Multiple Sclerosis Flashcards
what is multiple sclerosis
most common disease caused by inflammatory demyelinating process in CNS
1 per 1000 people suffer worldwide
what is myelin
fatty sheath (70% fat, 30% protein) generated by cells in CNS called oligodendrocytes which produces it
myelin wraps around axon
insulates axon
how does the brain look in MS
dramatic atrophy in later stages
outline conduction in myelinated and unmyelinated axon
myelinated = electrical impulse jumps across nodes of ranvier (saltatory transmission)
unmyelinated = lose insulation, SLOWS the transmission
how does MS arise
when the axon is unmyelinated and the transmission is slow so you lose the axon and neuron starts dying
but we do have ability to repair neurons
outline the epidemiology of MS
2:1 F:M
age on onset - 30/40 years
europeans and US caucasians are high risk
what are the first symptoms of MS
optic neuritis - inflammation damages the optic nerve
diplopia - double vision
vertigo
micturition - passing of urine
muscle weakness
paraesthesia - pins and needles due to damage to peripheral nerves
why is MS a relapsing remitting disorder
long periods of remission but also very profound presentation
often slow progression to disability
RR forms are most common
what is the other forms of multiple sclerosis , that is less common
relapsing-persisting
2nd progressive - very rare
when diagnosing the eye, how can you tell someone has MS
swollen optic disc
this is a non-invasive method and the eye can tell clinicians a lot about the brain and inflammation
what are the 3 investigations to take when diagnosing MS
MRI
EP (evoked potentials)
CSF (oligoclonal banding)
what would an MS patients MRI show
white dots - lesions
these abnormalities are found in 90% of MS cases
lesions can change from month to month
outline CSF analysis of someone with MS
oligoclonal bands - immunoglobulins
proteins (antibodies) migrating, in patients of MS - tells you there is inflammation in CSF
what do we know about the aetiology of MS
MS is a T-cell mediated inflamamtory demyelinating disease of CNS
irreversible damage is due to axonal loss/harm
dont know the exact aetiology of the disease but it is autoimmune
what do B cells and T cells carry
b cell - immunoglobulins
t cell - t cell antigen receptor
is ms a t cell or b cell disease
t cell mediated disease
recently identified TH17 association because they secrete IL17
what subpopulation of t cells mediate MS
TH17 secrete IL17
what do t cells recognise
only ‘processed’ antigens displayed on MHC of cell surface of antigen presenting cell
what are the two types of MHC (major histocompatibility complex)
MHC I - from any internal (cytosolic) peptide, presented by any cell type
MHC II - from internalised invader (intracellular vacuoles), presented by specialsied immune cell such as macrophage, dendritic cell, B cell
outline the immune synapse
space between T cell and APC is brought together physically by the interaction of trimolecular complex (peptide, MHC and T cell receptor)
MHC II presents , recognised by T cell receptor on outside of CD4+ T cells - glued together by protein expressed
join to CD4/CD8 for recognition
what is the strength of the immune response mediated by
trimolecular complex
on the immune synapse, the 2 plasma membranes also have proteins that mediate the response
protein to protein interaction but also expression of cytokines
what does TCR ligation to APC lead to
initiation of signal transduction pathway
- phosphorylation of PKC
- influx of intracellular Ca2+
- upregulation of DNA binding protiens/txn factors
- T-cell activation and proliferation
what is the immunopathogenesis hypothesis of MS
dysregulation of the immune system by inflammation leading to autoimmune attack on CNS
outline how rodents are used to test the ms hypothesis
EAE model - experimental autoimmune encephalitis
generated by sensitisation/injection of various CNS antigens
proteins found in myelin sheath
useful model
what is molecular mimicry in multiple sclerosis
t cells become activated by molecular mimicry - bits of myelin protein are used to produce T cell response i rodent and this has similarity to common virus/bacteria that would have invaded us before
what does molecular mimicry tell us about t cell activation in multiple sclerosis
similarities in protein structure of myelin sheath with the mimiced molecule - reason activated T cekks recognise myelin sheath in braisn because they think peptide in myelin sheath is one from an invader
outline the pathogenic mechanism of MS
T cekks get through BBB by adhesion into subarachnoid space where it recognises pro-inflammatory concentration gradient of lymphokines, cytokines move along until come across autoimmune antigen
there is lots of APC in the brain
how does activated T cell get across BBB and through tissue?
upon activation, upregulate adhesion molecules (ICAM) allowing them to bind to endothelium
what are the 4 steps to extravasation (leakage)?
- selectin- binds weakly to glycosylated proteins on surface
- T cells roll along until integrin-ICAM interaction
- T cell squeezes through wall (DIAPEDESIS)
- migration through tissue down cytokine gradient
once in the CNS, the T cell must be confronted by autoantigen
which CNS cell acts as the MHC II APC?
macrophages or microglia
cell requires stimulation by proinflammatory cytokines to express MHC II
APCs present autoantigen generated by physiological turnover
T cells reactivated to generate more pro-inflammatory cytokines
what did EAE models show in MS?
EAE rodents showed many myelin proteins can be autoantigenic
led to idea of determinant spreading
what is determinant spreading
present small antigen from different part of myelin protein
body fights this
recognises it is SELF
further along, there is another peptide of same protein or another one in myelin sheath - now recognised again as foreign - disease relapse
outline t cell mediated demyelination
in EAE injection of activated T cells alone leads to inflammation
adding anti-MOG monoclonal promotes demyeln.
autoantibodies activate complement - attract macrophage/microglia, they then strip myelin from axons and generate ROIs - secrete TNF-alpha and protein-degrading enzymes
IL-3 promotes macrophage recruitment and demyelination
why are axons lost in MS?
scientists dont know
outline what happens in the 2nd progressive form of MS?
cant remyelinate neurons anymore
endogenous oligodendrocyte precursor cells (OPC) are activated - they make mature olgiodendrocytes
normally, when lesions are fixed, OPC is attracted to lesion, activated to mature and they generate new myelin
but in 2nd - this stops working
what are some possible reaosnf as to why remyelination eventually fails in some patients?
- depletion of OPCs in MS plaques
- inhibition of OPCs migration
- reduced OPC differentation
why do we think OPCs fail to differentiate/mature?
inhibition of activators or loss of activators
chronic lesions show limited inflammation in comparison to acute lesions, which are more readily repaired
what is one target for potential MS immunotherapy?
decrease proinflammatory signals (downregulate IFN-gamma, TNFalpha) - but selectivity problems
interferon beta downregulates synthesis of MHC II proteins - this increases remission period but doesnt cure disorder, expensive, downplays inflammatory signals recieved but makes you suscpetible to other invaders
what is the new research surrounding alphaB-crystallin
low levels in brain, major lens protein of eye
major protein in early MS lesions
it is a negative regulator of inflammatory signalling cascade
becomes immunogenic on MS progression
so much protein around the lesion that it seems the protein itself becomes target for immune system
what infection do all people with MS have?
epstein barr virus infection
2023 study identified there may be mimicry between EBNA-1 and alpha-Bcrystallin
maybe determinant spreading?
when administering statins (anti-cholesterol drugs) to EAE there is an anti-inflammatory response - why?
reprogramme CD4+ T cells not to secrete pro-inflammatory signals but anti-inflammatory (immunomodulatory)
block HMG-CoA reductase (essential for cholesterol synthesis)
inhibits expression of CIITA and therefore MHC II
also partially block LFA-1 - protein involved in co-stimulation and extravasation
outline the interest in research of using neuronal precursor cells
IPSC and MSC derived neural progenitors also very promising
to replace the loss of neurons in brain of individuals
what do other trials suggest to replace the lost neuronal cells in brains of MS patients
stem cells
- mature and differentiate to replace lost ones
