Multiple Sclerosis Flashcards
what is MS?
- a demyelinating disease
- Affects white matter of brain – myelin stripped from nerve axons
- When myelin is damaged, this interferes with messages between the brain and other parts of the body
- For some people, MS is characterised by periods of relapse and remission while for others it has a progressive pattern
- For everyone, it makes life unpredictable
which people are most affected by MS?
Affects young women
- Chronic relapsing-remitting form of disease at first, that progresses to chronic form
what is the incidence of MS?
The most common disabling, neurological condition affecting young adults
- >130,000 people in the UK affected
- Ratio of disease in women and men
- Association with HLA class II MHC
what are the 2 key risks for MS susceptibility?
- Link between HLA type and susceptibility to disease
- Link between sex and susceptibility to disease
For MS, 5x more likely to get if you have HLA-DR2 and are female
why do women have a greater risk of autoimmunity than men?
Women have stronger immune systems
- There is hormonal influence on 158 genes that control the immune system – oestrogen promotes inflammatory responses
- Women have XX chromosomes – many genes controlling inflammation are on the X chromosome
- Second X chromosome is not fully inactivated – women get two shots of inflammation
- Women respond better to infection as they are needed for species survival
is genetics the only risk factor for MS?
- If one twin develops MS, 1/3 chance the other will develop the disease
- genetics isn’t the only factor
- > 100 distinct genetic regions have been identified as being associated with multiple sclerosis through GWAS,
- SNPs make up 1/3 genetic component of MS
how did MS spread across the world?
Looked at ancient genomes from ancestor:
- Epicentre of MS in northern Europe which spread to north America
- Steppe herders migrated and settled in northern Europe, who had genetic predisposition to MS after fighting off a plague-like disease
what are the key clinical brain symptoms of MS?
- CNS inflammation due to demyelination - high water retention in the brain - water disrupts brain tissues
- periventricular lesions
- injection of gadolinium dye into bloodstream of patient before MRI, this shows breakdown of the BBB as the dye can enter the brain - blood vessels have been compromised
- BBB breakdown means immune cells can enter the brain
How do gadolinium-enhancing lesions effect the brain of an MS patient?
Axial T1-weighted scans after injection of Gadolinium, measured on a monthly basis:
- In one patient, lesions show all over the brain
- Every time a lesion happens, there is irreversible damage to nerve axons at that site – builds up to chronic progressive form of disease
- with every lesion, there is loss of nerve axons, so this part of brain is unable to function properly
what is the hallmark pathology of the brain in MS?
Jean Martin Charcot showed fibrotic plaques in brain of MS patient:
- He correlated these plaques to the triad of MS symptoms:
impact on vision, balance and spleech
what is white matter/myelin?
white matter – nerve axons (cell in middle)
- Myelin sheath is affected in MS
- Myelin is one cell that squeezes its membrane together and wraps around axon multiple times
- Fatty myelin sheath wrapped around by oligodendrocyte
- an oligodendrocyte can wrap around numerous axons
what are the distinct patterns of MS disease?
Relapsing-remitting form is most common:
- Difficult to diagnose MS – can look like clinically isolated symptoms so doctors may send away as a one-off incident – if patient comes back with second symptom, a lot of damage by then has been done – need to treat as early as possible
Chronic form:
- build-up of lesions and damage, patients lose ability to function
how are immune cells implicated in MS?
Immune cells cross blood- brain barrier and infiltrate parenchyma
- Immune cells then contribute to demyelination and axon loss
- Activation of myelin-reactive T cells – promote activation of microglia in brain and macrophages entering brain
what is the glia limitans?
a membrane formed by combo of basement membrane tissue and foot processes from astrocytes
- Astrocyte project feet which merge to form glia limitans
- T cell needs to go through blood vessels and glia limitans to enter brain – difficult to infiltrate brain
why is the brain distinct from other tissues?
Brain is unique as it is difficult to enter
- Brain is protected by blood vessels and the glia limitans
Protected from:
- Physical injury by the skull and associated tissues
- Blood-borne pathogens by the blood brain barrier (BBB)
- Cells and antibodies of the immune system by the BBB
what are perivascular cuffs?
around the blood vessel is a collection of lymphocytes and neutrophils
- These inflammatory cells queue up to cross the glia limitans into parenchyma of brain
what is the mouse model of MS?
experimental autoimmune encephalomyelitis mice - EAE pathology identical to human MS patients
can the stipping of myelin be seen in brain?
fatty luxol fast blue stains myelin in brain
- active demyelinating centre can be seen, where myelin is stripped away
what happens if the spinal cord is demyelinated?
Spinal cord carries motor messages to limbs
- if a massive part of spinal cord is demyelinated, motor messages will not reach the limbs
what causes myelin loss in MS?
Myelin loss is due to antibody deposition on sheath, which activates microglia
- Microglia attach to the myelin sheath and strip it away
- Microglia wraps around nerve axon to remove myelin
what immune cells are contained in MS plaques?
Plaques contain macrophages:
- macrophage contains vesicles full of fat
- White encapsulated spots are fat globules in macrophages from myelin
- macrophage strips away myelin, breaks it down and stores the lipids in vesicles
how does the loss of myelin by immune cells affect nerve conduction?
Metabolic change in neuron due to loss of myelin:
- ROS and NOS damage mitochondria and stop ion flow up the nerve axon
- Myelin sheath designed for saltatory conduction – action potential (AP) jumps from node to node
- Loss of myelin means jumping APs cannot occur – slow AP propagation
why does loss of myelin lead to impaired saltatory conduction?
Sodium channels in membrane become over expressed to compensate for slowed AP propagation:
- Causes glutamate accumulation in nerve axon
- Leads to nerve axon dividing = transection of nerve axon
- In the demyelinated region, nerve axon swells and breaks away
- Cut nerve axons which cannot recover
how can transected axons be studied?
Confocal image of axonal changes in active MS lesion
- used non-phosphorylated neurofilament stain - shows nerve axons to see where they have been transected
- can count number of transected axons in different lesions
how abundant are transected axons in MS lesions?
In an active lesion, there are over 11,000 transected axons in a square mm of CNS tissue – loss of function
-As number of active lesions build, there is accumulation of axonal function loss
fMRI shows some synaptic plasticity to allow the brain to recover function – but this doesn’t occur in parts of brain where axons have been lost
what immune cells were discovered in the EAE model to drive MS?
CD4 T cells cause this disease:
- Loss of CD4 from EAE model means the mouse can’t develop MS
Tregs also control this disease
how can CD4 T cells be studied in MS?
Immunise rat with MS antigen, myelin basic protein (MBP)
- MBP-specific CD4 T cells will be generated, which can be isolated
- retrovirally transduce the T cells with GFP
- transfer the MBP-specific CD4 T cells into naive rats
- over time, rats develop MS-like symptoms at day 3 - generation of EAE model
- imaged blood vessels of EAE model: by day 3, millions of cells migrating into the parenchyma of brain, lining up to pass through blood vessel and glia limitans into brain
what are the disease symptoms of the EAE model?
Clinical signs appear d3
Mean EAE grade 1 at d3
Disease peak, grade 3, at d4
Disease resolves d8
what enables leukocytes to enter the brain?
leukocyte emigration and inflammation, driven by selectins and integrins
what integrin controls CNS T cell migration?
The integrin that required for entry into CNS is different to blood vessels around rest of body
- In the body it is LFA1
- In brain it is a4b1 (VLA-4)
- a4b1 can be specifically targeted
how can VLA-4 be specifically targeted to inhibit CNS T cell migration?
- Injection of LFA-1 antibody does nothing as it is body specific
- Injection of VLA-4 antibody (natalizumab) stops leukocytes entering brain
why is natalizumab limited in MS treatment?
Blocking VLA-4 has downsides:
- We need T cells to enter the brain to prevent infection
- so blocking this migration may lead to brain infection
which T cells have been implicated in MS pathology via the EAE model?
Th17 and Th1 cells can promote MS pathology:
- Stimulate cells in vitro with IL-23 – promotes TH17 generation
- Stimulate cells in vitro with IL-12 – promotes Th1 generation
- Transfer these cells into naïve mouse – both TH1 and TH17 cells can cause disease
