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I&I WC2 > Immune disease of the central nervous system > Flashcards

Immune disease of the central nervous system Flashcards

1
Q

What is the timespan in which auto-immune encephalitis patients develop symptoms?

A

Days to weeks

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2
Q

What is the main symptom of auto-immune encephalitis?

A

Cerebellar degeneration

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3
Q

What is auto-immune encephalitis often associated with?

A

Tumours elsewhere in the body (can lead to discovery of the tumour)

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4
Q

Which antibody is associated with auto-immune encephalitis?

A

Yo-antibodies

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5
Q

What is the target of Yo-antibodies in auto-immune encephalitis? Where is this antigen present?

A

CDR2L = intracellular antigen

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6
Q

Are Yo-antibodies the causative antibodies of auto-immune encephalitis?

A

No, they are disease-associated, but they don’t cause disease when passively transferred

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7
Q

What is meant with ‘passive transfer of auto-immune disease’?

A

Transferring auto-antibodies or autoreactive T-cells to a non-diseased individual and seeing whether that causes disease

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8
Q

What is meant with ‘active transfer of auto-immune disease?

A

Injecting the causative antigen and seeing whether the immunized individual has an auto-immune response

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9
Q

What is reduction of Yo-antibody titre in auto-immune encephalitis correlated with?

A

Reduction in clinical symptoms

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10
Q

What is the role of Yo-antibodies in the diagnostics of auto-immune encephalitis?

A

While this antibody is not causative, it is frequently present -> can be measured to diagnose disease & track treatment success

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11
Q

What are the causative antibodies of (most) auto-immune encephalitis?

A

Anti-NMDA-R antibodies

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12
Q

True or false: auto-immune encephalitis is a group of diseases

A

True: various causative mechanisms and presentations

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13
Q

Which two groups of auto-immune encephalitis (AIE) can be distinguished?

A
  1. AIE with intracellular antibody targets
  2. AIE with surface/synaptic targets
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14
Q

What is the immunological mechanism of most auto-immune encephalites with intracellular targets?

A

T-cell mediated response

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15
Q

What is auto-immune encephalitis with intracellular targets often associated with?

A

Often cancer-associated

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16
Q

What are possible targets of auto-immune encephalitis with intracellular targets? (5)

A
  1. HHuD
  2. Yo
  3. RRi
  4. CRMP5
  5. Ma2
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17
Q

In which age group does auto-immune encephalitis with intracellular targets frequently occur? Why?

A

Older patients -> this disease is cancer-associated, cancer occurs more frequently in older people

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18
Q

What is the immunological mechanism of most auto-immune encephalites with surface/synaptic targets?

A

Mostly antibody-mediated

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19
Q

What is the functional effect of antibodies in auto-immune encephalitis?

A

They can interfere with cell surface receptor signalling

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20
Q

What is the advantage of auto-immune encephalitis with surface/synaptic antigens?

A

Can be effectively treated by removing antibodies

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21
Q

What are possible targets of auto-immune encephalitis with surface/synaptic targets? (5)

A
  1. NMDA-R
  2. AMPA-R
  3. GABA(B)
  4. LGI1
  5. Caspr2
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22
Q

What is the median age of anti-NMDA receptor encephalitis?

A

19 years (37% = <18)

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23
Q

Which biological sex is mostly affected by NMDA-receptor encephalitis? How many % of patients has this sex?

A

Female, 81%

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24
Q

How many % of anti-NMDA-R encephalitis is tumour-associated? Which tumor does this most frequently concern?

A

39%
96% of tumour-associated cases is associated with teratoma

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25
Why are teratomas especially capable of triggering anti-NMDA-R immune responses?
Neuronal tissue expressing NMDA-R in a non-immunologically privileged site can trigger anti-NMA-R immune responses
26
What are the stages of anti-NMDA-R encephalitis? (3)
1. Prodromal stage 2. Initial stage 3. Comatous stage
27
What are symptoms of the prodromal phase of anti-NMDA-R encephalitis?
Viral-like
28
What are symptoms of the initial stage of anti-NDMA-R encephalitis? (7)
1. Agitation 2. Psychosis 3. Catatonia 4. Speech reduction 5. Memory deficits 6. Abnormal movements 7. Seizures
29
What are symptoms of the comatous stage of anti-NDMA-R encephalitis? (3)
1. Coma 2. Hypoventilation 3. Dysautonomia
30
How many patients of anti-NMDA-R encephalitis require ICU admission?
75%
31
What is the mechanistical explanation of the symptoms in anti-NMDA-R encephalitis?
NMDA-R is essential for feedback loops between excitatory (NMDA) & inhibitory (GABA) neurons Normal situation: balance exchange between these neurons: excitation by glutamate triggers NMDA-R -> causes inhibition that breaks excitation -> controlled movement Blocking/inhibition of NMDA-R: no activation of inhibition -> too much excitation -> disinhibited behaviour
32
Which lobes are particularly active in anti-NMDA-R encephalitis?
Frontal & temporal lobes
33
What are possible triggers of breakdown of tolerance against the NMDA-R? (2)
1. Teratoma expressing neuronal tissue 2. Viral infection (HSV)
34
Where are plasmablasts that produce anti-NMDA-R antibodies located?
In the meninges -> production of antibodies within the CNS
35
What are the possible effects of anti-NMDA-R antibodies? (4)
1. Agonistic or antagonistic effects on receptors 2. Blocking of ligand interaction with receptor 3. Antigenic modulation -> receptors internalized after antibody binding 4. Cytotoxicity -> neurons damaged by presence of antibodies
36
Which effects of anti-NMDA-R antibodies have been observed in encephalitis? (2)
1. Direct activation of NMDA-R 2. Internalization of NMDA-Rs
37
How do antibodies cause direct NMDA-R activation? Why is this an unsatisfactory explanation of anti-NMDA-R encephalitis?
Antibodies bind to NMDA-R when it is in open confirmation, preventing closing of the NMDA-R calcium channel, causing permanent calcium influx Unsatisfactory explanation: the symptoms are more consistent with underactivation than with hyperactivation of the NMDA-R
38
How can anti-NMDA-R antibodies cause NMDA-R internalization?
Disruption of the interaction between the NMDA-R and its anchor protein EphB2
39
True or false: complement plays a role in cytotoxicity in anti-NMDA-R encephalitis
False; complement is not involved in brain lesion formation
40
Which factors negatively affect outcomes in anti-NMDA-R encephalitis? (2)
1. Severe disease 2. Long treatment delay
41
What is the recovery time of anti-NMDA-R encephalitis?
Years
42
How many % of anti-NMDA-R encephalitis patients recover without symptoms?
~45%
43
What is the first line treatment of anti-NMDA-R encephalitis?
Steroids + IVIG/plasma exchange
44
What are possible second line treatments of anti-NMDA-R encephalitis? (4)
1. Rituximab 2. Cyclophosphamide 3. Bortezomib 4. Tocilizumab
45
Why is IVIG not always effective as a treatment of auto-immune encephalitis?
IVIG does reduce the amount of circulating auto-antibody, but does not remove antibody & antibody-producing B-cells from the brain
46
When does post-infectious herpes simplex auto-immune encephalitis occur?
~4 weeks after prior herpes simplex encephalitis (HSE)
47
HSV-encephalitis (HSE) [does/does not] respond to antiviral therapy
HSE does respond to antiviral therapy
48
How can HSV-encephalitis be differentiated from post-infectious herpes simplex auto-immune encephalitis? (3)
1. HSE = HSV PCR+, auto-immune = HSV PCR- 2. HSE = new MRI abnormalities, auto-immune = no new MRI abnormalities 3. HSE = response to antiviral therapy, auto-immune = no response to antiviral treatment
49
What is the mechanism of post-infectious herpes simplex auto-immune encephalitis?
Formation of anti-NMDA-R auto-antibodies during herpes simplex encephalitis
50
Which three processes form the triad of MS pathology?
1. Inflammation 2. Demyelination 3. Axonal degeneration
51
Is demyelination in MS reversible?
Yes -> relapsing remitting MS
52
Is axonal degeneration in MS reversible?
No -> progressive MS
53
What are the two main risk factors correlated with MS?
1. Genetic predispositon 2. EBV
54
How is MS progression usually tracked?
Tracking white matter lesions with MRI
55
How can post-mortem pathology show white matter loss? (2)
1. Staining for myelin 2. Staining for myelin markers MAG or MOG
56
Which three routes could the causative cells of MS take into the brain?
1. CSF-blood barrier 2. Meninges 3. Glia limitans
57
Which cells form the blood-brain barrier? Which cells form the blood-CSF barrier?
Blood-brain = endothelial cells Blood-CSF = epithelial cells
58
What enables immune cells in MS to enter the brain?
Expression of specific chemokine receptors & adhesion molecules
59
What is an important chemokine receptor involved in MS? On which cell type is it present?
CCR6 on T-cells
60
What is a signature cytokine of T-cells involved in MS?
IL-17
61
Which T-cell subsets can be found in MS? (4)
1. Th17 2. Th17.1 3. Th22 4. DP
62
What is an important integrin receptor that T-cells use to enter the brain in MS?
VLA-4
63
What is VLA-4?
Integrin receptor, used by T-cells to migrate into the brain in MS
64
Why is understanding the role of VLA-4 in MS pathogenesis useful?
It can be blocked to prevent T-cell entry into the brain
65
Which drug blocks VLA-4, preventing T-cell entry into the brain?
Natalizumab
66
What is the effect on T-cells in the meninges vs. in the blood when VLA-4 is blocked by natalizumab in MS patients?
Meninges: lowering of T-cells Blood: T-cells accumulate in circulation
67
Which cells especially accumulate in circulation when VLA-4 in MS patients blocks T-cell entry into the brain?
Th17.1 cells
68
How can the amount of Th17.1 accumulation in circulation after VLA-4 blockage by natalizumab in MS patients be predictive of further disease?
Higher Th17.1 accumulation in circulation = more likely to be relapse-free Lower Th17.1 accumulation in circulation = more likely to relapse
69
How could functional impairment of Tregs lead to MS? Which syndrome functions as a model for this hypothesis?
Functional impairment of Tregs could lead to a lower threshold of activation of Th17.1 cells IPEX syndrome is a defect in FoxP3 = no Tregs. In this syndrome, there is a clearly impaired control of Th17.1 cells
70
What is the current official working definition of MS?
Cell-mediated auto-immune disease, caused by environmental factors and chance in a genetically susceptible individual
71
Which environmental factors have been linked to MS? (4)
1. Vitamin D/sunlight shortage 2. Infections (specifically: EBV) 3. Smoking 4. Toxins
72
In which way is sunlight exposure/vitamin D linked to MS? (2)
1. MS tends to occur in higher frequency in countries with lower sunlight exposure 2. Lower vitamin D levels lead to increased MS risk
73
MS risk in people that migrate from sunny regions to less sunny regions [stays low/increases]
MS risk increases when people move to less sunny regions
74
What is the role of vitamin D in MS pathogenesis?
Unclear; working hypothesis: disruption of T- and B-cell function in individuals with genetic susceptibility
75
Trials with vitamin D for the treatment of MS [showed a decrease in MS flares/failed to show a decrease in MS flares]
Failed to show a decrease in MS flares
76
What are possible reasons vitamin D trials in MS were not successful? (2)
1. Wrong kind of vitamin D 2. Vitamin D does not effectively reach the right parts of the body
77
Vitamin D is part of a hormone family. Which other hormones are part of this family? (3)
1. Sex hormones 2. Glucocorticoids 3. Steroids
78
Which changes in the hormone family of vitamin D have also been observed in MS patients? (2)
1. Lower sensitivity to glucocorticoids, especially for Th17.1 cells 2. Vitamin D seems to increase corticoid sensitivity of Th17.1 cells
79
Which infection is especially linked to MS?
EBV
80
Which types of genetic factors are associated with MS? (2)
1. SNPs 2. Copy number variations (CNVs)
81
SNPs in which gene are especially known to be a major risk factor for MS? What is the mechanistic explanation for this?
HLA II; SNPs in this gene could alter the way MS-related peptides are presented to T-cells
82
How many MS risk SNPs are currently known?
233
83
Risk for MS [is/is not] genetically inheritable
MS risk is inheritable
84
Which finding has lead to the belief that B-cells are (also) involved in MS?
The fact that anti-B-cell monoclonals (ritixumab) have been shown to be effective in MS
85
What is the disadvantage of anti-B-cell monoclonals for the treatment of MS?
They cannot enter the brain. By the time MS-patients show symptoms there is already a B-cell subset in the brain, which is unaffected.
86
What are the pathological functions of B-cells in the brain? (3)
1. Antigen presentation 2. Accumulation in the meninges & production of antibodies in the CNS 3. Interaction with T-cells, causing T-cell accumulation (follicle formation)
87
What allows B-cells to mature and produce antibodies in the brain?
The presence of T-cells offering T-cell help
88
What are important factors for B-cells to be able to enter the brain in MS? (2) How are they induced?
1. T-bet -> induced by T-cell help 2. CXCR3 -> induced by T-bet
89
CXCR3 on B-cells is induced by T-bet. How can this be used for MS diagnostics & immunology?
CRXR3 can be used as a marker for T-bet-positive B-cells
90
How are the levels of T-bet+ B-cells in circulation of MS patients compared to healthy individuals? What does this show?
Lower numbers of circulating T-bet+ B-cells in MS patients -> these cells have likely homed into the brain
91
What happens to T-bet+ B-cell numbers in the blood of MS patients when VLA-4 is blocked by natalizumab treatment?
Accumulation of T-bet+ B-cells in circulation
92
Why is knowledge of the role of B-cells in MS useful for treatment?
They can be targeted (using small molecule inhibitors) for treatment

I&I WC2 (25 decks)

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