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I&I WC2 > Fundamental immunology > Flashcards

Fundamental immunology Flashcards

1
Q

From which stem cells to T-cells derive, and where are these located?

A

Pluripotent haematopoietic stem cells in the bone marrow

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2
Q

What is the progenitor cell of T-cells?

A

Common lymphoid progenitor

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3
Q

Which two processes in T-cells take place in the thymus?

A
  1. Turning off non-T-cell lineage genes
  2. TCR gene rearrangement + selection based on TCR
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4
Q

Which chains make up the αβ-TCR?

A
  1. α-light chain
  2. β-heavy chain
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5
Q

Which regions comprise the α-light chain of the TCR?

A

V + J

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6
Q

Which regions comprise the β-heavy chain of the TCR?

A

V + D + J

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7
Q

Which processes lead to high TCR diversity? (2)

A
  1. VDJ recombination
  2. Junctional diversity
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8
Q

Which two forms of junctional diversity are there, and which is most important?

A
  1. n-nucleotide addition = most important
  2. p-nucleotide addition
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9
Q

How many % of T-cells is deleted during selection? Why?

A

90-98% are deleted, due to:
1. Negative selection
2. Non-productive rearrangements

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10
Q

On which cell types can MHCI be found?

A

Most nucleated cells

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11
Q

To which type of T-cell does MHCI present?

A

CD8+ T-cells

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12
Q

What is the structural makeup of MHCI?

A
  1. α heavy chain, consisting of 3 domains
  2. β2-microglobulin
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13
Q

Where is the antigen binding cleft of MHCI located?

A

Between domains 1 and 2 of the α heavy chain

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14
Q

What is the function of β2-microglobulin in MHCI?

A

Stabilization of the complex on the cell surface

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15
Q

On which cell types can MHCII be found?

A

Professional antigen-presenting cells

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16
Q

To which type of T-cell does MHCII present?

A

CD4+ T-cells

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17
Q

What is the structural makeup of MHCII?

A

α and β chains, each consisting of two domains

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18
Q

Where is the antigen binding cleft of MHCII located?

A

Between the α1 and β1 domains

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19
Q

What is the advantage of the MHC locus being highly polymorphic?

A

Population protection against pathogens

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20
Q

Which two forms of T-cell selection take place in the thymus?

A
  1. Positive selection
  2. Negative selection
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21
Q

In which part of the thymus does positive selection of T-cells take place?

A

Cortex

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22
Q

Which cell type is responsible for positive selection of T-cells in the thymus?

A

Cortical thymic epithelial cells = cTEC

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23
Q

What are T-cells selected for during positive selection? How does this work?

A

Their ability to bind self-MHC -> gives necessary survival signal

If the T-cell is unable to bind to self-MHC -> no survival signal -> death by neglect

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24
Q

What kind of antigen is presented to T-cells during positive selection in the thymus? What may one conclude from this?

A

Self-antigen is presented in the context of self-MHC

Conclusion: all T-cells are somewhat auto-reactive, for they are triggered by self-antigen presented in self-MHC

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25
Q

In which part of the thymus does negative selection of T-cells take place?

A

Medulla

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26
Q

Which cell types are responsible for negative selection of T-cells in the thymus? (2)

A
  1. Dendritic cells
  2. Medullary thymic epithelial cells = mTEC
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27
Q

What are T-cells selected for during negative selection? How does this work?

A

A wide variety of self-antigens is presented to T-cells -> if they react too strongly to this, they will be deleted by clonal deletion, preventing auto-reactive T-cell clones

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28
Q

Which two options are allowed to survive by the combination of positive and negative selection of T-cells in the thymus? Into which cell types will they develop?

A
  1. TCR with medium recognition of self-MHC and self-peptide -> Tregs
  2. TCR with weak recognition of self-MHC and self-peptide -> regular T-cells
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29
Q

How many % of T-cells survive negative selection in the thymus?

A

1-10%

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30
Q

What determines the total amount of T-cells in the body? (2)

A
  1. Thymic output
  2. Homeostatic proliferation
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31
Q

What determines the thymic output of T-cells?

A

Input of bone marrow-derived progenitor cells into the thymus

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32
Q

What is the approximate/average output of a human thymus in a young person? (CD4+ / CD8+)

A

CD4+ = ~17 million/day
CD8+ = ~8 million/day

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33
Q

How many antigen-specific T-cells/million are there to any specific antigen? (CD4+/CD8+)

A

CD4+ = 0,2-20/million
CD8+ = 0,6-60/million

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34
Q

Why doe higher frequencies of antigen-specific T-cells offer better protection?

A

Higher chance of encountering their antigen sooner upon infection

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35
Q

What are recent thymic emigrants (RTEs)? Why are they useful?

A

T-cells that have recently left the thymus -> can be used to reliably measure thymic function

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36
Q

In which situations is it especially useful to measure thymic output of T-cells? (2)

A
  1. After bone marrow transplantation
  2. During/after chemotherapy
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37
Q

Which three methods are available to measure thymic output?

A
  1. T-cell receptor excision circles (TRECs)
  2. Antigen expression
  3. In vivo labelling
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38
Q

What are T-cell receptor excision circles (TRECs)?

A

Circular DNA fragments, left behind after VDJ-recombination

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39
Q

Why are TRECs useful to measure thymic output?

A

TRECs do not replicate during mitosis -> frequency is stable, even is daughter cells divide. Therefore, TREC concentrations directly correlate with thymic output.

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40
Q

What is the TREC concentration in
1. Childhood
2. Elderly people

A

Childhood = high
Elderly = strongly decreased

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41
Q

In which clinical applications are TRECs mesured? (3)

A
  1. Newborn screening for SCID
  2. T-cell reconstitution for AIDS patients on cART
  3. T-cell reconstitution after bone marrow transplant
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42
Q

The total number of T-cells in the body of children and elderly people is roughly equal, despite a strongly decreased thymic output in elderly. How is this possible?

A

Proliferation of T-cells in the periphery

43
Q

Which two mechanisms can lead to a reduction of TRECs?

A
  1. Cell division -> natural dilution
  2. Intracellular degradation of TRECs
44
Q

How can antigen expression be used to measure thymic output? What is the weakness of this?

A

Certain antigens are enriched on naïve T-cells -> can be counted using flow cytometry

Weakness: while these antigens are enriched on naïve T-cells, they are not exclusive to them

45
Q

Which two methods of in vivo labelling are available to measure thymic output? Which can be used in humans?

A
  1. Deuterated water labelling
  2. Bromodeoxyuridine labelling

Deuterated water labelling can be used in humans

46
Q

How does deuterated water labelling to measure thymic output work?

A

Deuterated water is incorporated into macromolecules -> total uptake can be measured

47
Q

What is the half-life of naïve T-cells in humans? (CD4+/CD8+?

A

CD4+ = ~6 years
CD8+ = ~9 years

48
Q

How many % of human T-cells is produced in the thymus during their lifetime, and how many % is produced through homeostatic proliferation?

How does this differ from mice?

A

10-20% = produced in thymus
80-90% = produced using homeostatic proliferation in the periphery

In mice, near to 100% of T-cells is produced in the thymus

49
Q

Which T-cell subset is largest in young individuals?

A

Naïve T-cells

50
Q

Which T-cell subset is largest in elderly individuals?

A

Memory T-cells

51
Q

What is the disadvantage of a reduced thymic output in elderly individuals?

A

While total numbers of T-cells remain the same, T-cell diversity declines -> less protected against new antigens

52
Q

What is the difference in homeostatic proliferation between naïve and memory T-cells?

A
  1. Naïve T-cells: dependent on self-peptide-MHC complexes presented by DCs
  2. Memory T-cells: proliferation largely independent on self-peptide-MHC complex presentation by DCs
53
Q

Which cytokines are important for homeostatic proliferation of T-cells?

A
  1. IL-7
  2. IL-15
54
Q

What happens to the total number of T-cells when the CD4+ T-cell subset is depleted, for instance due to HIV?

A

Expansion of the CD8+ T-cell subset -> total number of T-cells stays the same

55
Q

Upon encountering an antigen, the antigen-specific T-cell expands. After clearning the antigen, a memory T-cell subset remains. How much is this memory subset expanded, compared to the the starting subset of naïve, antigen-specific T-cells?

A

~1000-fold expansion (1/100.000 -> 1/100)

56
Q

Upon encountering an antigen, the antigen-specific T-cell expands. How many times does the antigen-specific T-cell subset expand?

A

~10.000-100.000 fold expansion

57
Q

What is the advantage of the expanded memory T-cell subset after infection? (2)

A
  1. Higher amount of antigen-specific cells -> better immune surveillance
  2. Pre-activated state of memory T-cells -> swift reaction upon encountering antigen
58
Q

How do memory T-cell subsets stay around, even decades after encountering their antigen? Does their number stay similar?

A

Homeostatic proliferation; their number slowly drops as time passes without encountering their antigen

59
Q

What is the result of a thymectomy upon birth in mice?

A

As mice are wholly dependent on their thymic output for T-cells, no T-cell repertoire forms -> immunodeficiency

60
Q

What is the result of a thymectomy in adult mice?

A

T-cell subset has had the chance to establish -> no immunodeficiency, but lower T-cell numbers = more prone to infection

61
Q

When does the human T-cell repertoire start to form? What is the result of this?

A

~12-13 weeks post-conception
Result: full T-cell repertoire present upon birth

62
Q

What is the acute result of thymectomy upon birth in humans?

A

No acute clinical manifestation -> T-cell repertoire develops long before birth

63
Q

What is the result of thymectomy in humans in their later life? (3)

A

Premature immunosenescence:
1. Infectious diseases
2. Poor response to vaccinations
3. Increased malignancies

64
Q

What is DiGeorge syndrome, and what are its three main hallmarks?

A

22q11.2 deletion, resulting in:
1. Primary immunodeficiency
2. T-cell defects
3. Antibody isotype abnormalities

65
Q

What causes high phenotypic variability in DiGeorge syndrome?

A

30-50 genes can be deleted -> exactly which genes are deleted determines the clinical manifestation

66
Q

After a haematopoietic stem cell transplant, there is a transient altering of T-cell dynamics. What is the main determinant of how quickly T-cells repopulate?

A

Patient age

67
Q

Which T-cell subset is quickest to recover after chemotherapy?

A

CD8+ T-cells

68
Q

What determines the speed and ‘completeness’ of CD4+ recovery after chemotherapy?

A

Patient age

69
Q

Which solution is being investigated to improve CD4+ recovery after chemotherapy?

A

Thymic rejuvination -> boosting the thymus output to improve T-cell recovery in elderly patients

70
Q

Through which mechanisms can B-cells mediate auto-immune disease? (6)

A
  1. Antibody-mediated cytotoxicity
  2. Complement-mediated inflammation
  3. Ig-mediated antigen uptake
  4. FcγR-mediated antigen-antibody uptake
  5. Antigen (cross)presentation
  6. FcγR-mediated activation
71
Q

Which two strategies can be used to specifically reduce B-cell function?

A
  1. Biologicals that deplete (subsets of) B-cells
  2. Small molecule inhibitors that interfere with downstream BCR signaling
72
Q

Which surface marker is often targeted using B-cell depleting biologicals?

A

CD20 (rituximab)

73
Q

For which processes is BCR signalling in B-cells important? (4)

A
  1. Activation
  2. Survival
  3. Proliferation
  4. Differentiation
74
Q

What is are critical conditions for small molecule aiming to interfere with downstream BCR signalling?

A
  1. Must be specific for BCR downstream signalling -> no off-target effects
  2. Must target a part of BCR downstream signalling that does not have redundancy to prevent signalling via other parts of the pathway
75
Q

What is an important target of small molecule inhibitors used to target B-cell function?

76
Q

What is an often-used compound to interfere with BTK? How does it work?

A

Ibrutinib -> specifically targets the kinase domain of BTK, without interfering with other kinases

77
Q

What is XLA? How does it occur?

A

X-linked agammaglobulinaemia
Occurs in case of BTK deficiency -> obstructed pre-BCR signalling after heavy chain rearrangements completely prevents B-cell development

78
Q

What happens when BTK is deficient?

A

No pre-BCR signalling after heavy chain rearrangement -> complete developmental stop for all B-cells

Results in XLA

79
Q

How do BTK-negative mice differ from humans with complete BTK deficiency?

A

Mice are still able to produce some B-cells, but these have reduced survival & proliferaton

In humans, B-cells are alltogether absent

80
Q

What happens when the BCR of B-cells in BTK-negative mice is stimulated? What are the downstream effects of this? (2)

A

Reduced Ca2+ influx = lower activation of B-cells, leading to:
1. Lower NF-κB activation
2. Reduced expression of proliferation factors

81
Q

What is a way to stimulate BCRs, regardless of their antigen-specificity?

A

Using anti-BCR antibodies (anti-IgM, -IgG, -IgA)

82
Q

How does ibrutinib (and other small molecule inhibitors) interfere with BTK function?

A

Covalent binding to the ATP-binding site in the BTK kinase domain -> prevents kinase activity

83
Q

Is ibrutinib activity reversible or permanent? Why?

A

Permanent -> covalent binding of ibrutinib to BTK kinase domain

84
Q

Why does ibrutinib have limited adverse effects?

A

High specificity to BTK -> little interference with other pathways

85
Q

True or false: ibrutinib is currently the only BTK inhibitor

A

False; since the introduction of ibrutinib, many even more specific BTK inhibitors have been introduced

86
Q

What are the hypothesized mechanisms of action of BTK inhibitors? (4)

A
  1. Reduced BCR signalling
  2. Inhibition of B-cell integrin signalling
  3. Interference with chemokine signalling
  4. Interference in signalling from the microenvironment
87
Q

For what type of disease have BTK inhibitors been approved?

A

Haematological malignancies involving B-cells

88
Q

In which haematological malignancies can BTK inhibition currently be used? (6)

A
  1. Chronic lymphocytic leukaemia (CLL)
  2. Mantle cell lymphoma (MCL)
  3. Waldenström macroglobulinaemia
  4. Primary CNS lymphoma
  5. Marginal cell lymphoma
  6. Follicular lymphoma
89
Q

Why do BTK inhibitors likely have limited effect on pre-B-cell tmours?

A

Pharamcokinetics -> not enough inhibitor to block rapidly dividing B-cells

90
Q

Through which mechanisms can resistance to BTK inhibitors occur? (2)

A
  1. Spontaneous mutation of Cys481 = BTK inhibitor attachment site
  2. Gain of function of PLCγ
91
Q

How does a gain of function of PLCγ lead to BTK inhibitor resistance?

A

PLCγ = downstream of BCL -> if it is constitutively active, inhibiting BTK no longer has any effect

92
Q

What is the solution to prevent resistance to BTK inhibitors? (3)

A
  1. Increasing dosage
  2. Combining BTK inhibition with a compound that interferes in the same pathway
  3. Combining BTK inhibition with a therapy interfering with another pathway
93
Q

Which pathways are often targeted in concert with BTK inhibition to prevent resistance? (2)

A
  1. Bcl2-inhibitors
    OR
  2. Anti-CD20 (rituximab)
94
Q

What is unique to B-cell activation via the BCR, when compared with other activatory mechanisms (such as TLR signalling)?

A

Only signalling via the BCR causes a slight increase in BTK expression in the B-cell

95
Q

What happens when BTK expression is constitutively slightly increased to the levels of activated B-cells in mice? What does this imply?

A

Development of auto-immune diseases

This implies that BTK is involved in auto-immunity

96
Q

Which changes are observed in B-cells with constitutively increased BTK expression in mice? (3)

A
  1. Increased BCR signalling
  2. Increased NF-κB activation
  3. Spontaneous germinal centre formation in the spleen
97
Q

What is the result of the changes observed in B-cells of mice with constitutively increased BTK expression?

A

Production of anti-nuclear auto-antibodies -> triggers auto-immune phenomena

98
Q

What is the result of the use of BTK inhibitors in mice experiencing auto-immune disease due to constitutively increased BTK expression? What can be concluded from this?

A

Lower disease score -> conclusion: BTK inhibition might be useful in auto-immmune disease

99
Q

BTK expression in memory B-cells is [decreased/increased] as opposed to naïve B-cells

A

Increased -> more easily activated

100
Q

True or false: BTK only plays a role in B-cells

What is the implication of this?

A

False; BTK is also a signalling molecule in other immune cells

BTK inhibition could also work via cell types other than B-cells

101
Q

In the circulating B-cells of human auto-immune patients, BTK expression is [decreased/increased] when compared to controls.

This is the case for [all B-cells/antigen-specific B-cells].

What is the implication of this?

A

Increased, in all B-cells

Implication: if naïve B-cells also have increased BTK expression, it must be somehow induced by something other than BCR activation -> possibly an auto-immune micro-environment

102
Q

In which auto-immune disease has BTK inhibition shown to be succesful in a clinical trial?

A

Multiple sclerosis (MS)

103
Q

How can it be explained that BTK inhibition is not succesful in all auto-immune diseases? (2)

A
  1. BTK is nog a significant player in all auto-immune diseases
  2. Rewiring of BCR signalling, such that BTK is no longer a vital part of the cascade

I&I WC2 (1 decks)

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