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MB4030 > L4: Immunological Memory > Flashcards

L4: Immunological Memory Flashcards

1
Q

Which region encodes most of the antibody’s specificity?

A

CDRH3

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2
Q

Which regions of the antibody form the paratope (antigen-binding site)?

A

The hypervariable regions (CDRH1, CDRH2, CDRH3)

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3
Q

What drives the diversity of the B cell repertoire?

A

The combination of VDJ gene random recombinations coupled with N-nucleotide deletions and insertions

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4
Q

Why do only a small percentage of the overall B cells produced in the bone marrow ever exit the bone marrow?

A

A combination of failed recombinations and the deletion of self-reactive B cells/antibodies

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5
Q

3 main cell fates of naive B cells?

A
  1. They become plasmablasts and SLPCs, producing large amounts of secreted antibody
  2. Differentiate into LLPCs
  3. Become memory B cells (MBCs)
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6
Q

The migration process of naive B cells is controlled by

A

Cytokines, chemokines and adhesion molecules
(tightly regulated, adhesion cascade slows the movement of B cells)

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7
Q

Types of B cells

A

Naive B cells, plasmablasts, SLPCs, LLPCs, MBCs

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8
Q

Which chemokine is produced by macrophages and attracts neutrophils to the site of infection?

A

IL-8 (CXCL7)

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9
Q

Cells expressing CCR7 migrate to lymph nodes in response to secretion of which ligands?

A

CCL19 and CCL21

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10
Q

Lymph arrives to lymph nodes via

A

several afferent lymphatic vessels

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11
Q

Lymph leaves lymph nodes via

A

one efferent lymphatic vessel

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12
Q

How do naive B cells enter lymph nodes?

A

Via high endothelial venules (where homing of immune cells from circulation occurs)

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13
Q

What is the hilus of the lymph node?

A

Blood vessel entry/exit point

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14
Q

Where in the lymph node would you find B cells?

A

Cortex

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15
Q

Where in the lymph node would you find T cells?

A

Paracortex and medulla

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16
Q

Where are plasmablasts located in the lymph node?

A

Subfollicular area

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17
Q

What would you mainly find in the primary follicle of the lymph node?

A

Mature naive B cells

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18
Q

What are the sites of B cell proliferation in the lymph node?

A

Germinal centres

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19
Q

What do B cells do if they don’t encounter an antigen in the cortex of the lymph node?

A

They can exit the lymph node via the efferent lymphatic vessel and migrate to other lymph nodes or the spleen. Eventually B cells that do not encounter their antigen die by neglect (apoptosis).

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20
Q

What is B cell tethering?

A

L-selectin on B cells interacts with many HEV sialomucins, such as CD34, to slow down B cell movement (‘sticking’)

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21
Q

What is B cell arrest?

A

Chemokine receptors on the B cell surface (CCR7, CXCR4, CXCR5) trigger a process that leads to the expression of LFA-1 (an adhesion molecule) on B cells

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22
Q

What chemokine is expressed on the surface of HEVs?

A

CCL21 (receptor CCR7)

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23
Q

What chemokines are secreted by lymph node stromal cells?

A

CXCL12 (receptor CXCR4) and CXCL13 (receptor CXCR5). These ligands are immobilised on the surface of HEVs by heparin sulphate, allowing them to interact with their receptors on B cells.

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24
Q

What does LFA-1 bind to on HEV?

A

ICAM-1 and ICAM-2

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25
Q

Which chemokine attracts naive B cells to the subfollicular and follicular regions of the lymph node?

A

CXCL13/CXCR5 interaction

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26
Q

What do follicle stromal cells release?

A

BAFF, a critical B cell survival factor

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27
Q

What are examples of specialised APCs that can capture incoming antigens?

A

Follicular dendritic cells (FDCs) and tingible-body macrophages (TBM). These APCs migrate into the B cell zone of the lymph node and can display these unprocessed antigens for weeks to B cells.

28
Q

What is unique about FDCs?

A

They can capture particulate antigens in a non-phagocytic way and supply continuous supply of antigen during the B cell response. In this case, the APC (FDC) does not take up the bacteria/virus. The bound antigen is internalised in a clathrin-dependent manner.

29
Q

What cells supply the very earliest antibodies to the antigen?

A

Plasmablasts

30
Q

Main differences between plasmablasts and SLPCs?

A

Plasmablasts proliferate more, are shorter lived, but do not produce as much antibody

31
Q

Do plasmablasts undergo SHM?

A

No. Therefore, the affinity of their Abs for Ag tend to be moderate and unchanged.
But they may undergo some class switching to IgG

32
Q

Where do SLPCs accumulate?

A

In medullary cords (located in hilus region near efferent vessel) of lymph nodes, and red pulp of spleen. Their lifespan roughly correlates to the course of the infection. They do not have any role in the generation of long-term memory.

33
Q

Some B cells that have been successfully stimulated by their antigen do not go on to be SLPCs but

A

migrate further into the follicle to enter a GC response, giving rise to LLPCs that can live and produce Ab for months-years.

34
Q

Where do LLPCs mainly relocate?

A

Bone marrow and GALT

35
Q

What is the main objective of an ideal vaccine?

A

Generation of long-lived plasma cells

36
Q

Where does SHM and affinity maturation take place?

A

Germinal centres

37
Q

What enzyme is expressed by germinal centre B cells?

A

AID = activation-induced cytidine deaminase

38
Q

What can lead to the development of GC B cells Lymphomas?

A

High mutation rate in B cells (the rate of mutation in Ig V-regions is much higher than the rate in normal somatic cells)

39
Q

What survival factor do GC B cells express and what does it do?

A

Bcl6 - prevents premature activation and differentiation of GC B cells, also provides an environment for SHM and CS

40
Q

What is essential for positioning GC B cells to the DZ?

A

CXCR4

41
Q

What chemokine does the DZ produce?

A

CXCL12/SDF-1

42
Q

What occurs in the dark zone of the germinal centre?

A

B cell clonal expansion and somatic hypermutation

43
Q

What occurs in the light zone of the germinal centre?

A

The site of selection by antigen binding

44
Q

What do FDCs act as?

A

Long-term reservoirs of intact antigen

45
Q

What are T follicular helper cells positive for?

A

CD4, Bcl-6, CXCR5, PD-1

46
Q

What cells are strongly stimulated by Tfh cells?

A

B cells that have high numbers of high affinity BCR and MHC Class II-bound peptide receptors

47
Q

How do Tfh cells play a role in binding more antigen and rescuing cells from apoptosis?

A

By secreting IL-4, IL-21 and IFN𝛾

48
Q

B cells not receiving sufficient signals from Tfh cells succumb to?

A

Fas-mediated apoptosis, FasL on Tfh. This selects for B cells with high affinity for antigen by forcing them to compete for Tfh cell help. These cells then either become LLPCs or MBCs.

49
Q

Which cells form the basis of life-long immunity?

A

Memory B cells

50
Q

Characteristics of MBCs?

A

Typically GC-derived, class-switched and hypermutated. Can proliferate much faster than naive B cells to form plasmablasts/LLPCs, or they can reenter GCs and undergo further proliferation/SHM to produce more MBCs. Reexposure to Ag also leads to rapid reactivation of MBCs in spleen and LNs to produce Ab-secreting SLPCs.

51
Q

As the concentration of antigen decreases with time, B cells with a higher affinity for the antigen…

A

receive survival signals from DCs and Tfh cells. They also turn on anti-apoptosis pathways.

52
Q

What does SHM bring about?

A
  1. Point mutations in V gene (H and L chain genes)
  2. Affinity maturation of Ab
    (More mutation seen after secondary and tertiary immunisations)
53
Q

Mutation can change the nucleotide sequence of the original B cell close by as much as

A

5% - which is about 10 amino acid changes clustered in the V gene region!

54
Q

What enzyme initiates somatic hypermutation?

A

Activation-induced cytosine deaminase

55
Q

AID-promoted SHM appears to preferentially target…

A

transcriptionally active regions of the Ig H chain locus. This mainly occurs in the G1 phase of the cell cycle. AID preferentially targets WRCY motif.

56
Q

Evolution has selected for CDRs enriched in…

A

codons with AID ‘hotspots’

57
Q

Very high levels of SHM are seen in?

A

Chronic viral infections e.g. 15-30% of nucleotide substitutions are seen in CDR regions producing anti-HIV antibodies

58
Q

When is T cell immunity particularly important?

A

In response to viruses and cancer

59
Q

Main function of T cells?

A

Help other parts of the immune system

60
Q

Where does T cell differentiation take place?

A

in the thymus

61
Q

What are the 4 different types of T cells?

A

CD4+ T helper cells, CD8+ Cytotoxic T cells (CTLs), Natural Killer (NK) cells, and Regulatory T cells (Tregs)

62
Q

Primary role of Th cells?

A

Produce cytokines that help the efficient functioning of phagocytes, APCs, B cells, CTLs and NK cells

63
Q

Role of CTLs?

A

Recognise pathogen peptides bound to MHC molecules on the surface of virus-infected cells and cancer cells, and kill these cells by apoptosis

64
Q

Role of NK cells?

A

Detect and kill cells that do NOT have MHC molecules on their surface

65
Q

Role of Tregs?

A

Control and regulate the immune response by suppressing or down-regulating the immune response following control of an infection

66
Q

What are the 4 different subclasses of Th cells?

A

Th1, Th2, Th17 and T follicular helper cells

MB4030 (10 decks)

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