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I&I SC1 > Humoral adaptive immunology > Flashcards

Humoral adaptive immunology Flashcards

Lectures: -Week 1, day 3, lecture 2: Adaptive immune response - humoral -Week 3, day 3, lecture 2: Developmental aspects - B-cell development

1
Q

What do we mean by humoral immunity?

A

Humoral immunity refers to soluble macromolecules that are directed against pathogens

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2
Q

What are the three main groups of macromolecules involved humoral immunity? Are they innate or adaptive?

A
  1. Antimicrobial peptides, innate
  2. Complement proteins, mostly innate (can also be activated by antibodies)
  3. Secreted antibodies, adaptive
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3
Q

Which two phases can be distinguished in B-cell development?

A
  1. Antigen-independent B-cell differentiation in the bone marrow
  2. Antigen-dependent B-cell differentiation in perhipheral blood
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4
Q

What are the three main functions of antibodies?

A
  1. Neutralization of particles
  2. Opsonization: improve uptake by phagocytes
  3. Complement activation (classical pathway)
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5
Q

Where does gene rearrangement of B-cells take place?

A

Bone marrow

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6
Q

What is the structure of an antibody?

A

2 identical heavy chains + 2 identical light chains (either κ or λ), connected by disulfide bonds

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7
Q

How do antibodies promote phagocytosis?

A

By FcR-mediated endocytosis

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8
Q

Which complement pathway is activated by antibodies?

A

Classical pathway

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9
Q

Which domain of the antibody determines its antigen specificity?

A

Variable domain

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10
Q

Which domain of the antibody determines its biological function?

A

Constant domain

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11
Q

What is the difference between a B-cell receptor (BCR) and an antibody?

A

Antibodies are the BCR without a membrane anchor, allowing them to be secreted
These are created from the same gene through alternative splicing on RNA-level

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12
Q

Which 3 mechanisms add to antibody diversity?

A
  1. VDJ-recombination
  2. Combination of different heavy and light chains
  3. Junctional diversity: p- and n-nucleotide addition
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13
Q

What does the membrane anchor of a BCR consist of?

A

~25 hydrophobic amino acids

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14
Q

How is made sure that only one of the heavy and one of the light chain gene is expressed?

A

Allelic exclusion -> when a succesfull rearrangement is made and the (pre)receptor is functional, the other allele is shut down

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15
Q

What happens when the first rearrangement of the heavy chain is not succesful?

A

The B-cell will try to produce another succesfull arrangement with the other heavy chain allele

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16
Q

What is a pre-B-cell receptor (pre-BCR)? What is its function?

A

The product of the combination of a rearranged heavy chain with a surrogate light chain. Is used to test the heavy chain.

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17
Q

Can a pre-BCR bind antigen?

A

The pre-BCR cannot bind antigen

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18
Q

Where does negative selection of B-cells take place?

A

Bone marrow; it should not react to any self-antigen present there

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19
Q

What options are there when a B-cell reacts to self-antigen in the bone marrow?

A
  1. When binding a multivalent self-molecule: clonal deletion or receptor editing
  2. When binding a soluble self molecule: migration to periphery where the B-cell enters a state of anergy
  3. When binding a low-affinity non-cross-linking self molecule: migration to periphery, where the B-cell becomes clonally ignorant
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20
Q

What is receptor editing?

A

The B-cell will do another light chain arrangement to try to produce a BCR that is not self-responsive

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21
Q

What is an epitope?

A

The part of an antigen that is recognized by a BCR/TCR

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22
Q

What kind of interaction does an antibody have with an epitope/antibody?

A

Non-covalent binding

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23
Q

Which two signals are required for B-cell activation?

A
  1. BCR activation
  2. Encounter of repetitive structures (thymus-independent) or stimulation by Th-cells (thymus-dependent)
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24
Q

What are thymus-independent antigens?

A

Antigens that can activate a B-cell without the need for a Th-cell; these require repetitive structures on the surface of pathogens because this allows multiple BCR’s to activate simultaneously and crosslink, resulting in a strong signal
Example: LPS

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25
Q

What are thymus-dependent antigens?

A

Antigens that require Th-stimulation in order to activate B-cells

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26
Q

What is the difference between B-cells that can be activated by thymus-independent antigens and B-cells that are activated by thymus-dependent antigens?

A

B-cells that are activated by thymus-independent antigens don’t undergo a germinal centre reaction

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27
Q

What class of antibodies is secreted by B-cells that are activated by thymus-independent antigens, and why this class?

A

IgM, B-cells that are activated by thymus-independent antigens don’t undergo a germinal centre reaction, and therefore do not undergo class switch recombination

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28
Q

What is the process of thymus-dependent B-cell activation?

A
  1. B-cell takes up the antigen and presents it in MHCII to a Th-cell
  2. If the Th-cell recognizes the same antigen, it will provide costimulation to the B-cell, activating it
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29
Q

True or false: a Th-cell recognizing antigen presented by a B-cell in MHCII has to be specific for the same epitope as the B-cell

A

False -> they don’t have to be specific for the same epitope, as long as they recognize the same antigen

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30
Q

What is an additional requirement for Th-cells to be able to be activated by B-cells and in turn activate the B-cells?

A

The T-cell has to be primed by a DC (presenting the same antigen)

31
Q

Which receptor-ligand interaction takes place between the Th-cell and the B-cell in order to activate the B-cell?

A

CD40 (B-cell)/CD40L (T-cell)

32
Q

Why does thymus-dependent B-cell activation cause a stronger immune response? (2)

A
  1. Leads to long lived plasma cells (thymus-independent activation does not)
  2. Induces somatic hypermutation and class switch recombination
33
Q

What is linked recognition?

A

A T-cell and B-cell recognizing the same antigen, and thus being able to activate eachother (not the same epitope!)

34
Q

What is the process of B-cell activation in the lymph node?

A
  1. DC loaded with antigen enters the lymph node through afferent lymphatics and activates a Th-cell
  2. Th-cell activates B-cells -> begin to divide
  3. Some of these B-cells will encounter antigen in the lymphatic fluid in the T-cell zone, causing their BCR to be activated. These cells will form a primary focus.
  4. Some proliferating B-cells migrate to a follicle to form a germinal centre, others leave the lymph node as plasma cells
35
Q

Which two processes take place in the germinal centre reaction?

A
  1. Somatic hypermutation
  2. Class switch recombination
36
Q

In which part of the follicle does somatic hypermutation take place?

A

Dark zone of the follicle

37
Q

Which process takes place in the light zone of the follicle?

A

The light zone contains follicular dendritic cells that present antigen to B-cells that have undergone affinity maturation; B-cells that have a high affinity get selected to proliferate, B-cells that have lower/no affinity get selected out and undergo apoptosis

38
Q

Where does apoptosis of B-cells that have a low/no affinity after somatic hypermutation take place?

A

The mantle zone of the follicle

39
Q

How long after antigen stimulation does a germinal centre reaction take place?

A

~1 week after first stimulation

40
Q

True or false: follicular dendritic cells are not of haematopoietic origin

A

True: these cells are not of haematopoietic origin, but are part of the stromal cells of the lymph node

41
Q

How do follicular dendritic cells bind antigen and present it to B-cells? What is this process like?

A

Follicular DC’s bind and present antigen in Fc-receptors and complement receptors (CR’s). B-cells take up this antigen and process it to present it on MHCII to T-follicle helper cells (Tfh-cells) -> these provide survival signal to the B-cells

42
Q

How do cutting enzymes identify where to make DNA-breaks for class switch recombination?

A

Switch regions: repetitive sequences of DNA that allow for recombination

43
Q

Why can cells only undergo class-switching to a class that is downstream of their current class?

A

In class switch recombination, all upstream genes are deleted

44
Q

How do Th-cells direct class switch recombination?

A

Different subsets of Th-cells produce different cytokines, that induce class switching to different classes (e.g. TH1 = IFN-γ -> switch to IgG2/IgG3, whereas Th2 = IL-4 -> class switch to IgG1/IgE or IL-6 -> class switch to IgA)

45
Q

Which enzyme is involved to generate gene mutations in somatic hypermutation and class switch recombination? How does the same enzyme induce different effects?

A

AID
In somatic hypermutation, AID introduces a low density of AID-dependent lesions -> leads to mutations
In class switching, AID introduces a high density of AID-dependent lesions -> ssDNA-breaks that allows for the occurrence of dsDNA breaks, which get repaired by non-homologous end-joining or alternative end-joining

46
Q

What is the ‘default’ class of Ig of B-cells before class switching?

A

IgM/IgD

47
Q

How can a B-cells that has not undergone class switch recombination produce IgM antibodies and IgM/IgD BCR’s?

A

Alternative splicing of the same primary transcript to a Fc-domain (IgM antibody), μ-domain (IgM BCR) or δ-domain (IgD BCR)

48
Q

True or false: in class switch recombinations, frameshifts can occur

A

False: the switch regions ensure recombination without frameshifts

49
Q

What is the structural makeup of IgM?

A

Pentamer bound together by J-chains

50
Q

What is the structural makeup of IgA?

A

Dimer bound together by J-chains

51
Q

What is the advantage of multimerization of antibodies in IgA and IgM?

A

Allows for higher avidity -> low affinity (mainly IgM) compensated by the fact that there are many binding sites in the antibody multimer

52
Q

What is the avidity of an antibody? When is a high avidity especially important?

A

Affinity*number of antigen binding sites
A high avidity is important to bind pathogens with repetitive structures on their surface

53
Q

Where in the body is IgM mainly found, and why?

A

In the blood, because the high molecular weight of the pentamer makes it diffucult to penetrate into the tissue

54
Q

Why is the affinity of IgM low?

A

B-cells that produce IgM have not undergone a germinal centre reaction, and therefore also no somatic hypermutation

55
Q

In which of the three functions of antibodies (neutralization, opsonization, compliment activation) is IgM specialized?

A

IgM mainly induces a strong complement activation

56
Q

Which isotype of antibody is most abundant in serum?

A

IgG

57
Q

Which types of IgG can be identified?

A

IgG1, IgG2a, IgG2b, IgG3, IgG4

58
Q

Which isotype of antibody can be moved through the placenta?

A

IgG

59
Q

Which of the three functions of antibodies (neutralization, opsonization, complement activation) are carried out by the different IgG’s?

A

IgG1 = neutralization, opsonization, complement activation (+NK-activation)
IgG2 = neutralization, complement activation (weak)
IgG3 = neutralization, opsonization, complement activation (strong)
IgG4 = neutralization, opsonization (weak)

60
Q

Where in the body is IgA found?

A

Mucosal tissues and secreted fluids

61
Q

Where are IgA-secreting plasma cells located?

A

Lamina propria of mucosal tissues

62
Q

What is the name of the process that allows IgA to cross the epithelium? What are the steps of this process? (4)

A

Transcytosis:
1. Binding to poly-Ig-receptor
2. Endocytosis
3. Vesicular transport
4. Exocytosis

63
Q

How does IgA protect the mucosal tissues from pathogens?

A

Prevens attachments of pathogens to the epithelium (neutralization)

64
Q

How can maternal IgA be transferred to a child?

A

IgA is secreted in milk, and can be taken up into the blood in the gut

65
Q

The serum concentration of IgE is [high/low]

A

Low

66
Q

Where can IgE be found?

A

IgE can be found bound to high affinity Fc-ε receptors on mast cells and basophils

67
Q

What is the effect of an antigen binding to IgE bound to mast cells/basophils? What is released, and what does this often result in?

A

Degranulation, releasing histamine, prostaglandins and leukotrienes -> allergic reactions

68
Q

Where are mast cells located?

A

In the mucosal tissues of the gut, in the skin and in the lungs

69
Q

Where are basophils located?

A

Basophils that have not bound IgE circulate in the blood; upon binding IgE they move into tissues

70
Q

What is the original immunological function of IgE and mast cells/basophils?

A

Immune responses against parasitic worms

71
Q

What is the function of IgD?

A

The function of IgD is mostly unkown

72
Q

What are the characteristics of plasma cells? (4)

A
  1. Secretion of large amounts of antibodies
  2. Large cytoplasm and high density of RER
  3. No expression of membrane-bound Ig or MHCII
  4. Lifespan: several weeks up to years
73
Q

What are the characteristics of memory B-cells? (3)

A
  1. Only membrane-bound Ig
  2. Rapidly reactivated upon re-encounter with antigen
  3. Can survive for many years
74
Q
A

I&I SC1 (20 decks)

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