Lecture 28: Neuroinflammation and Multiple Sclerosis Flashcards
What is multiple sclerosis?
demyelinating autoimmune disease of the central nervous system
What is multiple sclerosis characterised by?
multiple lesions at multiple sites
What do people with MS develop and why?
decreases in brain volume due to significant atrophy of the brain
atrophy is due to demyelination and loss of axons and neurons
What are the symptoms of MS?
blurred vision, dysphagia, muscle weakness, muscle spasms, numbness, cognitive changes, incontinence, fatigue, dizziness, vertigo, balance
What do symptoms of multiple sclerosis depend on?
the location of lesions
What are the three clinical subtypes of multiple sclerosis?
relapsing remitting (85-90%) secondary progressive (>80% of RR) primary progressive (10-15%)
How is multiple sclerosis diagnosed?
notoriously difficult to diagnose
previously relied primarily on clinical observations, now use specialised tests and clinical observations
What are the key features of multiple sclerosis?
lesions occur in different parts of the CNS (dissemination in space)
lesions accumulate over time (dissemination in time)
What are two main diagnostic tests of multiple sclerosis?
MRI and oligoclonal bands in CSF
What are a key pathogenic cell type in multiple sclerosis?
T cells
What happens to immune cells that recognise self?
they are destroyed or inactivated
however this is error prone and some self-reactive lymphocytes remain -> autoimmunity
What are myelin reactive T cells like in people with MS compared to people without MS?
these cells are proinflammatory in people with MS and inactivated / anti inflammatory in people without MS
Why do myelin reactive T cells become active in people with MS and not in people without MS?
family studies demonstrate a link between genetics and risk of developing MS
What have genome wide association studies of MS identified?
risk loci -> immune related genes
What are the risk factors of multiple sclerosis?
no single cause of multiple sclerosis
complex genetic-environmental interactions
Does multiple sclerosis affect both the central and peripheral nervous system?
no, only affects the central nervous system
What is the role of cytotoxic T cells?
directly interacts with and kills cells e.g. oligodendrocytes
What is the role of helper T cells?
direct the response of other immune cells
What is the role of B cells?
produce antibodies against “self”
What is the role of antigen presenting cells?
activate / reactivate T cells
produce inflammatory mediators
phagocytose myelin
What do T cells initiate in multiple sclerosis?
a maladaptive autoimmune response against myelin
What are pathological and protective helper T cell subtypes in multiple sclerosis?
pathological = Th1 and Th17 protective = Th2 and Tregs
What is the role of pathological helper T cell subtypes in multiple sclerosis?
proinflammatory cytokine release
stimulate macrophages / microglia -> inflammation
recruitment of more inflammatory cells
What is the role of protective helper T cell subtypes in multiple sclerosis?
anti-inflammatory cytokine release
regulatory macrophages / microglia
tissue repair mechanisms
resolution of inflammation
What are lesion types of multiple sclerosis?
active lesions, mixed active / inactive lesions and inactive lesions
What are characteristics of active MS lesions?
early disease, hypercellular, inflammatory infiltration, demyelinating or post-demyelinating, axon loss
What are characteristics of mixed active / inactive MS lesions?
hypocellular center, demyelinating or post-demyelinating, axon loss, ring of microglia / macrophages at border, slowly expanding
What are characteristics of inactive MS lesions?
hypocellular, axon loss and glial scar (astrocytes)
What occurs in addition to lesions during MS?
diffuse injury is seen in the CNS -> brain atrophy
What are the features of diffuse global tissue injury?
inflammation, microglia activation, mild demyelination and axon loss
How is oligodendrocyte death and myelin damage caused in MS?
inflammatory cytokines, direct action of cytotoxic T cells and antibody / complement
What are the functional consequences of myelin damage?
disrupts saltatory conduction leading to slowed AP -> contributes to MS symptoms
axons are more vulnerable to damage
What is the role of oligodendrocyte precursor cells?
remyelination
lesions can be partially or fully remyelinated (20% are extensively remyelinated)
When does remyelination occur and what happens when it fails?
occurs early in disease
failure contributes to axon loss
Why does failure of remyelination occur?
inability of OPCs to proliferate, migrate, differentiate, and myelinate
What does axon dysfunction lead to?
contribute to MS symptoms and may lead to further axon damage
potentially reversible
What causes axon dysfunction?
ion channel distribution, inflammatory mediators and mitochondrial dysfunction
What does axon and neuron loss cause?
long-term disability
permanent damage which is untreatable
What causes inhibition of OPC differentiation?
inhibitory molecules e.g. myelin debris
inflammation (cytokines)
astrocyte derived compounds
activation of inhibitory receptors on OPCs and oligodendrocytes (e.g. LINGO-1)
How effective is interferon beta in treating MS? How is it delivered?
reduced relapse rate ~30%
subcutaneous or intermuscular injection
How effective is tysabri in treating MS? How is it delivered?
reduced relapse rate ~68% intravenous injection (monthly)
What is the mechanism of action of tysabri?
prevents immune cells transiting across BBB
How effective is gilenya in treating MS? How is it delivered?
reduced relapse rate ~52%
taken orally
What is the mechanism of action of gilenya?
sphingosine 1-phosphate receptor modulator which prevents immune cells leaving lymphoid organs
How effective is ocrevus in treating MS? How is it delivered?
reduced relapse rate ~50% intravenous injection (6 monthly)
What is the mechanism of action of ocrevus?
anti-CD20 antibody
B cell depletion
some T cell depletion
What is autologous haematopoietic stem cell transplantation?
depletion of immune system which is replaced with haematopoietic stem cells (absence of autoreactive lymphocytes)
Why are new treatments for MMS needed?
current treatments focus only on immune response a`nd new treatments are needed to promote remyelination and neuroprotection
What are multiple neurotrophic signalling pathways implicated in?
OPC maturation and myelination e.g. IGF-1, BDNF, FGF, PDGF
What may be sufficient to promote endogenous remyelination in MS?
removal of inhibitors of myelination e.g. myelin debris and LINGO-1
Can treatments that generate reparative microglia be a promising strategy for promoting remyelination?
yes
What are mesenchymal stem cells?
progenitor cells found in many tissues which differentiate into multiple cell types
What is the role of mesenchymal stem cells?
anti-inflammatory and promote tissue repair
How might EBV lead to MS?
molecular mimicry, B cell transformation or another mechanism
