Lecture 19: Early Lymphocyte Maturation - B cells

Question 1

What does it mean if there are low levels of IgA and IgM and there are normal levels of IgG?

Answer 1

there is an issue with isotype switching

this is because IgG is the isotype which all other isotypes originate from

Question 2

What leads to issues in isotype switching?

Answer 2

deficiency of B cells

Question 3

Where do B lymphocytes develop?

Answer 3

in the bone marrow

Question 4

What does engagement of BCR allow for activation of?

Answer 4

plasma cells / antibody secreting cells (ASC)

memory B cells

Question 5

What is the BCR capable of?

Answer 5

secretion of soluble forms of BCR (antibodies) which are important for opsonization, complement activation, and neutralisation

Question 6

What do BCRs recognise?

Answer 6

antigen

Question 7

What does allelic exclusion ensure?

Answer 7

only one type of antibody / BCR is produced per B cell

Question 8

What is vital to diversity of B cells?

Answer 8

V(D)J recombination

Question 9

What does B cell development start from?

Answer 9

uncommitted progenitors

initiation of differentiation from hematopoietic stem cells into multipotent progenitors

Question 10

What do interactions with molecules such as FLT3 allow differentiation to?

Answer 10

common lymphoid progenitors (CLP)

Question 11

What are common lymphoid progenitors (CLPs)?

Answer 11

a heterogenous population that commits to

different fates depending on their multipotent potential

Question 12

How are B cells generated throughout life?

Answer 12

generation of new B cells is continuous throughout life (in contrast to T cells)

Question 13

What is B cell development dependent on?

Answer 13

interactions with bone marrow stromal cells

Question 14

What does transitioning of B cells through developmental stages require?

Answer 14

each stage requires positive signals

cells require these signals to be rescued -> the default is death

Question 15

What happens after each progression of a premature B cell?

Answer 15

each progression decreases the cell’s potential and commits it further to its fate

Question 16

What is important for B cell commitment?

Answer 16

E2A and EBF

Question 17

What happens when a stem cell enters the bone marrow and starts committing to become a B cell? What is required in order for the cell to progress?

Answer 17

starts as an early pro-B cell which starts rearranging its D fragment with the J fragment -> requires successful heavy chain recombination in order to progress

Question 18

What is required for transition to large pre-B cells?

Answer 18

expression of pre-BCR using the successful μ chain

Question 19

What does formation of a large pre-B cell involve?

Answer 19

use of a surrogate light chain consisting of λ5, VpreB with signalling components Igα, Igβ -> signalling is antigen independent and requires dimerization / oligomerization

Question 20

What does signalling through pre-BCR enforce?

Answer 20

allelic exclusion and halts recombination

Question 21

What happens before commencing rearrangement of light chain?

Answer 21

expansion of the successful cell 30-60 fold

Question 22

What is light chain rearrangement also subject to?

Answer 22

allelic exclusion once successful

two types of light chain (kappa or lambda) and only one type is used (isotypic exclusion)

Question 23

How is IgM formed?

Answer 23

through successful light chain and μ heavy chain signals transition into an immature B cell

Question 24

What does ratio of kappa to lambda expression correlate with?

Answer 24

the number of functional gene segments in the genome -> implications on dominance of segments when it comes to order of expression

Question 25

What is the progression of a hematopoietic stem cells to an immature B cell?

Answer 25

HSC -> MPP -> CLP -> pro-B cell -> large pre-B cell -> small pre-B cell -> immature B cell

Question 26

How is pre-BCR formed?

Answer 26

using a surrogate light chain by pairing with VpreB and λ5 and if successful goes on to the large pre-B cell

Question 27

How does antigen independent pre-BCR stimulation occur?

Answer 27

via Bruton’s tyrosine kinase which halts heavy chain rearrangement and induces a burst of proliferation

Question 28

What occurs after antigen independent pre-BCR stimulation?

Answer 28

light chain rearrangement occurs in in the small pre-B cell

Question 29

What does successful pairing of a heavy chain and light chain result in?

Answer 29

an immature B cell that is able to leave the bone marrow

Question 30

What happens when recombination of gene segments results in unintended consequences?

Answer 30

some events might lead to cancer and autoreactivity is a major concern (various mechanisms in place to overcome this)

Question 31

What is central tolerance? What is it dependent on?

Answer 31

acts as the first checkpoint and is dependent on the how strongly interaction occurs between the BCR and self-antigen

Question 32

What are the four main outcomes of central tolerance?

Answer 32

no self reaction, multivalent self molecule, soluble self molecule or low-affinity non-cross-linking self molecule

Question 33

What is the role of receptor editing?

Answer 33

potentially rescues self-reactive B cells from clonal deletion

Question 34

What is still active at the receptor editing stage?

Answer 34

RAG expression and is able to continue light chain rearrangements

Question 35

What can defects in receptor editing contribute to?

Answer 35

diseases such as lupus and rheumatoid arthritis

Question 36

What is peripheral tolerance?

Answer 36

second checkpoint

similar to central tolerance

Question 37

Why doesn’t receptor editing occur in peripheral tolerance?

Answer 37

since these cells are somewhat more mature and can no longer rearrange the light-chain loci

Question 38

Where does maturation of B cells occur? What is required for maturation to occur?

Answer 38

in the spleen where immature B cells enter follicles to receive survival signals (requires the molecule BAFF and weak BCR interactions)