B Cell Development

Front 1

Pluripotent hematopoeitic stem cells express _______ that marks them

Back 1

CD34

Front 2

Earliest identifiable cells of B-cell lineage is ___________

Back 2

pro-B cells

Front 3

What is the main event during the pro-B cell phase?

Back 3

Heavy chain rearrangement

Front 4

What are the 6 stages of B Cell Development?

Back 4

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

Front 5

What is a critical cytokine expressed on B-cell precursor?

Back 5

IL 7

Front 6

Where is the site of B cell development?

Back 6

Bone marrow. primary lymphoid tissue

Front 7

Once a B cell expresses the heavy chain it is known as _________

Back 7

pre-B cell

Front 8

What is the main event during the pre-B cell phase?

Back 8

Light-chain rearrangement

Front 9

What are 2 roles the stromal cells play in development of b cells? the growth factors

Back 9

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

Front 10

What is stem-cell factor?

Back 10

A growth factor expressed by stromal cells, recognized by Kit (a receptor on maturing B cells)

Responsible for induction of IL7 receptor

Front 11

What is VLA-4?

Back 11

An integrin stem cells and pro B cells use to bind to adhesion molecule VCAM-1 on stromal cells.

Front 12

What is VCAM-1?

Back 12

The cell adhesion molecule (CAM) on stromal cells that VLA-4 (integrin on stem cells and pro B cells) binds to

Front 13

What role do cell adhesion molecules (CAM)s and integrins play in B-cell development?

Back 13

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.

Front 14

Non-productive rearrangements result from_________________

Back 14

Introduction of stop codons during joining --> no functional protein would be expressed

Front 15

Productive rearrangements result in_________

Back 15

generation of function protein

Front 16

What happens if developing B cells make nonproductive rearrangements at both copies of the heavy-chain gene loci?

Back 16

They lose their potential to make Ig; they die by neglect

Front 17

What two rearrangements in heavy chains must occur? What are the relative efficiencies?

Back 17

1) D-J : very efficient
2) DJ-V: less efficient, 50/50 chance (there are two chances)

Front 18

What genes must an early pro-B cell express to rearrange the Ig H chain genes?

Back 18

Recombination Activating Genes (RAG 1 and 2

Front 19

What is pre-BCR made of?

Back 19

The heavy chain and surrogate light chain (VpreB and λ5)

Front 20

What is the surrogate light chain made of?

Back 20

VpreB and λ5

Front 21

T/F pre-BCR expression required for B cell development

Back 21

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.

Front 22

What sends signal that allows a pro B cell to become a pre B cell? (stop heavy chain rearrangement)

Back 22

Presence of a pre-B-cell receptor

Front 23

What is allelic exclusion?

Back 23

cell expresses only one of its two copies of a gene. Responsible for in B cells monospecificity.

Front 24

What is the advantage of allelic exclusion?

Back 24

Results in homogeneous BCRs with high-avidity binding.

Front 25

T/F Light chains are more rearrangeable

Back 25

T. It's relatively more efficient.

Front 26

What are the implications for having multiple rearrangement opportunities?

Back 26

Increases the likelihood of forming a BCR (after H chains are made)

Front 27

What is light chain isotype exclusion?

Back 27

There are two isotypes of light chain (κ and λ); only one can be expressed

Front 28

How many chances to rearrange does the L chain have?

Back 28

4.

Two κ genes and Two λ genes.

Front 29

What are the two checkpoints that B cells have to pass in development in bone marrow?

Back 29

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.

Front 30

When are RAG genes turned on?

Back 30

During H and L chain rearrangement (NOT between these times)

Front 31

When are terminal deoxynucleotidyl transferase (TdT, the one responsible for adding the nucleotides resulting in junctional diversity) genes turned on? (What's implication?)

Back 31

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.

Front 32

Junctional diversity occurs most commonly in H or L chains?

Back 32

H. Due to activation of TdT genes.

Front 33

How do gene rearrangements affect transcription in the Ig locus?

Back 33

The promotor upstream of the variable region is brought closer to the enhancer after rearrangement, resulting in increased transcription.

Front 34

What does X-linked agammaglobulinemia result from?

Back 34

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.

Front 35

How can aberrant rearrangements lead to B cell tumors?

Back 35

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.

Front 36

What chromosomal rearrangement occurs in Burkitt's lymphoma?

Back 36

Proto-oncogene MYC gets juxtaposed with Ig locus --> comes under control of Ig locus --> gets turned on all the time.

Front 37

What characteristic marker do B1 cells express?

Back 37

CD5

Front 38

What do B1 cells do?

Back 38

Characteristics of innate and adaptive systems. Not an extensive repertoire, "neither here nor there" cells

Front 39

How are B1 cell antibodies different from conventional B cells?

Back 39

Exhibit polyspecificity - they bind with lower affinity to more things.

They make IgM but doesn't improve response (no hypermutation or junctional diversity)

Front 40

What are most cases of chronic lymphocytic leukemia caused by?

Back 40

B-1 cells, might stem directly from their capacity for self-renewal.

Front 41

How do non-self and self-reactive B cells in bone marrow have different fates?

Back 41

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

Front 42

How do self-reactive B cells maintained in bone marrow get a second chance?

Back 42

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.
If:
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>

Front 43

What is anergy? When does it happen?

Back 43

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

Front 44

Maturation and survival of B cells requires access to_____________

Back 44

Lymphoid follicles

Front 45

What are follicular dendritic cells (FDCs)?

Back 45

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

Front 46

What is the general route of B-cell circulation thru a lymphoid tissue?

Back 46

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.

Front 47

What is the key survival step of B cells into lymphoid tissue?

Back 47

Entry into a primary follicle. this step is competitive and results in survival signal.

Front 48

What things regulate B cell circulation and development?

Back 48

A variety of cytokines and chemokines

Front 49

Generally, how do cytokines/chemokines regulate B cell circulation and development?

Back 49

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

Front 50

What are the fates of antigen-stimulated B cells?

Back 50

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.

Front 51

What mainly comprises a primary lymphoid follicle?

Back 51

B cells enmeshed in a network of follicular dendritic cells.

Front 52

What is stage in development/normal cell equivalent to: <b>Acute lymphoblastic leukemia</b>

Back 52

Lymphoid progenitor

Front 53

What is stage in development/normal cell equivalent to: <b>Pre-B-Cell Leukemia</b>

Back 53

Pre-B cell

Front 54

What is stage in development/normal cell equivalent to: <b>Mantle Cell Lymphoma</b>

Back 54

Resting, naive B cell

Front 55

What is stage in development/normal cell equivalent to: <b>Chronic lymphocytic leukemia</b>

Back 55

Activated or memory B cell

Front 56

What is stage in development/normal cell equivalent to: <b>Follicular center cell lymphoma/Burkitt's lymphoma</b>

Back 56

Mature, memory B cell (resembles germinal center cell)

Front 57

What is stage in development/normal cell equivalent to: <b>Hodgkin's lymphoma</b>

Back 57

Germinal center B cell

Front 58

What is stage in development/normal cell equivalent to: <b>Waldenstrom's macroglobulinemia</b>

Back 58

IgM-secreting B cell

Front 59

What is stage in development/normal cell equivalent to: <b>Multiple myeloma</b>

Back 59

Plasma cell

Front 60

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

Back 60

F. They either die by apoptosis or by anergy

Front 61

before entering follicle, what are B cells expressing?

Back 61

IgD (little) and IgM (mostly)

Front 62

after entering follicle, what are B cells expressing?

Back 62

IgD (mostly) and IgM (little)

Front 63

When leaving bone marrow, B cells only express _________ at surface.

Back 63

IgM