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I&I WC1 > Immunology > Flashcards

Immunology Flashcards

Mechanisms of Leukocyte Migration

1
Q

What is an unique hallmark of cells of the immune system?

A

Motility -> most cells stay fixed through their lifetime

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2
Q

True or false: entry into secondary lymphoid organs is random

A

False; this is a restricted and controlled process

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3
Q

How do DCs enter lymph nodes? What happens after they have completed their function in the lymph node?

A

Entry: afferent lymphatics
DCs don’t leave the lymph nodes; they die there

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4
Q

What is an important regulator of location and movement of lymphocytes in lymph nodes?

A

Lymphocytes are attached to stromal cells & ECM; these regulate movement and location

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5
Q

Which two classes of signaling molecules are involved in cellular migration?

A
  1. Chemokines
  2. Integrins and integrin ligands
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6
Q

What are chemokines?

A

Small secreted proteins that drive chemotasis

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7
Q

How many structurally related families of chemokines are there?

A

Four

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8
Q

Which two groups of chemokines can be distinguished based on their expression?

A
  1. Inflammatory chemokines -> expressed in inflammation
  2. Homeostatic cemokines -> constitutive expression in lymphoid organs
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9
Q

Which cells are mainly attracted by inflammatory chemokines?

A

Activated cells (lymphocytes)

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10
Q

Which cells are mainly attracted by homeostatic chemokines?

A

Naïve lymphocytes & DCs

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11
Q

Which three mechanisms can be used for chemotaxis with chemokines?

A
  1. Leukocyte chemotaxis based on soluble gradient -> cells migrate towards higher concentration
  2. Leukocyte haptotaxis -> based on gradient of chemokines bound to sugar structures on cell membranes
  3. Leukocyte chemokinesis/haptokinesis -> migration without gradient
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12
Q

What are integrins & integrin ligands involved in?

A

Cell adhesion

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13
Q

What is the structural makeup of integrins?

A

Multimeric proteins consisting of α- and β-chains

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14
Q

Which classes of integrin receptors are there? (4)

A
  1. Leukocyte-specific receptors
  2. Laminin receptors
  3. Collagen receptors
  4. RGD-receptors
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15
Q

What are the ligands of integrin receptors?

A

ECM proteins or cell surface proteins (ICAM/VCAM)

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16
Q

How do DCs enter the lymph nodes? How do lymphocytes enter?

A

DCs enter via afferent lymphatics
Lymphocytes enter via HEV

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17
Q

What is special about the HEV?

A

It contains cuboidal epithelium with HEV-specific sugar structures: peripheral node adressins (PNAd)

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18
Q

What are peripheral node adressins?

A

HEV-specific sugar structures that allow lymphocytes to leave circulation there

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19
Q

What is the homing receptor used by lymphocytes to find the HEV?

A

L-selectin (CD62L)

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20
Q

What does activation of L-selectin on lymphocytes in the HEV lead to?

A

Rolling of cells

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21
Q

What happens after rolling adhesion using L-selectin?

A

Sticking, induced by inside-out chemokine signaling

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22
Q

What happens to integrins when they encouter chemokines? How does this relate to the term of inside-out signaling?

A

Integrins are usually present in inactive configuration to prevent binding to random surfaces; they are activated by chemokines encountered during rolling adhesion, allowing them to make high affinity bonds to molecules expressed on endothelium in HEV (ICAM)
There is a signal from inside the blood vessel, allowing the cell to extravasate

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23
Q

How does shear stress contribute to leukocyte extravasation?

A

Causes cytoskeletal rearrangements that cause clustering of integrins -> increases binding affinity

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24
Q

What are the steps of extravasation in the HEV?

A
  1. Rolling induced by selectins and adressins
  2. Sticking/stopping induced by chemokine-mediated activation of integrins (inside-out signaling)
  3. Diapedesis under the influence of chemokines
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25
Q

What is outside-in signaling? What is inside-out signaling?

A

Outside-in = activation of integrins through chemokines
Inside-out = integrin binding causing adhesion

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26
Q

What are location-specific markers of trans-HEV migration? What are cell type specific markers?

A

Local:
1. PNAd = peripheral node adressions
2. MAdCAM1 = mucosal adression cell adhesion molecule

Cell-specific:
T-cell: CCL21, produced by HEV
B-cell: CXCL13, produced by lymph node stromal cells

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27
Q

Where do lymphocytes collect when they do not encounter antigen in the lymph node?

A

Medullary sinuses

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28
Q

Which signaling mechanism regulates lymphocytes exit out of lymph nodes?

A

Sphigosine-1-phosphatase (S1P)

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29
Q

How does S1P regulate exit of lymphocytes?

A

S1P = synthesized by endothelial cells & red blood cells –> high concentraiton in body fluids –> lymhocytes want to migrate to body fluids
S1P-receptor gets internalized when it is activated –> downregulated in high [S1P] environments –> cell able to move into tissue again
When cell moves into tissue: repopulation of surface with S1P receptors –> once again allows cells to leave tissue

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30
Q

What is CD69 used as a marker for?

A

Early activation marker of lymphocytes

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31
Q

What is the function of CD69?

A

Prevents re-expression of S1P-receptor -> prevents lymphocytes from leaving lymph nodes to soon, allowing them to become fully activated

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32
Q

How can drugs that mimic S1P be used to influence immune disease?

A

Cause downregulation of S1P –> lymphocytes are sequestered in lymphoid organs, preventing them from causing damage elsehwere

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33
Q

How do activated T-cells know where to head after being activated in the lymph node?

A

They are instructed by activating DCs for their location -> signals can be traced back to specific tissue
Tissue-specificity of T-cells ensured by specific configuration of sugars, chemokines & integrins

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34
Q

What is the structural makeup of IgG?

A

Heavy chain: 3 constant, 1 variable domain
Light chain: 1 constant, 1 variable domain

Chains are connected by disulfide bonds in the hinge region

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35
Q

What is the function of the variable domain of the antibody? What is the name of this fragment?

A

Antigen binding, Fab-fragment

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36
Q

What is the Fc-fragment of the antibody?

A

The constant tail of the Ig

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37
Q

How can the Fc-domain of antibodies be modified?

A

Carbohydrate structures

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38
Q

What are the functions of the Fc-domain? (3)

A
  1. Fc-receptor binding
  2. Complement activation
  3. Transport, such as transport across epithelial surfaces
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39
Q

True or false: Fc-receptors are expressed on almost every immune cell

A

True

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40
Q

True or false: all antibody isotypes use the same FcR

A

False; every isotype has its own FcR

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41
Q

True or false: all antibodies of a certain isotype have the same affinity for their FcR

A

False; FcR’s have different affinities for antibody subclasses

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42
Q

True or false: FcRs always activate immune processes

A

False; FcR’s can also have an inhibitory function

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43
Q

What are the functions of FcR’s? (8)

A
  1. Clearance of immune complexes
  2. Phagocytosis, leading to antigen presentation
  3. Production of cytokines
  4. Antibody-dependent cellular cytotoxicity (ADCC)
  5. Modulation of cellular activation
  6. Mast cell degranulation
  7. Prevention of auto-immunity by forming a late auto-immune checkpoint for B-cells
  8. Transportation/recycling of IgG
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44
Q

What is the function of FcRs for mast cells/basophils?

A

Degranulation

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45
Q

What is the effect of FcRs on neutrophils, macrophages & monocytes?

A

Enables phagocytosis & oxidative burst

46
Q

What is the function of FcRs for DCs?

A

Modulation of antigen presentation & immune responses

47
Q

What is the effect of FcRs on plasma cells? Why is this useful?

A

Apoptosis -> plasma cells are stopped when antibody concentrations become (too) high

48
Q

What is the process of FcR-mediated ADCC?

A
  1. Antibody binds antigens on surface on target cells
  2. NK-cell recognizes Fc-tail of antibody
  3. FcR’s on NK-cell crosslink, leading to release of perforin/granzyme
  4. Target cell dies by apoptosis
49
Q

In which instances is FcR-mediated ADCC activated? (4)

A
  1. Defence against microbes
  2. Anti-tumour responses
  3. Auto-immune responses, when auto-antibodies bind to self-cells
  4. Depleting antibodies/plasma cells (when used with anti-CD20 Ab)
50
Q

How does FcR modulate antigen presentation on MHCII?

A

Immune complexes are recognized by through their Fc-tail by FcR -> complex internalized and degraded for presentation on the MHCII complex
Presence of FcR in the endosome prevents degradation of the antigen so that it can still be presented

51
Q

Why are FcR’s important for the loading of MHCI in cross-presentation pathways?

A

TRIM21 is an intracellular FcR that is necessary for the loading of MHCI, as it directs captured antigen to the proteasome instead of the MHCII-loading compartment -> antigens end up in the intracellular pathway and are presented on MHCI, allowing for the activation of T-cells

52
Q

Which Fc-γ receptors are present in humans, in order of high to low affinity? What is their CD number?

A
  1. FcγRI = CD64
  2. FcγRIIA/B/C = CD32
  3. RcγRIIIA/B = CD16
53
Q

What is unique about FcγRI?

A

Due to its high affinity, it is able to bind monomeric IgG, whereas the other receptors require multimeric IgG

54
Q

How do FcγR’s signal into the cell? What are the exceptions? (2)

A

Most have an ITAM -> activating motif, activating the cell
Exceptions:
1. FcγRIIIB -> no intracellular domain
2. FcγRIIB -> ITIM

55
Q

What is the effect of ITAM activation? What is the effect of ITIM activation?

A

ITAM = kinase -> activates cellular functions
ITIM = phosphatase -> inhibits cellular functions

56
Q

What is the function of the FcγRIIB on B-cells? How does it affect plasma cells?

A

Inhibitory receptor on B-cells, affects signaling through the BCR. When FcγRIIB and BCR crosslink at the same time: inhibition of BCR singaling

Causes apoptosis in plasma cells

57
Q

What does a lack of FcγRIIB result in?

A

Increased humoral responses

58
Q

Which factors influence FcR-mediated signal output? (3)

A
  1. Expression levels of receptors
  2. Polymorphisms in the receptor, increasing/decreasing activity
  3. Glycosylation of Fc-domain of the antibody -> affects binding strength of FcR and Ab
59
Q

How can expression levels of FcR’s vary?

A
  1. Regular gene activity regulation
  2. Copy number variations
60
Q

How does glycosylation of Fc-domains of antibodies affect their effect? What is the effect of a lack of glycans?

A

It changes their binding affinity to the FcR
Lack of glycans prohibits binding to FcR

61
Q

Which glycosylation strongly impacts binding affinity to FcγRIII?

A

Fucose -> 50x higher affinity

62
Q

What determines whether an antibodies becomes fucosylated or not?

A

Encounter of soluble antigens leads to fucosylated IgG (=high affinity), whereas crosslinking of BCRs by membrane-bound antigen leads to unfucosylated IgG

63
Q

Which factors are known to influence glycosylation of antibodies? (4)

A
  1. Age
  2. Following immunization
  3. During pregnancy
  4. Some auto-immune diseases
64
Q

On which chromosome are the FcγII/FcγRIII’s located? How does the gene locus impact FcR function?

A

Chromosome 1; can contain SNPs and CNVs that influence amount and/or activity of FcR’s

65
Q

With which disease are SNPs of FcγRIIB associated? Why?

A

SLE -> less inhibitory effect on BCR leads to more auto-immune features

66
Q

Can lack of FcγRIIB alone lead to auto-immunity?

A

No; it can be a contributing factor, but more factors are needed

67
Q

What is the effect of insufficient FcR-mediated clearence of immune complexes?

A

Sustained myeloid cell activation and induction of auto-immunity

68
Q

What are the funtions of the neonatal FcR (FcRn)? (2)

A
  1. Recycling of IgG, lengthening its half-life
  2. Transport through mucosa and placenta
69
Q

How does the FcRn mediate recycling of IgG?

A

Presence of FcRn in the endosome causes antibodies in the endosome to be transported back to the cell surface

70
Q

True or false: all subclasses of IgG are recycled efficiently by the FcRn

A

False; the efficiency of recycling is subclass-dependent

71
Q

What is the function of the polymeric IgR? Where can it be found?

A

Involved in transport of IgA/IgM through mucosal surfaces by binding to J-chains and allowing for transcytosis
Found in musocal surfaces

72
Q

Where can the FcεR be found? What is its function?

A

Mast cells & basophils -> degranulation of FcεR causes degranulation
This can lead to allergies

73
Q

What isotype does the FcαR bind?

A

Monomeric IgA

74
Q

Which therapy makes use of FcRs?

A

IVIG

75
Q

What are the described effector mechanisms of IVIG? (4)

A
  1. Blocking of FcR’s
  2. Saturation of FcRn, causing for less effective recycling of pathogenic antibodies
  3. Modulation of DCs
  4. Modulation of FcR’s on plasma cells
76
Q

What is the difficulty in studying FcR’s?

A

FcR’s in mice differ from humans -> hard to find a good model system

77
Q

What is the function of costimulation in T-cell activation? Is this process antigen-dependent or antigen-independent?

A

Ensures survival and proliferation of T-cell
Antigen-independent

78
Q

What is the function of cytokines in T-cell activation?

A

Differentiation

79
Q

What is the most important costimulatory molecule for T-cells? By which cells is it expressed?

A

CD28, expressed by naïve and some memory T-cells

80
Q

What is the effect of CD28 activation on T-cells?

A

Marked increase of TCR-induced proliferation and survival

81
Q

Which molecules activate CD28? Where can they be found?

A

CD80/CD86, found on professional APCs

82
Q

Which signal is necessary to sustain the immune response after CD28 has started T-cell proliferation? Which cells express its ligand?

A

ICOS -> maintains activity of already differentiated cells
ICOS-L is expressed by activated APCs

83
Q

Which T-cells express ICOS?

A

Effector and memory T-cells

84
Q

Which negative costimulatory molecules turn off T-cell activation (2)?

A
  1. PD-1
  2. CTLA-4
85
Q

What are the intracellular effects of costimulation? (2)

A
  1. Upregulation of pro-survival genes (example: Bcl-xL)
  2. Transcription of IL-2/IL-2R genes
86
Q

What happens in the absence of costimulation?

A

Clonal anergy -> important mechanism in peripheral tolerance

87
Q

What happens when anergic T-cells encounter costimulation at a later point?

A

They remain anergic

88
Q

True or false: CD28 is essential for memory T-cell subset formation

A

True

89
Q

What is 4-1BB? For which cell type is it especially important?

A

TNF-receptor family member that can replace CD28 to activate T-cells
Mianly important for CD8+ T-cells

90
Q

Which cytokines induce a Th1 cell? (3) What is its transcription factor?

A
  1. IL-12
  2. IFN-γ
  3. IL-18

Transcription factor = T-bet

91
Q

Which cytokine induces a Th2 cell? What is its transcription factor?

A

IL-4

Transcription factor = GATA3

92
Q

Which cytokines induce a Th17 cell? (4) What is its transcription factor?

A
  1. IL-1
  2. IL-6
  3. IL-23
  4. TGF-β

Transcription factor: RORγT

93
Q

Which cytokines induce a Treg cell? (2) What is its transcription factor?

A
  1. TGF-β
  2. IL-2

Transcription factor: FoxP3

94
Q

Which cytokines induce Tfh cells? (2) What is their transcription factor?

A
  1. IL-6
  2. IL-21

Transcription factor: BCL-6

95
Q

How does CTLA-4 inhibit costimulation?

A

Competes with CD28 for CD80/CD86, preventing costimulation (higher binding affinity)

96
Q

How quickly after activation is CTLA-4 induced?

A

~24 hours, peaking after 2-3 days

97
Q

Which cells express PD-1, and which PD-1L?

A

T-cells express PD-1
APCs express PD-L1

98
Q

What is presence of inhibitory receptors linked to?

A

Exhaustion of T-cells

99
Q

When does T-cell exhaustion occur? (3)

A

Situations of chronic antigen persistence:
1. Chronic viral infections
2. Tumours
3. Auto-immune disease

100
Q

What is the first exhaustion marker?

A

PD-1

101
Q

What is the effect of stimulation on exhausted T-cells?

A

Apoptosis of T-cells

102
Q

Which three signals need to be present for T-cell exhaustion to occur?

A
  1. Persistent antigen
  2. Negative costimulation
  3. Chronic inflammation through cytokines
103
Q

What are the two modes of action of inhibitory molecules? What are examples for each mode of action?

A
  1. Phosphatases, dephosphorylating tyrosine kinases involved in stimulatory signaling; PD-1
  2. Competition for costimulatory molecules; CTLA-4
104
Q

What are characteristic transcription factor changes in T-cell exhaustion?

A
  1. TCF1 = needed for T-cell proliferation -> drops after activation
  2. TOX = increased upon activation, then decreases after some time -> does not drop in case of exhaustion
105
Q

True or false: exhausted T-cells are completely inactive

A

False; they still reteain some activity

106
Q

What are the characteristics of exhausted T-cells? (7)

A
  1. Functional defects
  2. Upregulation of inhibitory receptors
  3. Proliferative effects (inhibited)
  4. Survival defects (tendency for apoptosis)
  5. Transcription factor changes: TOX+/TCF1-
  6. Epigenetic changes
  7. RNA transcriptome changes
107
Q

What is a CAR T-cell?

A

A T-cell with a chimeric antigen receptor (CAR)

108
Q

What is a CAR? How does it recognize antigen?

A

A chimeric combination of CD28 + 4-1BB + TCR ζ-chain that can robustly activate T-cells when encountering antigen
Recognizes antigen by Fab fragment of antibody as receptor unit

109
Q

What are the steps in CAR T-cell therapy?

A
  1. Remove blood from patient to obtain T-cells
  2. Make CAR T-cells in the lab with specific CAR for target antigen and multiply these
  3. Re-infuse T-cells, after which they will clear tumours
110
Q

What are the current problems with immune checkpoint inhibitor therapy? (5)

A
  1. Only minority of patients respond
  2. Not all types of tumour respond
  3. Responses may not be long-lasting
  4. Emergence of resistance in patients that previously responded
  5. Adverse effects

I&I WC1 (20 decks)

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