Exam 4: Chapter 6 Flashcards
How is B cell development regulated?
Via checkpoints that occur at the end of each step in B cell development
How are the different stages of B cell development characterized?
By distinct sets of surface CD antigens
What occurs in step one of B cell development?
The heavy chain rearranges
What occurs in step two of B cell development?
The light chain rearranges
In what stage of the B cell does heavy chain D-J rearrangement occur?
Early pro-B cell
In what stage of the B cell does heavy chain V-DJ rearrangement occur?
Late pro-B cell
In what stage of the B cell does light chain V-J rearrangement occur?
Small pre-B cell
In what stage of the B cell is IgM first on the surface?
Immature B cell
What cells make up the bone marrow microenvironment?
Stromal cells
How do stromal cells regulate B cell development?
Stromal cells bind to the developing B cells via adhesion molecule interactions, and stimulate development by producing growth factors and chemokines
What are the two key events in the development of a B cell?
The rearrangement of the heavy and light chains
What are productive rearrangements?
Heavy and light chain rearrangements that are in frame and produce a working protein
What are unproductive rearrangements?
Heavy and light chain rearrangements that are not in frame and/or do not produce a working protein
What happens if the first heavy chain allele fails to form a productive rearrangement?
The second heavy chain allele will attempt to produce a productive rearrangement
What happens if both heavy chain alleles fail to form a productive rearrangement?
The B cell dies via apoptosis
How many times can each heavy chain allele rearrange?
Once
How does a cell test for a productive heavy chain rearrangement?
By attempting to bind the heavy chain to the surrogate light chain to form the pre-B cell receptor
What two proteins make up the surrogate light chain?
VpreB and lambda-5
What is the role of the Pre-B cell receptor?
To signal to the cell that heavy chain rearrangement was successful, thus stopping further heavy chain rearrangement
Is the pre-B cell receptor able to bind antigen?
No, because the full binding site is not yet present
How does allelic exclusion apply to heavy chain rearrangement?
Only one productive heavy chain rearrangement is allowed to form
How does the B-Cell receptor prevent further heavy chain rearrangement?
By sending a signal into the cell that degrades RAG1/2
How would a lack of allelic exclusion affect IgM secretion?
IgM would be unable to be secreted as a pentamer due to multiple specificities being present
Where is the heavy chain held while the light chain rearranges?
In the Endoplasmic Reticulum
Which light chain rearranges first?
The kappa locus
How many times can each light chain allele (2 kappa loci and 2 lambda loci) rearrange?
As many times as it takes to produce a productive arrangement, or until all combinations have been tried
What checkpoint determines if the light chain productively rearranged?
Whether or not a full B cell receptor forms on the surface and sends a signal into the cell
Must the B cell receptor bind antigen in order to signal that light chain rearrangement is complete?
No
What would happen if developing B cells could not express lambda-5 or VpreB?
B cell development would stop at the pre-B cell stage, because the first checkpoint signal would not be received
In addition to productive heavy and light chains, what else does rearrangement produce?
Proper arrangements of the promotor and enhancer sequences
What are the two types of B cells produced by the body?
B1 cells and B2 cells
What are the defining qualities of B1 cells?
Primarily produced during fetal development; utilize fewer V segments; TdT is not expressed; bind with low affinity; recognize multiple antigens (polyspecificity), recognize polysaccharide and carbohydrate antigens
What is the third checkpoint in B cell development?
Whether or not the B cell receptor recognizes self antigens
What self antigens could potentially be recognized by B cells?
Any cell surface protein, glycoproteins, proteoglycans, and glycolipids
What happens to B cells that do not react with self antigens?
The immature B cells move into the blood stream and begin to express IgM and IgD
What happens to B cells that encounter and recognize multivalent antigen on the surface of a bone marrow cell?
The B cell receptor becomes crosslinked, sending a strong signal into the B cell that stops development; the B cell must either change its receptor specificity or die
What is clonal deletion?
The basis of central tolerance; B cells that are auto-reactive and cannot change their specificity die via apoptosis
What happens to B cells that encounter and recognize soluble antigens?
The B cell enters a state of anergy; the cell migrates into the periphery, but only express IgD; the B cell can no longer be activated
What is a tolerance to antigens outside the bone marrow called?
Peripheral tolerance
What happens to naïve B cells in the periphery?
They circulate through the blood and secondary lymphoid organs looking for antigens
How do chemokines affect B cells?
They guide B cells to the secondary lymphoid organs and promote their interactions with dendritic cells
What part of the secondary lymphoid organs do naïve B cells associate with?
Primary lymphoid follicles
What happens in the primary follicle?
Naïve B cells interact with follicular dendritic cells (FDCs), which provide survival signals to the naïve B cells
How long do naïve B cells last if they do not interact with FDCs and do not bind antigen?
A few days
How long do naïve B cells last if they do interact with FDCs, but do not bind antigen?
3 to 8 weeks
What happens to anergic B cells once they reach the secondary lymphoid organs?
They are sequestered in the T cell area and eventually die via apoptosis
Where do B cells encounter antigen and become activated into plasma cells?
In the secondary lymphoid organs
How are antigens brought into the lymph nodes?
Via dendritic cells and macrophages
What happens when a B cell recognizes antigen in the lymph node?
It moves to the T cell area and interacts with CD4+ T cells, which produces signals that induce the B cell to proliferate
What are germinal centers?
Sites within the lymphoid organs where somatic hypermutation, class switch recombination, and affinity maturation occur
What happens to B cells when they differentiate into plasma cells?
Switch from B cell receptors on the surface of the cell to secreted antibody via a poly-Adenylation site change
How are plasma cells different from B cells?
Plasma cells cease to divide, have a limited life span of approx. 4 weeks, no longer express MHC or surface immunoglobulin, and are are unresponsive to further antigen stimulation
What are centroblasts?
Large proliferating B cells
What are centrocytes?
Mature centroblasts that have undergone class switch recombination and somatic hypermutation and have been selected by affinity maturation
Where do plasma cells develop in the various lymphoid organs?
Lymph nodes - medullary cords
Spleen - red pulp
Gut associated lymphoid tissue - lamina propria
Why does the germinal center reaction continue on for several weeks?
The germinal center produces both plasma cells and memory B cells
What are memory B cells?
Resting B cells that express high affinity and have isotype switched B cell receptors on their surface
What are the properties of memory B cells?
Have high affinity B cell receptors, are long lived and do not require restimulation by FDCs, rapidly become plasma cells upon encountering antigen, mainly express IgG
What does it mean for B cell tumors to be clonal?
They descend from a single cell that was frozen in development
What is the High Endothelial Venule?
Part of the blood vessel in the lymph node that always expresses the adhesion molecules recognized by B cells
Where do B cells develop?
In the bone marrow
Why are plasma cells generated from germinal centers better than those directly generated by activated B cells?
Germinal center plasma cells have the correct Ig isotype and have higher affinity
