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Immunology: Research + Clinic > HC1: Immunological interactions and B-cell Research > Flashcards

HC1: Immunological interactions and B-cell Research Flashcards

HC1

1
Q

Infection starts with inflammation > how is it induced?

A

Infection
> Phagocytosis by macrophages
> Cytokine and chemokine production
> Reaction and activation of endothelium and immune cells
> Inflammation

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2
Q

Inflammation meaning

A

Influx of plasma with complement factors, neutrophils and monocytes, but also antibodies later on.

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3
Q

Reaction upon inflammation

A

Increased lymph drainage to lymph nodes (LNs) + activation antigen presenting cells (APCs)
> induction specific immune response
> influx antibodies and T-cells

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4
Q

Inflammation symptoms are result of:

A

Cytokines that activate endothelial cells to open up / increase permeability and vasodilation
> redness, heat, swelling

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5
Q

Signals from infection site (cytokines etc) are received by:

A

everything in the circulation > neutrophils, T-cells and monocytes > adhere to endothelium

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6
Q

Chemokine main functions

A

Upregulate receptors (integrins) to adhere to endothelium and cluster and create movement of immune cells against gradient when correct receptor expressed

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7
Q

Plasma contains this immune components

A

Complement factors and antibodies

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8
Q

How is pain generated in inflammation?

A

Inflammatory cells migrate into tissue upon activation and release inflammatory mediators that cause pain

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9
Q

Mast cells: localization and function

A

Mast cells are present in periphery
> secrete histamines and other toxins to kill parasites
> tissue reacts to secretions: to excrete the parasite
» make more fluids and contraction of smooth muscle in GI-tract

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10
Q

Allergy type of reaction

A

Anti-parasital reaction against non-pathogens

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11
Q

Which granulocytes are attracted to infection site?

A

Neutrophils, (mast cells), basophils, eosinophils.

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12
Q

Differentiation/maturation of dendritic cells

A

When recognition pathogens
> iDC to mDC
> Lymph drainage to LNs > activate adaptive immune cells

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13
Q

Antigen presenting cells (APCs) cross-presentation

A

Present the phagocytosed pathogen in two ways
> Linear peptide of antigen presented on MHC-I for CD8+ T-cells or MHC-II for CD4+ T-cells

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14
Q

T-cells use … to recognize other cells and potential pathogens upon activation

A

TCR and co-stimulation

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15
Q

Types of infected cells

A

By viruses, some bacteria and cancer cells
> recognized by T-cells to kill (CTLs)

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16
Q

B-cell function

A

Aided by some T-cells, produce antibodies to aid killing of infected cells and pathogens

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17
Q

Which receptors are used to recognize pathogen first?

A

PRRs (Pattern Recognition Receptors) including TLRs (Toll-like Receptors) to recognize PAMPs (Pathogen Associated Molecular Pattern) like LPS of bacterial cell wall
> tails receptor intracellularly come together
> signalling to activate transcription factors like NFkB to upregulate secretory cytokines etc.
> gene programs activated

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18
Q

Gene programs activated upon TLR signalling

A

For macrophages (innate)
> Cyto/chemokine secretion > inflammation
For Dendritic cells (adaptive)
> migration, antigen presentation, co-stimulation: naive T-cell priming

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19
Q

Co-stimulatory signal from mDCs to naive T-cells

A

CD80/86 on DC
CD28 on T-cell

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20
Q

T-cell cycling through lymph nodes

A
  • T-cell enters LN cortec via high endothelial venules (HEVs)
  • when not activated, leave within hours through HEVs
  • when activated by APC DCs, lose ability to exit T-cell zone and begin proliferation and differentiation into effector T-cells and exit via cortical sinuses
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21
Q

What do all T-cells do in LNs (naive)

A

Bind the DC with integrins and ‘try’ their TCR with the epitope
> not recognition: leave towards other LN
> recognition: stay

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22
Q

What happens upon TCR - MHC/peptide binding

A
  • Make very intimate synapse: immunological synapse
  • Interact via co-stimulation and costimulatory cytokines
    > once synapse formed: signal 2: CD80/86 (DC) - CD28 (T-cell)
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23
Q

When is CD80/86 upregulated on DC?

A

Only when PAMP triggering of DC by PRR like TLR
> so, recognition of CD80/86 by nT-cell is to check that DC has seen a pathogen

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24
Q

T-cell and DC
> signal 1: TLR-MHC/Peptide
> signal 2: costimulation
What happens when:
- Only signal 1
- signal 1 + 2

A

Only signal 1: inactivation of T-cell > anergy of T-cell (anergic T-cell)
Both: clonal expansion

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25
Q

Signal 3 in T-cell activation

A

Cytokines released by DC into immunological synapse
> for differentiation signal to make cell a CD8+ cytotoxic T-cell or to different CD4+ T helper cell subtypes

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26
Q

Cytokines (signal 3) for CD8+ T-cells drive:

A

Upregulation signals for perforins, granzymes and FAS-ligand > to induce apoptosis in target cells

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27
Q

Types of CD8+ T-cells

A

Naive, memory and effector

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28
Q

Cytotoxic T-cell (CTL) killing mechanism

A
  • Perforines and granzymes secreted in immunological synapse between target cell and CTL
  • Perforines make hole in cell membrane
  • Granzymes induce apoptosis in cell when entering
  • Or: upregulation FAS-ligand to recognize FASR on target cell (death receptors)
    > Apoptosis rather than necrosis: no release intrinsic contents > little leakage
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29
Q

DAMPs

A

Danger Associated Molecular Patterns
> related to autoimmunity
> are inside cells, sometimes released by necrosis, and can induce immune response against healthy cells like PAMPs do

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30
Q

Immunological synapse (IS)

A
  • Strong interaction after TCR recognition
  • DC and T-cells make extensions > interfacial podosomes: for maximal interaction
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31
Q

IS: SMACs

A

On outside of synapse: adherence, and on inside: TCR and costimulation
> Most cytokines are secreted in synapse core (in autoimmunity also outside synapse)
> cSMAC: central supramolecular activation cluster: TCR, CD28, CD4, CD8 and cytokies
> pSMAC: peripheral supramolecular activation cluster: adherence

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32
Q

Signal 4 of APC-T-cell

A

Homing inducing signal
> upregulate some chemokine receptors to direct T-cells to a certain direction for certain chemokines
> most important homing: go through circulation and pass by chemokines nearby the infecion site

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33
Q

CD4+ effector T-helper cells and functions

A

Th1: help macrophage kill all phagocytosed contents better, for resistant microbes to innate response, and help in CTL maturation and response
Th2: promote eosinophils, neutrophils and mast cells in response against helminth parasites
Th17: promote neutrophils for killing of extracellular bacteria
Tfh: assist B-cell antibody response to create plasma cells which secrete antibodies for nearly all microbes
Treg: when little costimulation, create tolerance

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34
Q

Th1 cytokine released to macrophages with intracellular microbe

A

IFN-y, released in IS

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35
Q

Differentiation to Tregs

A

TCR- MHCII/Peptide
Little CD28-CD80/86 costimulation
TGFb and IL-10

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36
Q

Cancer and cytokines made

A

Upregulate TGFb and IL-10 to create tolerance and no attack to tumor

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37
Q

Targets of all CD4+ T-cell subtypes

A

Th1: bacteria and tumor
Th2: parasites
Tfh: help antibody production
Th17: neutrophul activation, fungi/bacteria
Treg: downmodulation/tolerance

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38
Q

Which signal regulates pathogen class-specific CD4+ Th differentiation

A

PRRs and PAMP signal regulates which cytokines produced by APC, which determines the differentiation

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39
Q

Costimulatory cytokines and T helper subtypes

A

Made by APC
Th1: IL-12
Th17: TGFb, IL-1, IL-6
Treg: low costimulation and TGFb and IL-10 (no TLR activation)

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40
Q

Which T-cells involved in response to extracellular pathogen: bacteria?

A
  • CTLs
  • Th1: help CTLs
  • Tfh: help B-cells make antibodies for extracellular bacterium
  • Th17: promote neutrophils in extracellular bacteria killing
    > multiple TLRs activated > multiple CD4+ T-cell subtypes made. > one TLR for one cytokine program
41
Q

IFN-y as confirmer

A

Confirms the Th1 phenotype by contributing to progeny to being Th1

42
Q

Th1/2 plasticity

A

Can interchange when getting too much IFN-y (Th1) or IL-4
> little plasticity

43
Q

Acquired B-cell response: B-cels differentiates to two antibody secreting cells:

A
  • Plasmablasts
  • Plasma cells
44
Q

B-cell precursor to plasma cell or memory cell

A
  • B-cell precursor rearranges its immunoglobulin genes in bone barrow
  • Negative selection in bone marrow: immature B-cell bound to self-surface antigen in bone marrow is removed from repertoire by receptor editing or apoptosis
  • Mature B-cell bound to foreign antigen is activated (in LNs or lymphoid organs like spleen
  • Activated B-cells give rise to plasma cells or memory cells: antibody secretion and memory in lymphoid tissue and bone marrow
45
Q

Signals for B-cell activation, survival and proliferation, in case of thymus-independent antigen

A

Signal 1: BCR signal
> Pro-apoptotic and activation signal
> Three dimensional antigen
Signal 2: TLR signal
> Anti-apoptotic signal
> Three dimensional epitope (PAMP)
Only signal 1 > apoptosis

46
Q

BCR structure and Fc, Fab, Fab2

A
  • Two heavy chains and two light chains
  • Disulfide bonds
  • Antigen binding fragment with three antigen specific variable loops on ends: Fab
  • Fc: constant tail
  • Fab2 fragment: two Fab fragments together: the variable Y form with disulfide bond between them
  • both heavy chain and light chain have 3 loops: six loops per Fab fragment
47
Q

What happens after naive B-cell activation? T cell independent

A

Differentiation to short-living plasmablast that makes IgM only
> always made
> early response, when no T-cells to assist

48
Q

Affinity BCR

A

Low affinity > low binding energy per Fab
» which is okay: when enough BCR bound to antigen then still activation: high total avidity (total binding force) of the B-cell

49
Q

IgM structure

A

Secreted as multimer complex (pentamer) by crosslinking the pentamer with the J-chain (joining chain)
» increase avidity

50
Q

BCR is either … or …

A

IgM or IgD

51
Q

IgM compared to other antibodies

A
  • Produced immediately
  • Low affinity
  • Penta / hexamer
  • Does not need T-cell help or GC reaction
52
Q

Use of Penta/hexameric structure of IgM

A

IgM does not need somatic hypermutation and affinity maturation > low affinity. So the multimeric structure generates high avidity.

53
Q

IgM and localization

A

It is big > cannot easily extravasate to infection site

54
Q

IgM and opsonization

A

Is not very good, no free Fc tails avaiable where macrophages and other phagocytes can bind to with Fc receptors to phagocytose targeted pathogen

55
Q

Where is IgM very good for?

A

Complement activation!

56
Q

What is needed to make other antibodies than IgM?

A

T-cell help

57
Q

Three signals for B-cell activation, survival and proliferation: Thymus-dependent antigen

A

Signal 1: BCR
Signal 2: MHC-II - TCR
> B-cell can phagocytose antigen upon binding to BCR and break down content and load on MHC-II to activate T-cell
» B-cells can express CD40 that binds CD40L on T-cell as co-stimulation.
» In the B-cell zones of the LNs
Signal 3: cytokines

58
Q

Germinal centre creation

A

B-cells that encounter antigen in follicle of LN form primary focus, some proliferating B-cells migrate into follicle to form germinal centre
> after GC reactions: plasma cells migrate to medullary cords or leave via efferent lymphatics to bone marrow to stay as long living plasma cells

59
Q

Plasma cells function

A

Make steady-state protecting antibodies

60
Q

Memory cells made in which B-cell response?

A

Mainly in T-cell dependent B-cell response.

61
Q

Signal 1 of T-cell dependent B-cell response

A

BCR
> upon activation: CD40 upregulation and phagocytosis and MHC-II loading with antigen linear peptide to present to T-cells.
> All activated B-cells get chemokine receptor to go to T-cell zone and some T-cells get chemokine receptor to go to B-cell zone
> meet on the edge of zones to interact
> only T-cell help when antigen is presented by the B-cell (to check: B-cell is directed to the specific pathogen / antigen)
> pro-apoptotic signal

62
Q

Signal 2 of T-cell dependent B-cell response

A

MHC-II/ linear peptide to TCR
> anti-apoptotic signal
> Co-stimulation CD40

63
Q

Signal 3 of T-cell dependent B-cell response

A

CD4+ T-cell (Tfh) cytokines: IL-21 for IgG generally!
> induce specific class-switching by IL-21 and CD40 signalling by CD40L of Tfh (to IgG/ IgE, somatic hypermutation and affinity maturation) > eliminate antigens with high-affinity antibodies

64
Q

Difference lacking signals of B-cells and T-cells in activation

A

T-cells become anergic
B-cells undergo apoptosis and die

65
Q

Presentation antigen on MHC by B-cell

A

Phagocytose whole pathogen, breaks it down to present it upon BCR recognition: phagosome fuses with the vesicle containing MHC-II

66
Q

Results B and T-cell interaction

A

Both start dividing, and maturing of B-cells to make more IgM and IgG

67
Q

Which three components essential for IgG response

A

Pathogen, T-cell (for CD40L and IL-21), B-cell

68
Q

Tfh cells in B-cell help

A

Needed for the germinal centre reaction and therefore for long-lived immunity
» B-cells which leave after first- T-cell interaction and do not enter GC reactions: become short-lived plasmablasts and early memory B-cells (IgM producing cells ready to make GCs after re-infection)
» Tfh cells give TCR signal and CD40L costimulation with Il-21 for survival and class switch and further SHM

69
Q

When are B-cells going to B-cell zone for GC reaction rather than leave to become plasmablast?

A

After receiving signals 2 and 3 from the Tfh cell
> CD40L to CD40
> IL-21 to IL-21R

70
Q

GC reactions create specific memory B-cells, why needed

A

Higher affinity needed and class-switching
> create high affinity memory B-cells and short and long-living plasma cells > after re-infection directly to plasmablasts and plasma cells

71
Q

Where do plasma cells go upon maturation?

A

To bone marrow to create high affinity antibodies for long time

72
Q

Germinal centre reactions (name the zones as well)

A

Initial contact: border T-cell zone and GC light zone
> Then: B-cell to GC dark zone (because, many nuclei): proliferation, somatic hypermutation and class-switch recombination
> Then: Antigen acquisition in light zone by interacting with FDC (follicular DC) which presents antigen to BCR: take it up
> Then: Present antigen on MHC-II and co-stimulation with CD40 (via BCR signalling) to Tfh cell and receive cytokines
> Then: if high affinity: leave for differentiation and migration
> or if not high affinity enough: go back to dark zone for another cycle (affinity maturation)

73
Q

Somatic Hypermutation

A

Induce mutations on antigen binding site loops when proliferating

74
Q

What happens to all B-cells coming fro first GC reactions in dark zone when returning in light zone?

A

First: do they recognize the antigen of the FDC better with their BCR?
> Yes: capture it and present to T-cell (Tfh) with CD40 which is upregulated
» receive survival and mitogenic (induce mitosis, proliferation) signals via CD40 and cytokines: go back to dark zone
> No: no antigen capture by interacting with FDC: death by neglect

75
Q

Which form of cell death is death by neglect of B-cells?

A

Apoptosis

76
Q

In affinity maturation, regular antigen check with FDCs is needed. What makes FDCs special dendrites?

A

They can hold antigens for a long time

77
Q

Class-switch recombination

A

T-cell gives signals to induce this after interaction (CD40L+IL-21)
> Different switch regions before the genes for parts of different antibodies
> Switch regions before different gene regions can interact and loop out parts of DNA (is irreversible because DNA level)
> Switch to different antibody type
> most 5’ is the C-mu part (determining IgM)
> switch to C-delta (IgD, rare), C-gamma (IgG), C-epsilon (IgE) or C-alpha (IgA) (in this order 5’>3’, so all parts need to be looped out except C-alpha to get IgA, whereas only C-mu and C-delta out for IgG)

78
Q

Why are there many C-gamma genes?

A

Multiple subclasses of IgG

79
Q

How is class-switching, also called isotype switching, determined?

A

By costimulatory cytokines received from T-cells, IL-21 for IgG

80
Q

IL-4 induces the subtype…. and IL-12 the subtype …

A

IL-4 > IgG1 and IgE
IL-12 > IgG3, IgG1, IgA

81
Q

Different isotypes of antibodies have different functionalities. Name those

A

Best opsonization: IgG
Best complement activation: IgM and IgG3
Best neutralization: IgG and IgA
Best sensitization of mast cells: IgE
(IgD is weird, worst at everything, function not clear)

82
Q

Why is opsonization by IgM and IgA not very good

A

IgM is penta/hexamer, IgA is dimer
> no free Fc tails for Fc-receptors of phagocytes

83
Q

Selection upon after GC reactions: results

A

Class-switched during GC reactions
Selected for affinity matured high-affinity cells to differentiate to plasma cells and B memory cells

84
Q

Where does the affinity maturation selection step take place?

A

At FDC and B-cell interaction
> if antigen taken up and presented to Tfh cell > then further selection

85
Q

IgA antibodies may lay ready on mucosae to bind pathogens: can viruses or other pathogens still bind receptors of human target cells for infection?

A

Yes

86
Q

Transcription factor markers for differentiation for plasmablast vs plasma cell

A

Plasmablast: Blimp1
Plasma cell: Pax5

87
Q

Big research question in B-cell research is how TFs for differentiation of maturing B-cells after affinity maturation for differentiation is acquired. Which markers are there for plasma cells?

A

CD38, CD27, CD138

88
Q

Why matching HLA in blood transfusion? How to detect mistakes early? Why?

A

No antibody response wanted > inflammation and lung problems
> sickle cell anemia requires blood donation
> prevent plasma cells from going to bone marrow, then permanent autoimmune response
> research into selecting B-cell maturing for differentiation needed
> markers needed for maturing B-cells (before the plasma cells)

89
Q

Markers for long living B memory cells

A

Not there yet

90
Q

In vitro B-T cell interactions for differentiation

A

3T3 (epihelial) cells with induced CD40L expression in lab and added IL-4 and IL-12 in vitro to naive B-cells
» BCR signal is to present peptides, but CD40 and cytokine signals (and how strong they are) determine how the B-cell differentiates

91
Q

CD27 and CD38 in scatter plot (FACS): what are the double positives and double negatives?

A

Double positives: PB/PC: plasma blast or cell
Double negatives: naive B-cell

92
Q

Why no PB/PC formed after B-T cell interaction in culture

A

The B-cell needs to get the signal multiple times
> adding new cytokines to replicae GC reactions
> PB/PC formed

93
Q

How to analyze pre-stadia between naive B-cell and PB/PC

A

Single-cell RNA-seq and clustering with UMAP to show cell populations
> Different populations: one is high in Pax5 (PB) and one in Blimp1/Prdm1 (PC)
> quite dramatic transition state: no intermediated population shown

94
Q

Analysis B-cell premature stages with SARS-CoV-2 research

A

rGCG (recent Germinal Centre Graduate) is precursor of short-lived plasmablast and long-lived plasma cells from GC reactions
> put biotin on Spike (S) antigen > streptavidin (binds biotin) bound to fluorophore > incubate > B-cells bind with fluorophore
> SARS-CoV-2 specific B-cells found with different fluorophores
> performed with other epitopes as well and controls like tetanus toxoid
> more severe disease: higher antibodies for Receptor binding domain (RBD) antigen and NC markers against SARS-CoV-2

95
Q

Antibody titers over time:

A

Decrease

96
Q

scRNAseq of SARS-CoV-2 incubated B-cells: which markers and which population

A

Resting memory and activated memory and active B-cells (plasma cells)
> CD73: for long-living memory B-cells (resting memory B-cells have less than active ones, long ago)
> CD71: decreasing gradient,: activated IgG B-cells (rGCGs) that have recently undergone GC reactions express CD71 and CD43

97
Q

Which B-cells more enriched with more severe disease?

A

IgG+ memory B-cells and activated IgG B-cells (rGCG)

98
Q

Activated IgG B-cells are precursors for:

A

Antibody secreting cells (ASCs) but also possibly B memory cell precursors.
> MBs (memory) go from active to resting

Immunology: Research + Clinic (7 decks)

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