lecture 5- B cell development

Question 1

generation of antibody diversity is due to:

Answer 1

1- combinational diversity
2- junctional diversity
—- after rearrangement and activation—
3. somatic hypermutation
4. isotype switching

Question 2

somatic hypermutation increases ___

Answer 2

increases affinity of receptor for antigen

Question 3

6 phases of B cell development and where they happen

Answer 3

in bone marrow:
1- repertoire assembly
2- negative selection
in secondary lymphoid organs and circulation:
3- positive selection- move to follicles and interact with follicular dendritic cells- provide signals needed to keep B cell alive for weeks to have a chance to interact with pathogen its specific for
4- search for infection
5- finding infection- activation & clonal expansion
6- attacking infection- differentiation

Question 4

follicular DC’s are during what phase of B cell development and what signal do they provide?

Answer 4

positive selection
survival signal

Question 5

describe early events of B cell in bone marrow: stem cell –> immature

Answer 5

stem cell (germline configuration, no rearrangements yet) —->
when B cell receives signal for B cell development, becomes pro-B cell (1st event- joining of D + J in heavy chain ; kappa and lambda in germline) —>
Pre-B cell (V joins D + J), heavy chain can be tested for its ability to pair with light chain —>
immature B cell (kappa & lambda join VJ in light chain), now assembled IgM, undergoes selection in bone marrow, if not strongly reactive to self, can leave bone marrow

Question 6

VDJ recombination (heavy chain) has formed the _____-

Answer 6

antigen-binding site

Question 7

what are the components of the surrogate light chain?

Answer 7

VpreB and lambda5 (invariant molecules)

Question 8

structure of pre-B cell receptor

Answer 8

2 heavy chains
2 surrogate light chains
signaling machinery (Igbeta & Igalpha)

Question 9

what role does the pre-B cell receptor play?

Answer 9

signals from a properly assembled pre-B cell receptor induces allelic exclusion at other heavy chain locus

• surrogate light chain takes place of rearranged light chain, allowing testing of the structural integrity of heavy chain

Question 10

negative selection is testing the ____

Answer 10

affinity of the antigen binding site of the completed BCR for self

Question 11

what happens to B cells in secondary lymphoid organs before activation?

Answer 11

immature B cell (IgM) leaves bone marrow — alternative splicing co-expresses 2 isotypes: IgM (mu heavy chain) and IgD (delta heavy chain) – mature naive B cell (IgM and IgD)

Question 12

what happens to B cells in secondary lymphoid organs after activation?

Answer 12

antigen-activated B lymphoblast- cell gets larger before it divides- gives rise to different cell types- secrete diff. isotypes
- alternative splicing to secrete Ig
- isotype switching
- somatic hypermutation

Question 13

describe somatic hypermutation

Answer 13

• induced by AID- Activation Induced Cytidine Deaminase
• antigen-binding site altered by AID by point mutations to either increase or decrease the affinity for antigen
• AID attacks cytidine in ssDNA to produce uridine

Question 14

how does somatic hypermutation give rise to affinity maturation of the B cell response to antigen?

Answer 14

• after activation, B cells undergo clonal expansion
• some clones will experience mutations in the antigen binding site that enhance antigen binding
• other clones will sustain mutations that reduce the affinity of the antigen binding site for antigen

Question 15

once a B cell is activated, it follows one of two fates…

Answer 15

becomes antibody-secreting plasma cells (terminally differentiated)
or
memory cell- maintains BCR & MHC to interact with T cells, amplify and refine B cell response- allows further affinity maturation in germinal centers

Question 16

after AID makes point mutations in antigen-binding sites in BCR, what happens?

Answer 16

AID increases affinity (increased antigen uptake, processing, and presentation) and decreases affinity (decreased…)
- selection depends on T cells, the higher affinity B cell captures more antigen, more processing, and more presentation on surface which attracts T cells

Question 17

AID helps with these two processes that contribute to diversity of antibodies

Answer 17

1- somatic hypermutation
2- isotype switching

Question 18

describe isotype switching

Answer 18

• happens after B cell activation in proliferating B cells
• also dependent on AID
• causes irreversible changes in DNA, removing intervening C regions (loops them out)
• however, remaining C regions could still be used in subsequent switches

Question 19

once you have a functional VDJ rearrangement, you still have several ___ regions to choose from that can provide specific ____

Answer 19

C
functions

Question 20

what is the impact of lacking enzyme RAG on host immune response

Answer 20

SCID- no B or T cells produced

Question 21

what is the impact of lacking enzyme TdT on host immune response

Answer 21

significantly reduced diversity in B cell repertoire

Question 22

what is the impact of lacking enzyme AID on host immune response

Answer 22

no somatic hypermutation or iostype switching, produce only low affinity IgM (hyper IgM immunodeficiency)