EXAM 2 B Cells: Development Flashcards
what are the 6 B cell life phases? Where do they occur?
Bone marrow:
- repertoire assembly
- negative selection
- positive selection
Periphery:
- searching for infection
- finding infection
- attacking infection
is there a stockpile of B cells?
no, they are not stockpiled but instead constantly replaced
- 30 billion per day
- mature half-life of 50-100 days
the vast majority of B cells will die before they reach maturation
populations of B cells ___ at each life phase
winnow
ie. populations are reduced; nonfunctional or dysfunctional B cells are destroyed
describe the lineage of pro-B cell development during the first 3 phases in the bone marrow
describe the lineage of B cell development during the second 3 phases once it reaches secondary lymphoid organs and circulation
fill out this chart for immature B cell development
how do stromal cell interactions drive B cell development?
- **don’t need to know any of the factors**
- **this is positive selection**
- stromal cells express adhesion molecules and growth factors
- B cell receptor expression changes with progression through developmental stages
- pro-B cells are programmed to die in the absence of survival signals
- CCL21 expressed by stromal cells
- BAFF released by dendritic cells to stimulate immature B cells to become mature
describe heavy chain rearrangement in pro-B cells
- early pro-B cell
- RAG proteins activated
- heavy chain D and J segments joined
- occurs on both chromosomes
- late pro-B cell
- heavy chain V and DJ segments joined
- occurs subsequentially on chromosomes
- two chances for rearrangement
___ signaling causes the transition from pro to pre-B cell
pre-BCR
how does pre-BCR signaling cause the transition from pro to pre-B cell?
- VDJ rearrangement produces pre-BCR
- pre-BCR expressed in the ER
- surrogate light chain expressed
- Ig alpha/beta expressed
Ig beta signaling:
- checkpoint clearance
- turns off RAG proteins
- initiates cell division
- allelic exclusion - a functional heavy chain is produced by only one chromosome
pre-B cell light chains are rearranged ___
sequentially
describe pre-B cell light chain rearrangement
- sequential
- 4-5 recombination attempts possible per chromosome
- kappa then lambda
- approximately 85% of small pre-B cells survive
- functional antibody expressed on the cell surface
___ ensure immunoglobulin integrity
checkpoints
describe how checkpoints ensure immunoglobulin integrity
describe B cell maturation and immunoglobulin expression
describe how immature B cells undergo negative selection
- exposure to self antigen ensures tolerance
- an inability to respond to self antigen (aka the ability to not respond to self antigen…)
- central tolerance (bone marrow) and peripheral tolerance (periphery)
- an inability to respond to self antigen (aka the ability to not respond to self antigen…)
what are the 3 fates of B cell negative selection?
- light chain reorganization
- apoptosis
- anergy - cells that are still alive but signaling and activating processes are shut down; they eventually die
immature B cells migrate to ___
lymphoid tissues
what are the 3 secondary lymphoid tissues?
spleen, lymph nodes, and GALTs
describe the maturation of B cells within secondary lymphoid tissues
- HEV - high endothelial venule
- FDC - follicular dendritic cell
- PF - primary follicle
- BAFF - B cell activating factor (immature to mature)
- LT - lymphotoxin
positive selection:
- lymph node localization
- BAFF signaling
- increased IgD expression, decreased IgM expression
B cells are activated in ___
lymphoid tissues
describe how B cells are activated in lymphoid tissues
what are polyclonal antibodies?
multiple antibodies targeted against the same antigen
what are monoclonal antibodies?
a single antibody targeted against a single antigen
how are antibodies used diagnostically and therapeutically?
- diagnostic
- pathogen identification
- cellular identification
- protein quantification
- therapeutic
- targeted killing
- chemical delivery
- immunomodulatory
dysfunctional B cell development causes ___
cancers
no allelic exclusion would give ___ B cell receptors with ___ binding
- heterogenous
- low-avidity
- the point of allelic exclusion is to make sure that a functional heavy chain is produced by only one chromosome
- if there is no allelic exclusion, heavy chains will be produced by the paternal chromosome, maternal chromosome, and a mixture of the two, so it would reduce the specificity of that B cell
B cell negative selection occurs in the ___, and positive selection occurs in the ___
- bone marrow
- periphery
___ prevents immediate reinfection by a pathogen that the immune system has already been exposed to
memory B cells
at what developmental stage do B cells express both IgM and IgD?
mature naive B cell
at what stage is the light chain rearranged?
small pre-B cell
what occurs between the large pre-B cell and small pre-B cell developmental stages?
- cell division
- 100 small pre-B cells
- RAG genes reactivated
- unique recombination per cell
- after heavy chain rearrangement, all of the large pre-B cells in that group will have the same heavy chain; light chain rearrangement can be different for every B cell in that group, so it introduces even more diversity
what happens during the two stages of heavy chain rearrangement?
- early pro-B cell:
- RAG proteins activated
- heavy chain D and J segments joined on both chromosomes at once
- late pro-B cell:
- heavy chain V and DJ segments joined sequentially on chromosomes
- 2 chances for rearrangement
- 50% signaled to die by apoptosis, 50% signaled to survive and become pre-B cells
what are the two main functions of the surrogate light chain?
- after heavy chain rearrangement, it binds to the heavy chain and acts as a placeholder protein to ensure that the new light chain will be able to bind the heavy chain
- allows the heavy chain to bind Ig beta and Ig alpha
at what B cell developmental stages are the two checkpoints, and what is the function of each checkpoint?
- 1st checkpoint between late pro-B cell and large pre-B cell (aka after heavy chain rearrangement)
- expression of functional (productive rearrangement) or nonfunctional (nonproductive rearrangement) heavy chain
- 2nd checkpoint between small pre-B cell and immature B cell (aka after light chain rearrangement)
- expression of functional (productive rearrangement) or nonfunctional (nonproductive rearrangement) antibody on cell surface
describe the 3 steps of B cell negative selection
occurs in the bone marrow
- 1: light chain reorganization
- self antigen ligates immature B cell’s IgM
- immature B cell continues to rearrange light-chain genes
- immature B cell makes a new light chain and thus an IgM with a different specificity
- 2: apoptosis
- if the new receptor is self reactive, light chain genes continue rearranging
- successive new receptors are now self-reactive. no further rearrangements are possible and apoptosis occurs
- if the new receptor is not self-reactive, the B cell leaves the bone marrow
- if the new receptor is self reactive, light chain genes continue rearranging
- 3: anergy
- IgM of immature B cell binds soluble univalent self antigen
- B cell is signaled to make IgD and become unresponsive to antigen
- enters peripheral circulation and doesn’t survive long
