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82 Cards in this Set

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In utero, where does the maturation of B-cells take place?
In the yolk sac, fetal liver, and fetal bone.
After birth, where does the generation of B-cells take place?
After birth, generation of B-cells is in bone marrow.
B-cell development occurs in how many phases? List them.
Occurs in two phases.

1. Ag-independent phase

2. Ag-dependent phase
Describe what generally occurs during the Ag-independent phase of B-cell development.
1. A progenitor B-cell expresses CD45R

2. It then matures and proliferates into pre-B-cells in the stromal cell environment.

3. These cells then leave the bone marrow and go to the Ag-dependent phase.
In which phase do B-cell become active? Once activated what occurs?
They become active in the Ag-dependent phase. Once active they are still in a naive state and they primarily enter into the lymph nodes and spleen (however only about 10% of naive b-cells survive, the other 90% undergo apoptosis).
What do progenitor B-cells require direct contact with?
They require direct contact with the stroma. (stromal cells in the bone marrow, a microenvironment)
Once progenitor B-cells make contact with stromal cells what is the contact mediated by?
The contact is mediated by CAMs, ie. Cell Adhesion Molecules.
List 2 CAMs that mediate the contact between pro-B-cells and the stroma?
1. VLA-4 (on the cell surface of the pro-B-cell)

2. VCAM-1 (on the cell surface of the stromal cell)
After contact is made between pro-B-cells and stromal cells the ? (on the pro-B-cell) interacts with the ? of the stromal cells.
After contact is made, c-Kit (on the pro-B-cell) interacts with the SCF (Stem Cell Factor).

They contact and transduce signal into the plasma membrane of pro-B-cells.
After contact is made and the c-Kit interacts with the SCF list 4 steps after signaling occurs.
1. Signal transduction is thru tyrosine kinase on pro-B-cell.

2. The pro-B-cell divides and differentiates into pre-B-cell.

3. The stroma then secretes IL-7 (interleukin 7). IL-7 is then bound by the IL-7R on the pre-B-cell. This drives the maturation process so that they will be capable of making Ab.

4. Adhesion molecules then down regulate so cells can detach from the stroma and go to the lymph nodes or spleen.
Pre-BCR is essential for what?
Pre-BCR is essential for cell development.
In the stroma what is essential for the formation of a light-chain-like structure?
A surrogate light chain made up of two proteins which associate noncovalently to form the light-chain-like-structure.

1. Vpre-B

2. Lamda-5
List 4 essential transcription factors for B-cell development in the stroma that were discovered in KO experiments? What are all of these transription factors mediated by?
1. E2A

2. Early B-cell factor (EBF)

3. B-cell-specific activator protein (BSAP)

4. Sox-4

All of these transcription factors are mediated by IL-7.
What occurs if E2A is KO'd?
You will not get lamda-5. This means that you won't even get to a pre-b-cell.
Where is B-cell specific activator protein (BSAP) seen that is unrelated to B-cells? What happens if this is KO'd?
It is also expressed in the nervous system. If not expressed then you won't have very good brain development.
List 6 B-cell development markers observed on Progenitor B-cells.
1. CD45R (protein tyrosine phosphatase)

2. Ig-alpha/Ig-beta (signal transducing molecule)

3. CD19 (part of B-cell coreceptor)

4. CD43 (leukosialin)

5. CD24 (heat stable Ag)

6. c-Kit
List the development markers of the pre-B-cell.
1. CD45R

2. Ig-alpha/Ig-beta

3. CD19

4. CD24

5. CD25 (alpha chain of IL-2 receptor)

(So same as pro-B-cell except minus c-Kit and CD43 and with the addition of CD25)
List the development markers of immature B-cells.
1. CD45R

2. Ig-alpha/Ig-beta

3. CD19

4. CD24

5. Pre-BCR (replace CD25 of pre-B-cell)

6. Heavy and light chains appear.
What are B-1B cells?
They are a subset of B-cells.
What percentage of B-cells are B-1B cells?
They make up only 5% of total B-cells in the lymph nodes and spleen.
Where are B-1B cells found in most detail?
They are the major B-cell population of peritoneal and pleural cavitities.(gut and lungs)
B-1B cells arise from stem cells in ? ? and express only surface ?.
B-1B cells arise from stem cells in fetal life and express only surface IgM.
B-1B cells are self-renewing. So what do they keep making duplicates of?
They keep making IgM duplicates.
B-1B cells have ? V-regions. Explain.
B-1B cells have restricted V-regions. This means that their variable regions aren't very variable. They are restricted in the Ag they can bind. These are activated mostly by carbohydrate Ag (not protein Ags like most B-cells).
B-1B cells do not require help from ?.
B-1B cells do not require T-cell help.
B-1B cells are not likely to differentiate into what?
It is unlikely that they will become memory cells.
B-1B cells are part of ? immune system.
They are part of the innate immune system.
Conventional B-cells are not B-1B cells, they are ?.
They are B-2B cells.
Where does negative selection of self-reactive B-cells occur? Explain what it is.
In the bone marrow. About 90% of B-cells produced each day die without ever leaving the bone marrow (the evidence for this is purely experimental). The negative selection is of immature B-cells that express auto-Abs against self-Ag.
In the absence of Ag, how long does it take B-cells to die?
B-cells will die in a few weeks by apoptosis.
How many routes are there from B-cell activation to Ab production? List them.
1. Thymus independent (T-cell dependent) (aka TD)

2. Thymus independent (T-cell independent) (aka TI)
The thymus dependent route (aka T-cell dependent or TD route) from B-cell activation to Ab production requires what? What does this mean?
It requires direct contact with Th cells. This means that although the cytokines that come from the T-cells are necessary for B-cell activation they are not sufficient, direct contact is required.
Which route (from B-cell activation to Ab production) is the most common?
The thymus dependent route (TD or T-cell dependent route)
In the thymus-dependent route, contact with the T-cells allows the B-cells to then go on and perform what functions?
1. Generate memory cells

2. Switch Isotypes

(Without contact these actions will not occur)
Does the thymus independent route (of a B-cells going from activation to Ab production) give a weaker or a stronger response than the TD route?
It gives a weaker response.
Does the TI pathway generate memory cells?
No, only the TD pathway does.
What are the observed Antigens in the TI pathway?
Ags are mitogens. These are anything that will push a cell through division. So Ag specificity doesn't matter much.
Which isotype is typically made by the TI route?
It mostly makes IgM. There is not isotype switching like there is in the TD route.
How many types of thymus independent routes are there? List them and give a brief description.
Two types

1. Type 1 : Bacterial cell wall components in gram negative bacteria. Lipopolysaccharide coat (LPS). Interacts with TCRs which are a part of innate immunity. Also interacts with BCRs which is a part of the aquired pathway and secretes antibodies.

Type 2 : Highly repetitious molecules. Activation is by cross-linking.
? drives the B-cell.
Activation drives the B-cell. It drives the resting cell (Go) through the cell cycle.
Activation of a resting cell to go thru the cell cycles requires how many signals?
Two (can be driven by cytokines and other ligands). Signal 1 and signal 2 are largely driven by cytokines.
With the BCR all isotypes of mIg have ? cytoplasmic tails. What does this mean?
They all have short cytoplasmic tails. Anything with a short tail needs help signaling.
For BCRs, mIgM and mIgD have ? a.a. at their tail region.
They have 3 a.a. at their tail region.
BCRs, that have short cytoplasmic tails and mIgM/mIgD with 3 a.a. at their feet, associate with what? What does this form?
Association is with Ig-alpha/Ig-beta forming a BCR-complex.
In the BCR signaling pathway, signaling is initiated by what?
In the BCR signaling pathway, signaling is initiated by the cross-linking of Ag to the BCR. Tyrosines at ITAMs get phosphorylated. Docking sites get created (just like they like in TCRs) and cause them to become active.
2nd messenger BCR and TCR signaling is what?
They are pretty much the same.
BCR and TCR signaling both have compartmentalization of what?
They both have compartmentalization of function within receptor units.
Activation by membrane-associated Src protein tyrosine kinases are involved with BCR or TCR signaling?
BCR (Src is not seen observed in TCR signaling)
The B-cell co-receptor is ?.
The B-cell co-receptor is stimulatory. It has proteins that help it stimulate.
What is X-linked Agammaglobulinemia?
It is a genetic disease characterized by an inability to make all classes of Igs. It mostly afflicts males. It can appear in the first year of life and those who have it don't live very long; they are very sick. Those afflicted suffer from a high frequency of infection with bacterial pneumonia, sinusitis, meningitis, and septicemia. There is no long term anti-viral immunity (because B-cells have to communicate with T-cells).
The absence of what gene causes X-linked agammaglobulemia?
BTK (Bruton's Tyrosine Kinase). Tyrosine is important for making immunoglobulins.
What is the animal model for X-linked agammaglobulemia?
XiD KO mice
Th cells are essential for most B-cell responses. Give a quick (9 step) review.
1. Go

2. Ag cross links with membrane bound Ig and generates signal

3. Increased expression of class II MHC.

4. Ag presented on MHC to Th

5. Th expresses ligand for CD40

6. B7 and CD40 (on the B-cell) join together with CD28 and CD40L (on the Th cell)

7. Both cells stim. eachother

8. B-cells make receptors for a variety of cytokines

9. Cytokines released by Th cell and help drive the B-cell toward DNA synthesis and to differentiation.
Cytokines are necessary for what? List 3.
They are necessary for B-cell proliferation and differentiation.

1. IL-2

2. IL-4

3. IL-5
True or False. The primary and secondary humoral responses are very similar.
False, the primary and secondary humoral responses differ greatly. The kinetics and characteristics vary greatly. In both cases, activation leads to secreted Abs of various isotypes. Primary response to Ag has a lag phase.
What is the responding B cell of the primary Ab response verses the secondary Ab response?
1. Primary = Naive B cell

2. Secondary = Memory B cell
How long is the Lag period of the primary Ab response verses the secondary Ab response following antigen administration?
1. Primary = generally 4-7 days.

2. Secondary = generally 1-3 days.
The time of the peak response in primary vs secondary antibody response?
1. Primary = 7-10 days

2. Secondary = 3-5 days
The magnitude of the peak response in primary and secondary antibody responses?
1. primary = varies depending on Ag

2. Secondary = generally 100-1000 times higher than primary response.
The isotypes produced in the primary verses the secondary Ab response?
1. Primary = IgM predominates early in the response

2. Secondary = IgG predominates
The antigens in primary vs secondary antibody responses?
1. Primary = Thymus dependent and thymus independent

2. Secondary = Thymus dependent
The antibody affinity for primary vs. secondary antibody responses?
1. Primary = Lower

2. Secondary = Higher
Where does In Vivo induction of humoral immunity occur?
In the lymph nodes.
The lymph nodes can capture more than ?% of any Ag carried by ? ?.
The lymph nodes can capture more than 90% of any Ag carried by afferent lymphatics.
Ag or Ab-Ab complexes enter either alone or with Ag transporting cells. List some transporting cells.
1. Langerhan's Cells

2. Dendritic Cells

3. Macrophages
Blood borne Ag goes to the ? but Ag from tissue/extravascular spaces goes to ?.
Blood borne Ag goes to the spleen from tissue/extravascular spaces goes to the lymph nodes.
Which cells are in the cortex?
Which cells are in the paracortex?
Which cells are in the medulla?
B and T-cells fully coupled.
When B-cells are found in the T-cell rich zone differentiation is into what?
Differentiation is into IgM and IgG secreting isotypes.
Most of the Ab seen in the primary response is from where?
It is from plasma cells in the paracortex.
Where and when does B-cell differentiation take place?
In germinal centers of the cortex within 7-10 days (primary response) after initial exposure to a TD Ag. (ie, within 7-10 days after initial exposure to a TD Ag, germinal centers arise)
List three important B-cell differentiation events that take place.
1. Affinity maturation (so they are based on Ag they see)

2. Class switching (ex. IgG becomes IgM)

3. Formation of plasma cells and memory B-cells.
List 4 cellular events that take place in the germinal centers of the cortex.
1. B-cell population enters

2. Centroblasts (activated B-cell) branch out into low affinity, high affinity, and centrocytes.

3. High affinity B-cells are surrounded by follcular dendritic cells

4. Go on to form memory and plasma cells
Affinity maturation is a ? process of selection and variation.
Affintiy maturation is a Darwinian process of selection and variation.
B-cell clones ? but the cloning isn't ?.
B-cell clones itself but the cloning isn't perfect.
Cloning is subject to high ? rates. What is this referred to?
Cloning is subject to high mutation rates (defects). Referred to as somatic hypermutation.
During affinity maturation the daughter cells of B-cells could have somewhat different ? from the parent.
Could have somewhat different receptors from the parent.
Give an example of possible somatic hypermutation.
Flu shots (possibly); getting one will keep you relatively healthier throughout the winter against more than just the flu. This is because following the presentation of Ag some memory Ab cells may mutate so they can capture Ag they have not encountered before. (not sure how or why)
Define class switching?
The change in an Ab class produced by the B-cell. Basically gene rearrangement based upon presence of cytokines.
Differentiation of mature B-cells into plasma cells requires a change in what of RNA? Why?
Differentiation of mature B-cells into plasma cells requires a change in RNA processing so that the secreted form of the H-chain is made rather than the membrane form.
The rate of transcription of H-chains and L-chains is greatest where?
The rate of transcriptions of H-chains and L-chains is greatest in the plasma cells. This makes sense because the rate of transcription in plasma cells is high.