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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
Q

Why are teratomas especially capable of triggering anti-NMDA-R immune responses?

A

Neuronal tissue expressing NMDA-R in a non-immunologically privileged site can trigger anti-NMA-R immune responses

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26
Q

What are the stages of anti-NMDA-R encephalitis? (3)

A
  1. Prodromal stage
  2. Initial stage
  3. Comatous stage
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27
Q

What are symptoms of the prodromal phase of anti-NMDA-R encephalitis?

A

Viral-like

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28
Q

What are symptoms of the initial stage of anti-NDMA-R encephalitis? (7)

A
  1. Agitation
  2. Psychosis
  3. Catatonia
  4. Speech reduction
  5. Memory deficits
  6. Abnormal movements
  7. Seizures
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29
Q

What are symptoms of the comatous stage of anti-NDMA-R encephalitis? (3)

A
  1. Coma
  2. Hypoventilation
  3. Dysautonomia
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30
Q

How many patients of anti-NMDA-R encephalitis require ICU admission?

A

75%

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31
Q

What is the mechanistical explanation of the symptoms in anti-NMDA-R encephalitis?

A

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

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32
Q

Which lobes are particularly active in anti-NMDA-R encephalitis?

A

Frontal & temporal lobes

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33
Q

What are possible triggers of breakdown of tolerance against the NMDA-R? (2)

A
  1. Teratoma expressing neuronal tissue
  2. Viral infection (HSV)
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34
Q

Where are plasmablasts that produce anti-NMDA-R antibodies located?

A

In the meninges -> production of antibodies within the CNS

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35
Q

What are the possible effects of anti-NMDA-R antibodies? (4)

A
  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
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36
Q

Which effects of anti-NMDA-R antibodies have been observed in encephalitis? (2)

A
  1. Direct activation of NMDA-R
  2. Internalization of NMDA-Rs
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37
Q

How do antibodies cause direct NMDA-R activation? Why is this an unsatisfactory explanation of anti-NMDA-R encephalitis?

A

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
Q

How can anti-NMDA-R antibodies cause NMDA-R internalization?

A

Disruption of the interaction between the NMDA-R and its enchor protein EphB2

39
Q

True or false: complement plays a role in cytotoxicity in anti-NMDA-R encephalitis

A

False; complement is not involved in brain lesion formation

40
Q

Which factors negatively affect outcomes in anti-NMDA-R encephalitis? (2)

A
  1. Severe disease
  2. Longe treatment delay
41
Q

What is the recovery time of anti-NMDA-R encephalitis?

42
Q

How many % of anti-NMDA-R encephalitis patients recover without symptoms?

43
Q

What is the first line treatment of anti-NMDA-R encephalitis?

A

Steroids + IVIG/plasma exchange

44
Q

What are possible second line treatments of anti-NMDA-R encephalitis?

A
  1. Rituximab
  2. Cyclophosphamide
  3. Bortezomib
  4. Tocilizumab
45
Q

Why is IVIG not always effective as a treatment of auto-immune encephalitis?

A

IVIG does reduce the amount of circulating auto-antibody, but does not remove antibody & antibody-producing B-cells from the brain

46
Q

When does post-infectious herpes simplex auto-immune encephalitis occur?

A

~4 weeks after prior herpes simplex encephalitis (HSE)

47
Q

HSV-encephalitis (HSE) [does/does not] respond to antiviral therapy

A

HSE does respond to antiviral therapy

48
Q

How can HSV-encephalitis be differentiated from post-infectious herpes simplex auto-immune encephalitis? (3)

A
  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
Q

What is the mechanism of post-infectious herpes simplex auto-immune encephalitis?

A

Formation of anti-NMDA-R auto-antibodies during herpes simplex encephalitis

50
Q

Which three processes form the triad of MS pathology?

A
  1. Inflammation
  2. Demyelination
  3. Axonal degeneration
51
Q

Is demyelination in MS reversible?

A

Yes -> relapsing remitting MS

52
Q

Is axonal degeneration in MS reversible?

A

No -> progressive MS

53
Q

What are the two main risk factors correlated with MS?

A
  1. Genetic predispositon
  2. EBV
54
Q

How is MS progression usually tracked?

A

Tracking white matter lesions with MRI

55
Q

How can post-mortem pathology show white matter loss? (2)

A
  1. Stajning for myelin
  2. Staining for myelin markers MAG or MOG
56
Q

Which three routes could the causative cells of MS take into the brain?

A
  1. CSF-blood barrier
  2. Meninges
  3. Glia limitans
57
Q

Which cells form the blood-brain barrier? Which cells form the blood-CSF barrier?

A

Blood-brain = endothelial cells
Blood-CSF = epithelial cells

58
Q

What enables immune cells in MS to enter the brain?

A

Expression of specific chemokine receptors & adhesion molecules

59
Q

What is an important chemokine receptor involved in MS? On which cell type is it present?

A

CCR6 on T-cells

60
Q

What is a signature cytokine of T-cells involved in MS?

61
Q

Which T-cell subsets can be found in MS?

A
  1. Th17
  2. Th17.1
  3. Th22
  4. DP
62
Q

What is an important integrin receptor that T-cells use to enter the brain in MS?

63
Q

What is VLA-4?

A

Integrin receptor, used by T-cells to migrate into the brain in MS

64
Q

Why is understanding the role of VLA-4 in MS pathogenesis useful?

A

It can be blocked to prevent T-cell entry into the brain

65
Q

Which drug blocks VLA-4, preventing T-cell entry into the brain?

A

Natalizumab

66
Q

What is the effect on T-cells in the meninges vs. in the blood when VLA-4 is blocked by natalizumab in MS patients?

A

Meninges: lowering of T-cells
Blood: T-cells accumulate in circulation

67
Q

Which cells especially accumulate in circulation when VLA-4 in MS patients blocks T-cell entry into the brain?

A

Th17.1 cells

68
Q

How can the amount of Th17.1 accumulation in circulation after VLA-4 blockage by natalizumab in MS patients be predictive of further disease?

A

Higher Th17.1 accumulation in circulation = more likely to be relapse-free
Lower Th17.1 accumulation in circulation = more likely to relapse

69
Q

How could functional impairment of Tregs lead to MS? Which syndrome functions as a model for this hypothesis?

A

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
Q

What is the current official working definition of MS?

A

Cell-mediated auto-immune disease, caused by environmental factors and chance in a genetically susceptible individual

71
Q

Which environmental factors have been linked to MS?

A
  1. Vitamin D/sunlight shortage
  2. Infections (specifically: EBV)
  3. Smoking
  4. Toxins
72
Q

In which way is sunlight exposure/vitamin D linked to MS? (2)

A
  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
Q

MS risk in people that migrate from sunny regions to less sunny regions [stays low/increases]

A

MS risk increases when people move to less sunny regions

74
Q

What is the role of vitamin D in MS pathogenesis?

A

Unclear; working hypothesis: disruption of T- and B-cell function in individuals with genetic susceptibility

75
Q

Trials with vitamin D for the treatment of MS [showed a decrease in MS flares/failed to show a decrease in MS flares]

A

Failed to show a decrease in MS flares

76
Q

What are possible reasons vitamin D trials in MS were not successful? (2)

A
  1. Wrong kind of vitamin D
  2. Vitamin D does not effectively reach the right parts of the body
77
Q

Vitamin D is part of a hormone family. Which other hormones are part of this family? (3)

A
  1. Sex hormones
  2. Glucocorticoids
  3. Steroids
78
Q

Which changes in the hormone family of vitamin D have also been observed in MS patients?

A
  1. Lower sensitivity to glucocorticoids, especially for Th17.1 cells
  2. Vitamin D seems to increase corticoid sensitivity of Th17.1 cells
79
Q

Which infection is especially linked to MS?

80
Q

Which types of genetic factors are associated with MS? (2)

A
  1. SNPs
  2. Copy number variations (CNVs)
81
Q

SNPs in which gene are especially known to be a major risk factor for MS? What is the mechanistic explanation for this?

A

HLA II; SNPs in this gene could alter the way MS-related peptides are presented to T-cells

82
Q

How many MS risk SNPs are currently known?

83
Q

Risk for MS [is/is not] genetically inheritable

A

MS risk is inheritable

84
Q

Which finding has lead to the belief that B-cells are (also) involved in MS?

A

The fact that anti-B-cell monoclonals (ritixumab) have been shown to be effective in MS

85
Q

What is the disadvantage of anti-B-cell monoclonals for the treatment of MS?

A

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
Q

What are the pathological functions of B-cells in the brain? (3)

A
  1. Antigen presentation
  2. Accumulatin in the meninges & production of antibodies in the CNS
  3. Interaction with T-cells, causing T-cell accumulation (follicle formation)
87
Q

What allows B-cells to mature and produce antibodies in the brain?

A

The presence of T-cells offering T-cell help

88
Q

What are important factors for B-cells to be able to enter the brain in MS? (2) How are they induced?

A
  1. T-bet -> induced by T-cell help
  2. CXCR3 -> induced by T-bet
89
Q

CXCR3 on B-cells is induced by T-bet. How can this be used for MS diagnostics & immunology?

A

CRXR3 can be used as a marker for T-bet-positive B-cells

90
Q

How are the levels of T-bet+ B-cells in circulation of MS patients compared to healthy individuals? What does this show?

A

Lower numbers of circulating T-bet+ B-cells in MS patients -> these cells have likely homed into the brain

91
Q

What happens to T-bet+ B-cell numbers in the blood of MS patients when VLA-4 is blocked by natalizumab treatment?

A

Accumulation of T-bet+ B-cells in circulation

92
Q

Why is knowledge of the role of B-cells in MS useful for treatment?

A

They can be targeted (using small molecule inhibitors) for treatment

I&I WC2 (25 decks)

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