid for MS detection?
these bands are not normally found in the nervous system
- these bands are immunoglobulins (IgG) or IgG fragments
- these Abs are against debris cause in MS they themselves are not pathogenic just a secondary effect
this marker is found in 75-85% of MS patients
What particular tests is done to visualize the oligoclonal bands?
protein electrophoresis
What are the two ways to detect MS?
MRI scanning
Lumbar puncture to tests the cerebrospinal fluid
Currently there is no cure for MS but there are treatments to help manage symptoms. What are some of these treatments?
corticosteroids
Interferons
Mayzent (siponimod) Novartis
Stem cells
Corticosteroids are routine therapy for MS patients. What do they achieve for MS patients?
reduced swelling and inflammation in regions of demyelination
How do corticosteroids help the body reduce swelling and inflammation?
stimulates the release of cortisol by adrenal glands to suppress the immune system from attacking myelin
What are the negative factors associated with using corticosteroids?
- they are only effective short term and have not shown impact on long-term recovery
- require a high intravenous dose to be administered which can lead to other side effects
Treatment with interferon beta 1-alpha for MS patients resulted in:
a decreased risk of developing clinical definite MS
What are the proposed mechanisms for interferon beta 1-alpha?
- decreases T cell activation by APC’s
- decreases T cell adhesion and penetration of BBB
3.decreases antigen presentation - promotes anti-inflam cytokine production
- decreases Th1 cytokine release which reduces macrophages coming to the area
- decreases B cell proliferation reducing antibody production against myelin
How does treating MS with interferons benefit the patient?
balances pro and anti inflam agents in brain
- by reducing amount of inflam cells which cross BBB
overall reduced neuronal inflammation
Mayzent (siponimod) novartis has been an effective treatment in phase 3 clinical trials for secondary progressive MS (SPMS) and was FDA approved early 2019. How does this drug work in MS patients and what does it achieve?
sphingosine 1-phosphate (S1P) receptor modulator
- receptor found on lymphocytes (T and B cells)
- bind to them which blocks their migration to the CNS
no lymphocytes in brain = no autoimmune response
There are two types of stem cells.
1. what are they known as?
2. what is the difference in the ability to differentiate?
- adult and embryonic stem cell
- adult = limited capacity to differentiate as they have already differentiated into 1 lineage type (e.g., neural stem cells)
embryonic = pluripotent (can differentiate into any cell type- can divide without differentiating in correct conditions
can turn into which ever cell type is wanted
- can divide without differentiating in correct conditions
Mesenchymal stem cells are a type of adult stem cell. Where are they located? What type of cells do they differentiate into?
- bone marrow
- immune cells (e.g lymphocytes)
In mice experiments what were the findings of using mesenchymal cells for MS symptoms which lead to the technique being used in human trials?
mesenchymal stem cells:
- reduce T cell reactivity to myelin
- inhibit antibodies against myelin
- suppress/ inhibit lymphocyte prolif and modulate activity
Human trails using mesenchymal stem cells for MS have had some positive results. What are these results?
evidence of tissue repair
release hormones/growth factors (e.g. hepatocyte growth factor) which provides re-myelination
Autologous hematopoietic stem cell transplant (AHSCT) has been developed in last 20 years to help treat MS by rebooting the immune system. How is the immune system rebooted?
hematopoietic stem cell harvested from each patient and frozen before patients undergo aggressive chemotherapy to wipe out their immune system.
frozen stem cells are transplanted back into patient creating a new immune system
Why are hematopoietic stem cells used in AHSCT treatment?
hematopoietic stem cells can renew themselves and differentiate to produce cells of the immune system
What were the results of clinic trials with AHSCT treatment?
high risk approach
- 16 free from MS progression
- 7 still had MS activity
- 1 dies from treatment
