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NEUR30002 - Neurophysiology: Neurons and Circuits > Lecture 28: Neuroinflammation and Multiple Sclerosis > Flashcards

Lecture 28: Neuroinflammation and Multiple Sclerosis Flashcards

1
Q

What is multiple sclerosis?

A

demyelinating autoimmune disease of the central nervous system

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2
Q

What is multiple sclerosis characterised by?

A

multiple lesions at multiple sites

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3
Q

What do people with MS develop and why?

A

decreases in brain volume due to significant atrophy of the brain
atrophy is due to demyelination and loss of axons and neurons

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4
Q

What are the symptoms of MS?

A

blurred vision, dysphagia, muscle weakness, muscle spasms, numbness, cognitive changes, incontinence, fatigue, dizziness, vertigo, balance

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5
Q

What do symptoms of multiple sclerosis depend on?

A

the location of lesions

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6
Q

What are the three clinical subtypes of multiple sclerosis?

A 
relapsing remitting (85-90%)
secondary progressive (>80% of RR)
primary progressive (10-15%)
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7
Q

How is multiple sclerosis diagnosed?

A

notoriously difficult to diagnose

previously relied primarily on clinical observations, now use specialised tests and clinical observations

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8
Q

What are the key features of multiple sclerosis?

A

lesions occur in different parts of the CNS (dissemination in space)
lesions accumulate over time (dissemination in time)

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9
Q

What are two main diagnostic tests of multiple sclerosis?

A

MRI and oligoclonal bands in CSF

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10
Q

What are a key pathogenic cell type in multiple sclerosis?

A

T cells

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11
Q

What happens to immune cells that recognise self?

A

they are destroyed or inactivated

however this is error prone and some self-reactive lymphocytes remain -> autoimmunity

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12
Q

What are myelin reactive T cells like in people with MS compared to people without MS?

A

these cells are proinflammatory in people with MS and inactivated / anti inflammatory in people without MS

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13
Q

Why do myelin reactive T cells become active in people with MS and not in people without MS?

A

family studies demonstrate a link between genetics and risk of developing MS

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14
Q

What have genome wide association studies of MS identified?

A

risk loci -> immune related genes

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15
Q

What are the risk factors of multiple sclerosis?

A

no single cause of multiple sclerosis

complex genetic-environmental interactions

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16
Q

Does multiple sclerosis affect both the central and peripheral nervous system?

A

no, only affects the central nervous system

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17
Q

What is the role of cytotoxic T cells?

A

directly interacts with and kills cells e.g. oligodendrocytes

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18
Q

What is the role of helper T cells?

A

direct the response of other immune cells

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19
Q

What is the role of B cells?

A

produce antibodies against “self”

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20
Q

What is the role of antigen presenting cells?

A

activate / reactivate T cells
produce inflammatory mediators
phagocytose myelin

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21
Q

What do T cells initiate in multiple sclerosis?

A

a maladaptive autoimmune response against myelin

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22
Q

What are pathological and protective helper T cell subtypes in multiple sclerosis?

A 
pathological = Th1 and Th17
protective = Th2 and Tregs
23
Q

What is the role of pathological helper T cell subtypes in multiple sclerosis?

A

proinflammatory cytokine release
stimulate macrophages / microglia -> inflammation
recruitment of more inflammatory cells

24
Q

What is the role of protective helper T cell subtypes in multiple sclerosis?

A

anti-inflammatory cytokine release
regulatory macrophages / microglia
tissue repair mechanisms
resolution of inflammation

25
Q

What are lesion types of multiple sclerosis?

A

active lesions, mixed active / inactive lesions and inactive lesions

26
Q

What are characteristics of active MS lesions?

A

early disease, hypercellular, inflammatory infiltration, demyelinating or post-demyelinating, axon loss

27
Q

What are characteristics of mixed active / inactive MS lesions?

A

hypocellular center, demyelinating or post-demyelinating, axon loss, ring of microglia / macrophages at border, slowly expanding

28
Q

What are characteristics of inactive MS lesions?

A

hypocellular, axon loss and glial scar (astrocytes)

29
Q

What occurs in addition to lesions during MS?

A

diffuse injury is seen in the CNS -> brain atrophy

30
Q

What are the features of diffuse global tissue injury?

A

inflammation, microglia activation, mild demyelination and axon loss

31
Q

How is oligodendrocyte death and myelin damage caused in MS?

A

inflammatory cytokines, direct action of cytotoxic T cells and antibody / complement

32
Q

What are the functional consequences of myelin damage?

A

disrupts saltatory conduction leading to slowed AP -> contributes to MS symptoms
axons are more vulnerable to damage

33
Q

What is the role of oligodendrocyte precursor cells?

A

remyelination

lesions can be partially or fully remyelinated (20% are extensively remyelinated)

34
Q

When does remyelination occur and what happens when it fails?

A

occurs early in disease

failure contributes to axon loss

35
Q

Why does failure of remyelination occur?

A

inability of OPCs to proliferate, migrate, differentiate, and myelinate

36
Q

What does axon dysfunction lead to?

A

contribute to MS symptoms and may lead to further axon damage
potentially reversible

37
Q

What causes axon dysfunction?

A

ion channel distribution, inflammatory mediators and mitochondrial dysfunction

38
Q

What does axon and neuron loss cause?

A

long-term disability

permanent damage which is untreatable

39
Q

What causes inhibition of OPC differentiation?

A

inhibitory molecules e.g. myelin debris
inflammation (cytokines)
astrocyte derived compounds
activation of inhibitory receptors on OPCs and oligodendrocytes (e.g. LINGO-1)

40
Q

How effective is interferon beta in treating MS? How is it delivered?

A

reduced relapse rate ~30%

subcutaneous or intermuscular injection

41
Q

How effective is tysabri in treating MS? How is it delivered?

A 
reduced relapse rate ~68%
intravenous injection (monthly)
42
Q

What is the mechanism of action of tysabri?

A

prevents immune cells transiting across BBB

43
Q

How effective is gilenya in treating MS? How is it delivered?

A

reduced relapse rate ~52%

taken orally

44
Q

What is the mechanism of action of gilenya?

A

sphingosine 1-phosphate receptor modulator which prevents immune cells leaving lymphoid organs

45
Q

How effective is ocrevus in treating MS? How is it delivered?

A 
reduced relapse rate ~50%
intravenous injection (6 monthly)
46
Q

What is the mechanism of action of ocrevus?

A

anti-CD20 antibody
B cell depletion
some T cell depletion

47
Q

What is autologous haematopoietic stem cell transplantation?

A

depletion of immune system which is replaced with haematopoietic stem cells (absence of autoreactive lymphocytes)

48
Q

Why are new treatments for MMS needed?

A

current treatments focus only on immune response a`nd new treatments are needed to promote remyelination and neuroprotection

49
Q

What are multiple neurotrophic signalling pathways implicated in?

A

OPC maturation and myelination e.g. IGF-1, BDNF, FGF, PDGF

50
Q

What may be sufficient to promote endogenous remyelination in MS?

A

removal of inhibitors of myelination e.g. myelin debris and LINGO-1

51
Q

Can treatments that generate reparative microglia be a promising strategy for promoting remyelination?

A

yes

52
Q

What are mesenchymal stem cells?

A

progenitor cells found in many tissues which differentiate into multiple cell types

53
Q

What is the role of mesenchymal stem cells?

A

anti-inflammatory and promote tissue repair

54
Q

How might EBV lead to MS?

A

molecular mimicry, B cell transformation or another mechanism

NEUR30002 - Neurophysiology: Neurons and Circuits (36 decks)

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