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Module 3 > MS and Neuroinflammatory disease > Flashcards

MS and Neuroinflammatory disease Flashcards

1
Q

What are the 4 types of MS?

A

benign MS; relapsing and remitting; secondary chronic progressive; primary progressive

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2
Q

In relapsing remitting MS what is a mrker of severity?

A

time between relapses

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3
Q

How is latitude related to risk of MS?

A

MS occurs with much greater frequency in higher latitudes away from the equator

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4
Q

What happens to an individuals risk of MS if they are born in an area of high risk then move to an area of low risk?

A

acquire a risk similar to that of new home IF move happens before adolescence

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5
Q

What ethnic groups is MS more frequent in?

A

Caucasians- especially northern European ancestry

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6
Q

What happens to the MS risk of a Pakistani person who moves to london as a hcild?

A

increases by 20 fold

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7
Q

What is the monozygotic twin concordance rate for MS?

A

30%

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8
Q

What are the environemntal factors thought to be invovled in MS pathogenesis?

A

infection; climate; sunlight; diet; stress

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9
Q

Which HLA is most expressed of hte HLA-II genes?

A

HLA-DR

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10
Q

What HLA allele is the biggest marker of MS risk?

A

HLA-DR15*01

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11
Q

What is the evidence seen in the CSF for immune involvement in MS?

A

oligoclonal immunoglobulin bands

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12
Q

What is the pharmacological evidence for immune involvement in MS?

A

immunsuppression works

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13
Q

What is the genetic evidence for immune involvement in MS?

A

GWAS inficates that multiple immune genes espeically HLA are RFs for MS

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14
Q

What is hte cellular evidence for immune involvement in MS?

A

presence of T cell infiltrates at the site of plaques; disease is mimicked by EAE in which T cells are necessary and sufficient to induce disease

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15
Q

What are autoreactive T cell responses in MS nad EAE seen against?

A

myelin peptides

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16
Q

How is EAE induced in mice?

A

combine spinal cord antigens with a strong adjuvant to induce a T and B cell repsonse

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17
Q

What are the main myelin proteins T cells target in MS?

A

myelin basic protein; proteolipoprotein; myelin oligodendorycte glycoprotein

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18
Q

Which cells target myelin proteins in MS?

A

CD4; CD8 T cells and B cells

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19
Q

What is the MOA of natalizumab?

A

antibody against a4 integrin preventing leukocyte getting though BB and infiltrating the CNS

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20
Q

What other diseases is natalizumba effective in?

A

crohns and UC

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21
Q

What was a main problem with natalizumab?

A

JC virus reactivation and progressive multifocal luekoencephalopthy

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22
Q

Where does the evidence that T cells may be involved in neurodegenerative disorders come from?

A

studies on alteration of T cells subsets in the peripehry of patients during disease

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23
Q

What suggests that T cells may have a role in clearing amyloid b plaques?

A

decline in those responses with ageining adn the absence of those responses in Alzhemiers; as well as in mice

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24
Q

What is the evidence for T cells in Parkinsons?

A

CD4 cells are observed in the substantia nigra

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25
Q

What is the neurodegeneration seen with EBV infection?

A

grey matter atrophy; encephalopathy and acute quadriparesis; anterior horn cell degeneration

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26
Q

What is the evidence for EBV involvement in MS?

A

in severe MS ectopic lymphoid follicles are found with B cells specific for EBV

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27
Q

Is the brain an immune priviledged site?

A

T cells patrol the meninges and secrete cytokines with impact on the brain; T cells can cross the BBB in the contect of trauma or pathology

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28
Q

When may tT cells in the brain be bad for you?

A

in stroke there an overall detrimental role for CNS T cells

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29
Q

When may T cells in the brain be good for you?

A

CNS T cells are protective in traumtic brain injury

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30
Q

Which type of T cell response is typicall beneficial in CNS injury?

A

Th2

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31
Q

What may T cell derived IFNy be beneficial for?

A

regulating neuronal connectivity and development of learning and social behavioural traits

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32
Q

What is seen on gross pathology of brain tissue with MS?

A

multiple sharply demarcatated plaques in the CNS white matter with a prediliction to the optic nerves and white matter tracts of hte periventricular regions; brain stem and psinal cord

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33
Q

What happens to oligodendrocyte numbers in MS plaques?

A

reduced

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34
Q

What are relapses of MS thought to be caused by?

A

the traffic of activated, myelin-reactive T cells into the CNS causing acute inflammation with associated oedema—responds to streoids

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35
Q

What self-limits the acute attacks of MS?

A

Tregs

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36
Q

How many relapsing remitting patietns develop secondary progressive disease?

A

80%

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37
Q

What does the insensitivity to immunotherapy over the disease timecourse suggest about the pathogenesis of MS?

A

there are acute inflammatory events early on with secondary induction of a neurodegenerative process refractory to immunologic interventio

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38
Q

What suggests that primary progressive MS is a very different disease to relapsing remitting?

A

no acute attacks and gradual clinical decline- associated wiht a lakc of response to any form of immunotherapy

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39
Q

What B cell repsonse confrims the role of B cells in MS pathogenesis?

A

there are antimyelin autoantibodes by ElISA in sera and CSF of patients with MS; in MS CNS plaque tissue antimyelin oligodendrocyte natibodes are found

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40
Q

What is a4 integrin also known as?

A

VLA-4

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41
Q

What is epitope spreading found in EAE?

A

injection of single myelin protein epitope into mice, T cells become activated against other epitopes of hte same protein

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42
Q

What does epitope spreading suggest about the tissue damage in the CNS?

A

epitope spreading required costimulation which suggests that the tissue damage creates an adjuvant in the CNS with high express ion of costimulatory moelcules

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43
Q

What suggests that MS is initiated by a microbial infection?

A

high frequency of activated myelin-reactive T cells in the cirulcation and CSF of patients with MS

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44
Q

What determines which cytokines are secreted by the T cell?

A

strength of the signal delvered through the TCR

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45
Q

How does the strength of hte signal through the TCR change the cytokine expression?

A

cell apparently meausres affinity in part by timing hte engagement between TCR and pMHC- with longer engagement a different complex forms with xeta chain phosphorylation increasing

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46
Q

How can the signal strength be manipulated pharmacologically to alter the cytokine expression of a T cell?

A

altered peptide ligands bind with low affinity to the TCR weaken the signal and can change cytokine rpogram from Th1 to Th2

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47
Q

What is a problem with altered peptide ligands?

A

some highly degenerate TCRs can recognise APLs as self-antigens and activate reactive T cells against the patient’s tissues: espeically if given at high doses

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48
Q

How is bet-IFN thought to work in MS?

A

alterations of different pathways including induction of IL-10 and blocking of T cell traffic by blocking metalloproteinases

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49
Q

What is secondary progressive MS characterised by?

A

not immune cell infiltration but by continual irreversible neurological decline, a reduction in brain volume and axonal loss

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50
Q

Why may reducing relapses not halt progressive disease

A

may require direct targeting of neurodegenerative processes occuring independently of immune attacks in later stages

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51
Q

What suggests that immune cells may be helping to drive a seemingly less inflammatory form of the disease?

A

CD20 B cell depleting drug has been reporting to lower rates of clinical and MRI ascertained progression of primary progressive

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52
Q

What are the possible mechanisms by which EBV may promotes MS development?

A

EBV-infected autoreactive B cells in the CNS producing autoantibodies and activating autoreactive T cells- molecular mimicry between EBV and myelin antigens or EBV cells in the periphery or CNS causing bystander activation

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53
Q

Which cells are most prominent in acute MS lesions?

A

macrophages and CD8 T cells

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54
Q

What is the difference between demylination in early relapsing remitting compared with late?

A

demyelination is largely localised to the focal lesions however over time T and B cell infiltration becomes more diffuse, axonal injury is more widespread and there is whtie and grey matter atrophy

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55
Q

What drives the inflammatory processes in the later stages of MS?

A

action of CNS-resident innate microglia ells

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56
Q

what are hte MOA for glatiramer acetate?

A

modulation of APCs, the Th1-Th2 axis and Tregs to inhibit effector function

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57
Q

Why do some patients become refractory to treatment with IFNb and glatiramer acetate?

A

neutralising antibodies

58
Q

What is the MOA of mitoxantrone?

A

inhibits DNA synthesis and repair- reduces lymphocyte numebrs

59
Q

How effective is natalizumab at reducing relaspe rates?

A

annual relapse rate dcrease of around 70%

60
Q

What happens in PML?

A

acute oligodendrocyte destruction

61
Q

What is the MOA of alemtuzumab?

A

binds CD52 expressesed on all leukocytes and promotes depletion of large proportions of T and C cells then leading to reconstitution with cells with a different repertoire

62
Q

what is hte problem with alemtuzumba?

A

30-40% of treated patients develop other AI disoreders

63
Q

What is the efficacy of autologous haematopoietic stem cell transplatation?

A

suppresses MS for 4-5 years in over 70% of patients

64
Q

When is AHSCT primarily beneficial?

A

in young patients with active disease in which irreversible CNS damage has not occurred

65
Q

What is the MOA of daclizumab?

A

antibody against CD25 preventing prolfieration of T cells, increases avaiability of IL2 to NK cells which then exert regulatory effects on T cells

66
Q

What is neurodegeneration?

A

slow and progressive dysfunction and loss of neurons and axons in the CNS

67
Q

what is a common feature of neurodegeneration?

A

chronic immune activation, especially of microglia

68
Q

What is a protective role for the immune response in the CNS?

A

microglia clear debris after myelin damage, if impeded-delayed regeneration occurs; removes necrotic cells; limits neurotropic viral infections

69
Q

What is immune privilege in the CNS?

A

it has developed strategies to limit the entry of immune elements as well as the emergence of immune activation in the tissue itself

70
Q

What is a major difference between peripheral macrophages and microglia?

A

microglia have an opposing role- they limit inflammation

71
Q

What is the function of atrocytes in the immune response?

A

suppress Th1 and Th2 activation, the proliferation and efector functions of activated T cells and can induce apoptosis in activated T cells

72
Q

What role do neurons play in dampening hte immune repsonse?

A

many of the products such as neuropeptides and transmitters as well as neuronal membrane proteins all regulate inflammation; promote T-cell apoptosis through Fas-FasL;

73
Q

How do neurons favour the differentation of Tregs?

A

produce TGFb

74
Q

what happens to neurons once damaged?

A

their ability to maintain the protective sheild is reduced, allowing further insults

75
Q

What suggests a role for TLR2 and TLR4 in neurodegeneration?

A

mice deficient in these TLRs exhibit reduced levels of pro-inflammatory cytokines and milder clinical disease following traumatic brain injury or MCA occlusion

76
Q

Which diseases have increased TLR2 and TLR4?

A

parksinsons; stroke; ALS; increased in amyloid beta plaques in AD

77
Q

How does amyloid beta activate microglia in vitro?

A

TLRs

78
Q

What suggests a role for TLRs in MS

A

mouse knock out of TLR4 are resistent to EAE; TLR9 deficient mice devleop less inflammation less severe clinical disease

79
Q

Why may TLRs play a beneficial role in AD?

A

aid uptake of amyloid beta and other aggregated proteins, promoting clearance from the CNS

80
Q

what family of PRRs are highly expressed in EAE

A

NLRs

81
Q

In which disorders are accelearted accumulation of advanced glycation end-products seen?

A

MS and AD

82
Q

When is the receptor for AGE (RAGE) increased?

A

following oxidative stress; immune/ infalm repsonses

83
Q

What happens when RAGE is engaged?

A

relase of proinflammatory cytokines and free radicals

84
Q

How is RAGE related to MS?

A

expressed on oligodendrocytes and is a predictor of disease severity

85
Q

Why are there attempts to target adenosine receptors in neurodegenerative disorders?

A

assumed to be beneficial in disease by both modulating inflammation and aiding neuroprotection

86
Q

What is foudn in the CSF of SLE patients with neurological involvement?

A

inflamamtory cytokines and matrix metalloproteinases

87
Q

What is seen in the brain disease with SLE?

A

gliosis; axonal death; basal ganglia abnormalities

88
Q

What is the brain dsiease in SLE assocaited with?

A

IgG and C4 deposition of necrotic cells

89
Q

What is the function of C1q and C3 during development in the brain?

A

markers of synapses destined for elimination by microglia-expressing C3 receptors

90
Q

What indicates a broad role for complement in neuronal degeneration?

A

increased C1q and C3 is seen in the CNS with AD; SLE; ALS; huntingtons; MS; PD; cerebral ischaemic injury

91
Q

What shows that there is an anti-inflammatory environment in the CNS making adaptive responses hard?

A

survival of foreign tissues grafts in the CNS

92
Q

why is it apparent that antibodies are produced intrathecally in MS?

A

oligoclonal immunoglobulins are present in CSF not serum

93
Q

why is difficult to implicate T cells directed to myelin or neuronal antigens in the blood as a casative factor in CNS disorders?

A

they are also foudn in the healthy control stubjects

94
Q

In what diseases are alterations in the peripheral levels of CD4 and CD8 t cells seen?

A

AD; ALS; traumatic brain injury

95
Q

What usggests taht neuronal damage in MS may be mediated by CD8 cells?

A

they outnumber CD4 cells and have shown to be in clsoe contact with neurons

96
Q

What is a role for T cells in protection and repair in the CNS?

A

produce neuroprotective factors e.g brain-derived neurotrophic factor

97
Q

When may autoimmune T cells be curcial for repair and regeneration?

A

they have been shown to augment the uptake of myelin by microglia during damage

98
Q

Give an example of a virus which directly kills neurons as a reuslt of viral replciation and cell lysis?

A

poliomyelitis

99
Q

Why is the CNS the ideal environemnt for viral latency?

A

immun-privileged status of hte CNS as well as post-mitotic state of neurons

100
Q

what is the difference between the inside-out and outside-in models of EAE?

A

inside-out: when neuronal damage happens before myelin; whereas outside-in: myelin damaged bfore neurons

101
Q

What mechanisms may neuronal death occur?

A

necrosis; apotosis; autophagy

102
Q

When is necrosis observed in acute brain injury?

A

result of the release of glutamate, nitrix oxide; ROS and clacium

103
Q

What is the dual role of glutamate?

A

plays a major role in brain development, but in excessive quantities induces neuronal death

104
Q

Which neurodegenerative diseases have glutamate excitotoxicity implicated?

A

AD and PD

105
Q

why are proinflammatory cytokines produced by microglia detrimental>

A

not acute detrimental to neurons, and even protectuv, may signal to the bbb recruiting adaptive immune system into the CNS

106
Q

What is MS?

A

most common chronic, inflammatory demyelinating and neurodegenerative disease of the CNS in young adults

107
Q

How is diagnosis of MS made?

A

demonstration of the dissemination of demyelinating lesions to different regions of hte CNS in space and over time

108
Q

What showed that Th1 did not only drive MS?

A

When the p40 subunit was KO there was protection from EAE- thought to prove Th1 mediation, however when p35 subunit was KO, mice got KO, suggesting it could not be Th1, when p19 was KO there was protection—IL-23 was implicated and therefore Th17

109
Q

What may account for the latitudinal gradient seen with MS?

A

distribution of HLA-DRB1 haplotype; environmental e.g low vitamin D levels

110
Q

How has the female to male ratio of MS changed over time?

A

increased from a 2:1 ratio in the 50s to a 3:1 now

111
Q

What does the increase in female to male MS suggest?

A

possible role for environemntal risk factors that mainly affect women: occupation; increased smoking; obesity; birth control and childbirth

112
Q

What are hte most well established environmental risk factors for MS?

A

EBV infection in adolesecnce; tobacco exposure; lac of sun; low vit D and obesity during adolescence

113
Q

What suggests a role for EBV?

A

upto 100% of patients with MS are seropositive; potentially molecular mimicry leading to generation of cross-reactive T cells and antibodies - direct causality has not been established

114
Q

What is the main determinant of vitamin D levels?

A

sun exposure- especially UV-B radiation

115
Q

What genes are implicated in MS?

A

HLA-DRB1; IL2 and IL7R- T cell activation and proliferation; TNF; genes involvedi n vit d metabolism

116
Q

What causes the BBB breakdown in MS?

A

direct effects of pro-inflammatory cytokines and chemokines produced by resident cells and endothelial cells; indirect cytokine-dependent and chemokine leukocyte mediated injury

117
Q

What is the result of the dyregulation of the BBB?

A

increases the trans-endothelial migration of activated leukocytes, including macrophages, T cells and B ells- increased inflammation and demyelination–oligodendrocyte loss, reactive gliosis and neuro-axonal degeneration

118
Q

What are the active demyelinating lesions seen in early relasping remitting assocaited wtih?

A

heavy lymphocyte infiltration- CD8 T cells and CD20 B cells; activated microglia; macropahges; large reactive astrocytes

119
Q

What is seen in the inactive lesions in primary and seoncdary progressive MS?

A

sharply circumscribed, hypocellular with well defined demyelination; reduced axonal density and reactive astrocyte gliosis

120
Q

What is seen in the white matter aside fomr the typical focal lesions in MS?

A

disffuse inflammation (macrophage and lymphocyte infiltration and microglia activation) and neuro-axonal damage

121
Q

Which areas of the brain is extensive cortical demyelination seen particularly in in MS?

A

forebrain and cerebellum

122
Q

What has been suggested as the mechanism of clinical recovery after a relapse and a potential target for future therapies?

A

remyelination

123
Q

What is seen in MS relapses?

A

infiltration of cells of the innate and adaptive immune systems into the CNS parenchyma

124
Q

What is one potential cause of aberrant effector T cell activation in MS?

A

poorly functioning Tregs and resistance of CNS specific effector T cells to Treg regulation

125
Q

What abnormalities in Tregs have been seen in MS?

A

decreased expression of FOXP3

126
Q

What allows the immune cells access to the CNS?

A

after activation in the periphery, immun ecells upregulate cell surface moleucles- chemokine receptors and adhesion molecules which enables efficient tissue infiltration

127
Q

How did a role for B cells in the devleopment of MS relapses become recognised?

A

impressive results of selective B cell targeting therapies in MS; oligoclonal bands in the CNS

128
Q

What suggests an antibody independent role of B cells in MS?

A

reduction in relapse rate with anti-B cell therapies did not change the CSF immunoglobulin profile in patients

129
Q

What is different about B cells in MS patients?

A

abnormal propensity to produce pro-inflammatory cytokines and are deficient in regulatory cytokines e.g IL-10

130
Q

What causes neuronal apoptosis in MS?

A

acute or chronic oxidative stress promoted by innate and adaptive immune cell activation, mitochondrial dysfunction, loss of myelin support, altered glutamate homeostasis ; proinflammatory environment

131
Q

What suggests a role for myelin-reactive T cell in MS?

A

increased frequency, stability and/or pro-inflammatory repsonse profliles of these patients

132
Q

What suggests that the presence of autoreactive T ells is insuggicient to induce disease?

A

most healthy controls ahve autoreactive cells to the same myelin antigens

133
Q

What molecule is EBV thought to miic?

A

myeline basic protein

134
Q

What is the relationship between obesity and MS?

A

2/3 fold increased risk of MS, and negative effect on clinical and MRI outcomes

135
Q

What is ocrelizumab?

A

huamnised anti-CD20

136
Q

What is alemtuzumab?

A

anti-CD52

137
Q

What is the most common autoimmune adverse event assocaited with alemtuzumab?

A

thyroid disease

138
Q

What was the first disease modifying treatment for primary and secondary progressive MS?

A

mitoxantrone

139
Q

What new drug has been shown to work in PPMS and SPMS?

A

anti-CD20 DMTs- espeically in patients with active inflammation

140
Q

What are hte treatments for MS currently under development?

A

S1P inhibitors; antigen-specific therapies; other agnets with potential neuroprotective effects e.g simvastatin; phenytoin; drugs aimed at increasing remyelination- opicinumab

Module 3 (33 decks)

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