Feb. 21st (Exam 2) Flashcards
What are the checkpoints that the immune system utilizes in their conservative fashion of B cell production?
- At the Late Pro-B cell stage, the presence of a Pre-B cell receptor gives the cell survival signals to survive and continue onto more differentiation - this ensures a competent heavy chain can be made.
- At the Small Pre-B cell stage, the ability of a rearranged light chain to join a heavy chain and Ig (alpha) and Ig (beta) give it more survival signals to stay alive to become immature B cells.
Why is cancer relevant to lymphocyte development?
If there are improper expression of certain genes (proto-oncogenes) or translocations that happen as a result of heavy chain rearrangement, this can lead to tumor suppressors becoming faulty or proto to oncogene transition.
Think of the proto oncogene BCL-2 that usually prevents apoptosis but then gets expressed widely - not alone enough to cause cancer, but certainly could with other mutations.
What is the difference between B1 and B2 cells?
B1 cells are the early embryonic cells that express a cell surface marker called CD5 - they come from a stem cell that is most active during the prenatal period.
Because the TdT enzyme is not expressed that early, there is little N nucleotides (responsible for junctional diversity in part). By consequence, the antibodies are of lower affinity and they bind to many different antigens (they are less diverse).
B2 cells are the majority subset of B cells in humans.
What does the term Polyspecific mean?
Polyspecific is the idea that some antibody or antigen binding region, instead of binding to one specific antigen instead binds to many types of antigens present on the surface of a pathogen or otherwise.
What is the second phase of B cell Development called?
Negative Selection.
What are self antigens?
These are parts of our body (self) that an immature B-cell has the capacity to bind to and cause a disastrous immune response.
What does the term self-reactive or auto-reactive mean?
This is a characteristic of immature B cells and their receptors (or B cells and their antibodies in general if they are not filtered out) that bind to a person’s own tissues.
What happens to immature B cells that are self reactive?
What about immature B cells that are not self-reactive?
What percent of them make it out?
If they are, they are retained in the bone marrow.
If they are not, they get to leave.
Only like 25 percent make it out.
What will a B cell that makes it out of the bone marrow begin to express on its surface (Ig)?
Ig-D
Why is phase 2 of deciding which immature B cells can leave the bone marrow called negative selection?
Because immature B cells have receptors that are wired to generate negative intracellular signals if it binds to antigen.
AKA, once the immature B cell binds to something within the bone marrow, it receives negative signals to, back up, try again.
What is the first part of maturation of an immature B cell that is self tolerant?
What comes next?
The first step is that we see alternative splicing of the heavy chain mRNA sot hat the cell makes IgD as well as IgM
As the alternative splicing begins, there is presently more IgM than there is IgD, so the next step is that there is a shift to there being more IgD than IgM on the surface of the mature B cell.
What is a multivalent antigen?
This is an antigen that contains more than one epitope or more than one copy of the same epitope.
What happens to immature B cells if they are self-reactive?
After the first rearrangement after interaction with self antigen, what happens?
- Binding to a multivalent (stronger signal) self antigen in the bone marrow causes the immature B cell to reduce the amount of IgM on its surface and to maintain the expression of RAG.
Because RAG is still expressed, the cell can continue to rearrange its light-chain loci.
Further rearrangement takes out the old rearrangement, and it has the ability to make another functional light chain.
- If the rearrangement was successful and the immature B cell does not run into any more self antigens, it may be able to leave the bone marrow. If not it can undergo the same mechanism as in the first question - this is called receptor editing.
What is clonal deletion?
After many attempts at receptor editing, if the B cell can still not avoid running into self antigen, the B cell dies via apoptosis and is eaten by macrophages.
What happens to B cells that bind to monovalent self antigens?
What is this called?
They become inactivated and unresponsive to their specific antigen.
This is called anergy.
What is characteristic of anergic cells?
They may make both IgM and IgD, but unlike mature B cells, the IgM is unable to make a functioning B-cell receptor, so it stays in the cytoplasm.
If there is still plenty of IgD on the surface of these anergic B cells, why can’t they activate the B cell when they encounter antigen?
They just are unable to activate the B cell for some reason.
What happens to Anergic B cells that are deemed anergic within the bone marrow?
They are allowed to enter the peripheral circulation, but they have a much smaller life-span.
What is central tolerance?
These is the B cells that are tolerant to the cell antigens that are present in the bone marrow - it is called central because it is induced within the primary lymphoid organ.
Why can B-cells who encounter a monovalent self antigen, in say, the blood after being deemed centrally tolerant, not undergo receptor editing once more?
Because the machinery for doing all of that has been shut down.
What is peripheral tolerance?
This is the tolerance induced to antigens outside the bone marrow - it removes B cells reactive against the self antigens of all the tissues that are not bone marrow.
Fate of B cells that are deemed NOT peripherally tolerant?
They either die by apoptosis or they are rendered anergic.
Beyond central tolerance and peripheral tolerance, what have we missed?
There are places that are still going to be inaccessible to B cells - like the inside of other cells.
What can happen in times of stress disease, or trauma?
Self antigens that are new to the B cell population can provoke an autoimmune response.
DNA
autoimmune lupus erythematosus
What is the difference between B cells that have just left the bone marrow and are developing and mature B cells?
Developing B cells have high levels of IgM on their surface and low levels of IgD.
Mature B cells have low levels of IgM on their surface and high levels of IgD.
What are phases 3-4 of B cell Development?
Positive Selection and Circulation.
Where do B cells circulate once they have left the bone marrow?
They circulate in the lymph, the blood, and the secondary lymphoid tissues.
Where do B cells mature?
What are the three places that we talked about?
They mature in the secondary lymphoid tissues
- Spleen
- Lymph Nodes
- Peyer’s Patches
Where do immature B cells enter the lymph node?
What is the mechanism by which they get there?
They enter through the High Endothelial Venule
They follow the chemokine gradient.
What is a chemokine?
They are a type of cytokine that act as chemoattactants.
What are the cells and the types of chemokines that help B cells get to where they need to be?
- Stromal Cells in the lymph node
- They release CCL21 (this is recognized by a receptor on the surface of B cells called CCR7
- Dendritic Cell in the lymph node
- They release CCL21 as well as CCL19
How do the B cell actually get into the lymph node (be specific).
They squeeze through the high endothelial cells.
Where do the B cell congregate in the lymph node?
How do they get there?
They make their way to what is called the Primary Lymphoid Follicle
There are stromal cells that are called Follicular Dendritic Cells (FDC) that secrete:
- another chemokine called CXCL13
- B-cell activating Factor (BAFF), which is a part of the TNF family.
Explain the codependent relationship between B-cells and Follicular Dendritic Cells.
The FDCs provide signals that allow B cells to mature and survive.
The B cells also maintain the integrity of the FDC network using a surface protein called lymphotoxin.
How tough is it for an individual (immature) B cell to make it the Primary Lymphoid Follicle?
Very rare, most of them won’t make it and eventually undergo apoptosis - they have to compete with B cells that are already mature - there is preferential advantage to mature B cells to get to the follicle.
Why can anergic B cells not make it to the Primary Lymphoid Follicle?
They can’t because they don’t express a receptor that responds to one of the important chemokines (CXCL-13)
How do mature B cells get out of the lymphnode?
They must detach from the FDC network and then they can leave via the efferent lymphatic vessel.
What is a mature B cell that has NOT encountered an antigen called?
They are called Naive B cells.
What is the 5-6 phases of B cell Development?
Activation, Expansion and Differentiation.
How many types of CD4 T cells are there?
What do they interact with?
5
They interact with:
- Phagocytes
- Lymphocytes
- Granulocytes
What is another word for the defining transcription factor of the varieties of CD4 T cells?
It is called the Master Regulator
What type of T cells are relevant to B cell maturation?
They are called (follicular helper) T cells - they help activate B cells.
What happens when a B-cell binds a specific antigen?
It binds it and then internalizes it via receptor mediated endocytosis - the antigenic proteins are then degraded and presented on MHC II complexes.
Describe how B and T cells meet (location).
Then, explain their interaction.
The follicular helper T cells remain in the secondary lymphoid tissue and move from the T cell area to the border of the B cell area
The T cell will recognize a peptide that is on the surface of the B-cell; they then exchange signals which begins the process of B cell activation.
T-cell sends cytokines.
B-cell shows antigenic peptide
Linked via CD40 on B cell and CD40L on T cell.
What is linked recognition?
Linked recognition is the idea that both B and T cells recognize different epitopes that are present on the same antigen.
Explain one sequence of events that can happen if a B cell gets activated by a follicular helper cell.
We see proliferation and differentiation of B cells - they become plasma cells that solely secrete antibodies.
- They don’t divide anymore
- They get rid of MHC II complexes
- They stop responding to T-cells and antigens.
Explain THE OTHER sequence of events that can happen if a B cell gets activated by a follicular helper cell.
What do B cells become once they get to the germinal center?
How are centroblasts and centrocytes different?
What do centrocytes undergo?
What happens to the surviving centrocytes?
What happens in the bone marrow?
Can cells in this sequence also become memory cells? How?
Once they get activated they migrate to the primary follicle, which changes morphology to become a secondary follicle containing a germinal center.
B cells become centroblasts - large proliferating lymphocytes that mature into slowly dividing B cells called centrocytes.
Centrocytes undergo affinity maturation (see previous)
Surviving B cell will either go to other secondary lymphoid organs or make their way back to the bone marrow.
In the bone marrow, the B cells can complete their differentiation into plasma cells that secrete high-affinity isotype-switched antibodies.
If they stay in the germinal center after the primary response has gone down they can also become memory cells.
