Multiple Sclerosis

Question 1

what is multiple sclerosis

Answer 1

most common disease caused by inflammatory demyelinating process in CNS
1 per 1000 people suffer worldwide

Question 2

what is myelin

Answer 2

fatty sheath (70% fat, 30% protein) generated by cells in CNS called oligodendrocytes which produces it
myelin wraps around axon
insulates axon

Question 3

how does the brain look in MS

Answer 3

dramatic atrophy in later stages

Question 4

outline conduction in myelinated and unmyelinated axon

Answer 4

myelinated = electrical impulse jumps across nodes of ranvier (saltatory transmission)
unmyelinated = lose insulation, SLOWS the transmission

Question 5

how does MS arise

Answer 5

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

Question 6

outline the epidemiology of MS

Answer 6

2:1 F:M
age on onset - 30/40 years
europeans and US caucasians are high risk

Question 7

what are the first symptoms of MS

Answer 7

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

Question 8

why is MS a relapsing remitting disorder

Answer 8

long periods of remission but also very profound presentation
often slow progression to disability
RR forms are most common

Question 9

what is the other forms of multiple sclerosis , that is less common

Answer 9

relapsing-persisting
2nd progressive - very rare

Question 10

when diagnosing the eye, how can you tell someone has MS

Answer 10

swollen optic disc
this is a non-invasive method and the eye can tell clinicians a lot about the brain and inflammation

Question 11

what are the 3 investigations to take when diagnosing MS

Answer 11

MRI
EP (evoked potentials)
CSF (oligoclonal banding)

Question 12

what would an MS patients MRI show

Answer 12

white dots - lesions
these abnormalities are found in 90% of MS cases
lesions can change from month to month

Question 13

outline CSF analysis of someone with MS

Answer 13

oligoclonal bands - immunoglobulins
proteins (antibodies) migrating, in patients of MS - tells you there is inflammation in CSF

Question 14

what do we know about the aetiology of MS

Answer 14

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

Question 15

what do B cells and T cells carry

Answer 15

b cell - immunoglobulins
t cell - t cell antigen receptor

Question 16

is ms a t cell or b cell disease

Answer 16

t cell mediated disease
recently identified TH17 association because they secrete IL17

Question 17

what subpopulation of t cells mediate MS

Answer 17

TH17 secrete IL17

Question 18

what do t cells recognise

Answer 18

only ‘processed’ antigens displayed on MHC of cell surface of antigen presenting cell

Question 19

what are the two types of MHC (major histocompatibility complex)

Answer 19

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

Question 20

outline the immune synapse

Answer 20

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

Question 21

what is the strength of the immune response mediated by

Answer 21

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

Question 22

what does TCR ligation to APC lead to

Answer 22

initiation of signal transduction pathway
- phosphorylation of PKC
- influx of intracellular Ca2+
- upregulation of DNA binding protiens/txn factors
- T-cell activation and proliferation

Question 23

what is the immunopathogenesis hypothesis of MS

Answer 23

dysregulation of the immune system by inflammation leading to autoimmune attack on CNS

Question 24

outline how rodents are used to test the ms hypothesis

Answer 24

EAE model - experimental autoimmune encephalitis
generated by sensitisation/injection of various CNS antigens
proteins found in myelin sheath
useful model

Question 25

what is molecular mimicry in multiple sclerosis

Answer 25

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

Question 26

what does molecular mimicry tell us about t cell activation in multiple sclerosis

Answer 26

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

Question 27

outline the pathogenic mechanism of MS

Answer 27

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

Question 28

how does activated T cell get across BBB and through tissue?

Answer 28

upon activation, upregulate adhesion molecules (ICAM) allowing them to bind to endothelium

Question 29

what are the 4 steps to extravasation (leakage)?

Answer 29

1. selectin- binds weakly to glycosylated proteins on surface 2. - T cells roll along until integrin-ICAM interaction 3. T cell squeezes through wall (DIAPEDESIS) 4. migration through tissue down cytokine gradient

Question 30

once in the CNS, the T cell must be confronted by autoantigen which CNS cell acts as the MHC II APC?

Answer 30

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

Question 31

what did EAE models show in MS?

Answer 31

EAE rodents showed many myelin proteins can be autoantigenic led to idea of determinant spreading

Question 32

what is determinant spreading

Answer 32

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

Question 33

outline t cell mediated demyelination

Answer 33

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

Question 34

why are axons lost in MS?

Answer 34

scientists dont know

Question 35

outline what happens in the 2nd progressive form of MS?

Answer 35

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

Question 36

what are some possible reaosnf as to why remyelination eventually fails in some patients?

Answer 36

1. depletion of OPCs in MS plaques 2. inhibition of OPCs migration 3. reduced OPC differentation

Question 37

why do we think OPCs fail to differentiate/mature?

Answer 37

inhibition of activators or loss of activators chronic lesions show limited inflammation in comparison to acute lesions, which are more readily repaired

Question 38

what is one target for potential MS immunotherapy?

Answer 38

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

Question 39

what is the new research surrounding alphaB-crystallin

Answer 39

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

Question 40

what infection do all people with MS have?

Answer 40

epstein barr virus infection 2023 study identified there may be mimicry between EBNA-1 and alpha-Bcrystallin maybe determinant spreading?

Question 41

when administering statins (anti-cholesterol drugs) to EAE there is an anti-inflammatory response - why?

Answer 41

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

Question 42

outline the interest in research of using neuronal precursor cells

Answer 42

IPSC and MSC derived neural progenitors also very promising to replace the loss of neurons in brain of individuals

Question 43

what do other trials suggest to replace the lost neuronal cells in brains of MS patients

Answer 43

stem cells - mature and differentiate to replace lost ones