Lecture 24: Effector Mechanisms of Humoral (B cell) Immunity

Question 1

What are all the steps that occur in the life cycle of a B cell?

Answer 1

B cells develop / mature in the BM -> gene rearrangement / clonal deletion -> mature B cells leave the BM -> B cells encounter antigen -> clonal expansion -> isotype switching / affinity maturation / memory

Question 2

What do plasmablasts aid in?

Answer 2

short-lived extrafollicular antibody production

Question 3

What do plasma cells aid in?

Answer 3

long-lived humoral immunity

Question 4

What is a germinal centre?

Answer 4

the location where B cells can undergo two important modifications that ‘matures’ the antibody response

Question 5

What are the two important modifications that ‘matures’ the antibody response?

Answer 5

affinity maturation and isotype (class) switching

Question 6

What is affinity maturation?

Answer 6

antigen binding site develops higher affinity for antigen

somatic hypermutation

Question 7

What is the result of affinity maturation?

Answer 7

changes in the B cell receptor lead to increasing affinity and as a result the humoral response becomes more specific

Question 8

How does affinity maturation occur?

Answer 8

somatic mutations accumulate in Vh / Vl exon domains (predominantly but not exclusively in the CDRs)

Question 9

What enzyme is somatic hypermutation dependent on?

Answer 9

induced cytidine deaminase (AID)

not mediated by RAG proteins

Question 10

Where is AID enzyme expressed and what is its role?

Answer 10

only in B cells and introduces mutations into genes that are being transcribed

Question 11

How does the AID enzyme carry out its function?

Answer 11

attacks the exposed ring of cytidine, which is resolved by deamination into uridine
conversion of cytosine (C) to uracil (U) results in mismatch repair and the introduction of mutations

Question 12

What happens when mutations produce a BCR with low (or no) affinity for antigen?

Answer 12

the B cell will fail to capture and present antigen

Question 13

What happens when mutations produce a BCR with high affinity for antigen?

Answer 13

the B cell will present antigen to TFH cell, receive help through CD40 interaction and cytokines production, promoting survival and proliferation

Question 14

Why does AID initiate class switching?

Answer 14

to allow the same assembled Vh exon to be associated with different Ch genes in the course of an immune response

Question 15

What is class switching regulated by?

Answer 15

repetitive DNA ‘switch regions’ found upstream of each of the immunoglobulin C-region genes

Question 16

What does AID introduce? How are breaks repaired?

Answer 16

single-stranded nicks which become double-stranded breaks

the breaks are repaired by bringing switch regions together (and ligation excises intervening DNA)

Question 17

How does IgD switching occur?

Answer 17

through a different mechanism

occurs through RNA splicing events and usually only seen during B cell development in bone marrow or naïve B cells

Question 18

What is isotype switching directed by?

Answer 18

cytokines made by Tfh cells in T-dependent antibody responses

Question 19

What does signalling from the cytokine receptor enable?

Answer 19

specific transcription factors to initiate transcription of different promoters upstream of switch regions; e.g., IL-21 signalling initiates STAT3, which promotes transcription upstream of Sγ and the switching to IgG1 and IgG3

Question 20

What determines whether an immunoglobulin is going to be secreted or membrane-bound?

Answer 20

alternative RNA splicing events may remove membrane anchor = secreted or remove the tail sequence leaving membrane anchor = membrane-bound

Question 21

What is rapid production of IgM useful for? What is a limitation of IgM?

Answer 21

controlling infections in the bloodstream

pentameric structure limits diffusion into tissues

Question 22

Where is IgG and IgA commonly found? What are they able to easily do?

Answer 22

IgG = blood / extracellular fluids
IgA = secretions
can easily diffuse into tissues

Question 23

Where is IgE present?

Answer 23

in tissues often bound on mast cell receptors

present in very low levels in blood

Question 24

What allows for specialised functions in secreted immunoglobulins of different classes?

Answer 24

distinct structural features in their heavy chain constant domains that bind to Fc receptors on various cell types

Question 25

What are high-affinity IgG and IgA antibodies the best at?

Answer 25

neutralising toxins and blocking the infectivity of viruses and bacteria

Question 26

What does it mean if an Ig has high affinity for an FcR?

Answer 26

there will be stable binding even if a small number of antibodies are interacting with the receptor

Question 27

What does it mean if an Ig has low affinity for an FcR?

Answer 27

multiple antibodies must bind a pathogen to engage low affinity FcR

Question 28

What are Fc receptors on phagocytes activated by and what does this enable?

Answer 28

activated by antibodies bound to the surface of pathogens and this enables the phagocytes to ingest and destroy pathogens

Question 29

What happens when Fc receptors activate NK cells?

Answer 29

NK cells destroy antibody-coated targets

Question 30

What is the role of polymeric immunoglobulin receptor?

Answer 30

binds to the Fc regions of IgA and IgM and transports them across epithelial barriers

Question 31

What is the role of the neonatal Fc receptor?

Answer 31

carries IgG across the placenta and prevents IgG excretion from the body

Question 32

What do antibody:antigen complexes activate?

Answer 32

the classical pathway of complement by binding to C1q via Fc region (no FcR involvement)