B Cell Development (Week 5) Flashcards
Phase 1: Repertoire Assembly
- based on somatic (V(D)J) recombination and generation of a functional B cell receptor
- rearrange their heavy chain first,
followed by rearrangement of the light chain to generate a functional BCR (IgM)
Productive rearrangement
heavy chain reading frame is not altered
Non-productive rearrangement
heavy chain reading frame is altered, sequence is non-functional
Sequence of Heavy Chain Rearrangement (Phase 1)
Early pro-B cell
1. D-J rearrangements on both chromosomes
- productive rearrangement =
2. V-DJ rearrangement on first chromosome
- if productive rearrangement = signaled to survive and become pre-B cells
- if nonproductive rearrangement =
3. V-DJ rearrangement on second chromosome
- if productive rearrangement = signaled to survive and become pre-B cells
- if nonproductive rearrangement = signaled to die by apoptosis
Surrogate light chain
two proteins (with no recombination)
that mimic binding of light chain
to heavy chain
Checkpoint 1: Successful heavy chain rearrangement
tested through binding surrogate light chain and form a functioning pre-BCR
Light chain rearrangement (Phase 1)
- only require one recombination event
- Can make several attempts to
rearrange the same gene - light chains undergo allelic exclusion
Light chain genes
- π and π
- 4 different loci that can be rearranged multiple times to achieve a functional light chain
Steps in light chain rearrangment
- Rearrange π
gene on 1st chromosome
- if productive rearrangement: cell expresses ΞΌ and π
- if nonproductive rearrangement: - Rearrange π
gene on second chromosome
- if productive rearrangement: cell expresses ΞΌ and π
- if nonproductive rearrangement: - Rearrange π on 1st chromosome
- if productive rearrangement: cell expresses ΞΌ and π
- if nonproductive rearrangement: - Rearrange π gene on 2nd chromosome
- if productive rearrangement: cell expresses ΞΌ and π
- if non productive rearrangement then apoptis
Checkpoint 2: Successful Light Chain Rearrangement
Check functionality of rearranged
light chain (binding to heavy
chain and surface expression)
Classes of BCR/Antibodies
- Differ in their Fc regions = isotypes
- Perform different functions
1. IgG
2. IgM
3. IgD
4. IgA
5. IgE
IgM and IgD
- IgM is the first BCR made
- IgD is the second
- Both expressed on naΓ―ve mature
B cells that have left the bone
marrow and reside in secondary lymphoid organs - IgM antibodies form pentamers
Clonal Deletion
Immature B cells that fail to produce self-tolerant BCR undergo apoptosis
What is the purpose of Phase 2: Negative selection
- prevents maturation of self-reactive (autoreactive) immature B cells
- alteration, elimination, or inactivation of B-cell receptors that bind to components of the human body
Steps of Negative Selection
- Receptor editing
- Self-reactive B cells rearrange their light chain to produce a self-tolerant
BCR - Central Tolerance
- Once an immature B cell is
self-tolerant, it leaves the bone marrow
- when they leave they start to express IgM (high levels) and IgD (low levels) BCRs - Peripheral tolerance
- negative selection outside of bone marrow
- Immature B cells that bind monovalent self-antigens stop
expressing IgM BCRs and only express IgD BCRs
- IgD binding to antigen does not activate B cells
anergy
unresponsive to antigen
What happens in Phase 3: Positive Selection?
- promotion of a fraction of immature B cells to become mature B cells in the secondary lymphoid tissues
- Immature B cells with IgM (high)
and IgD (low) BCRs enter
secondary lymphoid tissues - B cells that compete for space in
this tissue become mature B
cells
