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63 Cards in this Set

  • Front
  • Back
Pluripotent hematopoeitic stem cells express _______ that marks them
Earliest identifiable cells of B-cell lineage is ___________
pro-B cells
What is the main event during the pro-B cell phase?
Heavy chain rearrangement
What are the 6 stages of B Cell Development?
1) Repertoire assembly: Generation of diverse and clonally expressed BCRs in bone marrow

2) Negative selection: Getting rid of BCRs that are self-reactive

3) Positive selection: Promotion of a fraction of immature B cells to become mature B Cells in secondary lymphoid tissue

4) Searching for infection - get circulated btwn lymph, blood and secondary lymphoid tissues

5) Finding infection: Activation and clonal expansion of B cells by pathogen-derived antigens in 2ndary lymphoid tissue

6) Attacking infection: Differentiation to plasma cells and memory B cells in 2ndary lymphoid tissue
What is a critical cytokine expressed on B-cell precursor?
IL 7
Where is the site of B cell development?
Bone marrow. primary lymphoid tissue
Once a B cell expresses the heavy chain it is known as _________
pre-B cell
What is the main event during the pre-B cell phase?
Light-chain rearrangement
What are 2 roles the stromal cells play in development of b cells? the growth factors
1) Make contacts with developing cells thru the interaction of adhesion molecules and their ligands

2) Make growth factors that act on the B cells they're attached to
What is stem-cell factor?
A growth factor expressed by stromal cells, recognized by Kit (a receptor on maturing B cells)

Responsible for induction of IL7 receptor
What is VLA-4?
An integrin stem cells and pro B cells use to bind to adhesion molecule VCAM-1 on stromal cells.
What is VCAM-1?
The cell adhesion molecule (CAM) on stromal cells that VLA-4 (integrin on stem cells and pro B cells) binds to
What role do cell adhesion molecules (CAM)s and integrins play in B-cell development?
Interactions between these promote binding of stem cell to stromal cell, which causes the cell to proliferate. Cells at different stages require stimulation of different things to grow.
Non-productive rearrangements result from_________________
Introduction of stop codons during joining --> no functional protein would be expressed
Productive rearrangements result in_________
generation of function protein
What happens if developing B cells make nonproductive rearrangements at both copies of the heavy-chain gene loci?
They lose their potential to make Ig; they die by neglect
What two rearrangements in heavy chains must occur? What are the relative efficiencies?
1) D-J : very efficient
2) DJ-V: less efficient, 50/50 chance (there are two chances)
What genes must an early pro-B cell express to rearrange the Ig H chain genes?
Recombination Activating Genes (RAG 1 and 2
What is pre-BCR made of?
The heavy chain and surrogate light chain (VpreB and λ5)
What is the surrogate light chain made of?
VpreB and λ5
T/F pre-BCR expression required for B cell development
True. The pre-BCR lets the cell show it can make a H chain that combines with light chain. Its presence sends signal that allows a pro B cell to become a pre B cell.
What sends signal that allows a pro B cell to become a pre B cell? (stop heavy chain rearrangement)
Presence of a pre-B-cell receptor
What is allelic exclusion?
cell expresses only one of its two copies of a gene. Responsible for in B cells monospecificity.
What is the advantage of allelic exclusion?
Results in homogeneous BCRs with high-avidity binding.
T/F Light chains are more rearrangeable
T. It's relatively more efficient.
What are the implications for having multiple rearrangement opportunities?
Increases the likelihood of forming a BCR (after H chains are made)
What is light chain isotype exclusion?
There are two isotypes of light chain (κ and λ); only one can be expressed
How many chances to rearrange does the L chain have?

Two κ genes and Two λ genes.
What are the two checkpoints that B cells have to pass in development in bone marrow?
1) Check to make sure H chain works by formation of functional pre-BCR (with final H chain and surrogate light chain)

2) Check to make sure the L chain works with the (already checked for function) H chain - make sure they can produce a functional BCR.
When are RAG genes turned on?
During H and L chain rearrangement (NOT between these times)
When are terminal deoxynucleotidyl transferase (TdT, the one responsible for adding the nucleotides resulting in junctional diversity) genes turned on? (What's implication?)
Mostly during pro-B Cell stage, less so during pre B cell;

Implications are that all VD and DJ joints of rearranged H chains show N nucleotides; BUT only about half of VJ joint of rearranged L chains do.
Junctional diversity occurs most commonly in H or L chains?
H. Due to activation of TdT genes.
How do gene rearrangements affect transcription in the Ig locus?
The promotor upstream of the variable region is brought closer to the enhancer after rearrangement, resulting in increased transcription.
What does X-linked agammaglobulinemia result from?
A tyrosine kinase that's essential for BCR development beyond pre B cell stage. Result in almost no circulating antibodies because their B cells are blocked at this stage.
How can aberrant rearrangements lead to B cell tumors?
Ig genes can get spliced onto other chromosomes, juxtaposing Ig with a proto-oncogenes (something involved in cell growth or proliferation) ---> may get turned on all the time resulting in a tumor.
What chromosomal rearrangement occurs in Burkitt's lymphoma?
Proto-oncogene MYC gets juxtaposed with Ig locus --> comes under control of Ig locus --> gets turned on all the time.
What characteristic marker do B1 cells express?
What do B1 cells do?
Characteristics of innate and adaptive systems. Not an extensive repertoire, "neither here nor there" cells
How are B1 cell antibodies different from conventional B cells?
Exhibit polyspecificity - they bind with lower affinity to more things.

They make IgM but doesn't improve response (no hypermutation or junctional diversity)
What are most cases of chronic lymphocytic leukemia caused by?
B-1 cells, might stem directly from their capacity for self-renewal.
How do non-self and self-reactive B cells in bone marrow have different fates?
A) non-self-reactive B cells express mIgD and exit to blood

B) self-reactive cells are retained in bone marrow and get a second chance
How do self-reactive B cells maintained in bone marrow get a second chance?
When self-antigen ligates immature B cells IgM, the cell continues to rearrange L chain genes. The cell makes a new L chain and thus has new IgM with a new specificity.
A) New IgM isn't self-reactive anymore --> B cells leave bone marrow
B) New IgM still is self-reactive, L chain genes keep rearranging until no further rearrangements are possible and cell apotoses.

<b>The second chance comes from rearrangement of the L chain while still in bone marrow.</b>
What is anergy? When does it happen?
State of inactivation and non-responsiveness to their specific antigen. Half life is shortened.

Happens when IgM of immature B cell binds soluble self-antigen
Maturation and survival of B cells requires access to_____________
Lymphoid follicles
What are follicular dendritic cells (FDCs)?
network of specialized stroma with the primary lymphoid follicle of lymph node (not related to conventional dendritic cells). They attract B cells into the follicle via a chemokine, which is a survival signal
What is the general route of B-cell circulation thru a lymphoid tissue?
1) B Cells in blood come in to lymph node via a HEV

2) The pass into primary lymphoid follicle

3) If they don't encounter their antigen they leave the follicle and exit from the lymph node in the efferent lymph.
What is the key survival step of B cells into lymphoid tissue?
Entry into a primary follicle. this step is competitive and results in survival signal.
What things regulate B cell circulation and development?
A variety of cytokines and chemokines
Generally, how do cytokines/chemokines regulate B cell circulation and development?
1) Naive B cells have receptors for chemokines secreted by stromal cells and dendritic cells

2) FDCs make an attractive chemokine

3) FDCs stimulate B cell survival via antigen or cytokines
What are the fates of antigen-stimulated B cells?
B cells that find antigen form a primary focus in T cell zone, some mature to plasma cells.

Once in the primary focus they can enter follicle and form a <b>germinal center</b> leading to isotype switching, affinity maturation, and memory cell development.
What mainly comprises a primary lymphoid follicle?
B cells enmeshed in a network of follicular dendritic cells.
What is stage in development/normal cell equivalent to: <b>Acute lymphoblastic leukemia</b>
Lymphoid progenitor
What is stage in development/normal cell equivalent to: <b>Pre-B-Cell Leukemia</b>
Pre-B cell
What is stage in development/normal cell equivalent to: <b>Mantle Cell Lymphoma</b>
Resting, naive B cell
What is stage in development/normal cell equivalent to: <b>Chronic lymphocytic leukemia</b>
Activated or memory B cell
What is stage in development/normal cell equivalent to: <b>Follicular center cell lymphoma/Burkitt's lymphoma</b>
Mature, memory B cell (resembles germinal center cell)
What is stage in development/normal cell equivalent to: <b>Hodgkin's lymphoma</b>
Germinal center B cell
What is stage in development/normal cell equivalent to: <b>Waldenstrom's macroglobulinemia</b>
IgM-secreting B cell
What is stage in development/normal cell equivalent to: <b>Multiple myeloma</b>
Plasma cell
T/F B cells specific for self-antigens not encountered in bone marrow (eg., the periphery) can also undergo receptor editing/rearrangement of light chains
F. They either die by apoptosis or by anergy
before entering follicle, what are B cells expressing?
IgD (little) and IgM (mostly)
after entering follicle, what are B cells expressing?
IgD (mostly) and IgM (little)
When leaving bone marrow, B cells only express _________ at surface.