Immunology - B-cell Development

Rearrangement usually starts with which locus? What is the success rate in the pre-B cell population?

kappa = baby k 85%

Further development of B-cells: First, a lot of B-cells in the bone marrow make Ig that react to normal constituents in the human body What is this called?

self-reactive or autoreactive

Early Pro-B cells have how many copies of the Ig heavy-chain locus

two copies

The pre-B-cell is pretty much causing what to happen?

Allelic exclusion. Which is exclusively expressing only one copy of a gene. They are doing this to ensure that B cell will have antigen receptors of only a single specificity

In B-1 cells, their antibodies are different compared to B-2 cells. What are these 2 differences?

B-1 cell antibodies tend to be of low affinity and polyspecific

These potentially self-reactive cells are inactivated and unresponsive to self-antigen. What are they called?

Anergy

What is the marker on the hematopoietic stem cell?

CD 34

The 6 stages of development are define by the rearrangement and expression of Ig genes. What are they?

Early pro-B cell Late Pro-B cell Large Pro-B cell Small pre-B cell Immature B cell

In contrast to heavy-chains, the rearrangement of light-chain loci by pre-B cells is considered what?

Efficient

The Pre-B-cell receptors signals RAG gene to do what?

End their transcriptions which will also degrade the RAG proteins and terminate rearrangement of the heavy-chain locus

However, what if nothing productive occurs?

Failure = death

Early pro-B cell

H-chain and D-J rearrangement

Late Pro-B cell

H-chain and V-DJ rearrangement

The Pro-B cell is marked by what?

Heavy chain rearrangement

Nonproductive light-chain gene rearrangments can be superseded by further gene rearrangement. Please elaborate on this

I wish I could

It's not the end for auto-reactive immature B-cells. If that immature B-cell binds to multivalent antigen within bone marrow, What happens? IgM RAG And what is this process called?

IgM production is reduced Rag protein activity continues to rearrange the light-chain gene loci until it becomes self-tolerant. If it is still self-reactive, then it will undergo apoptosis The process is called receptor editing

B-cell development is made where again?

In the bone marrow

Going into more detail, the B cell is now pre-B, what gene should be reactivated so that the light-chain loci can be rearranged?

The RAG gene

Pro-B-cell rearrangement of the heavy-chain locus is considered efficient or inefficient process?

Inefficient

Small pre-B cell

L-chain V-J rearrangement

Immature B cell

L-chain V-J rearrangement, tepee or k light chain IgM on surface

What is the basic function of stromal cells

Make specialized microenvironments in support of various stages of B-cell maturation

What is the general purpose of the pre-B-cell receptor

Monitor the quality of immunoglobulin heavy chain

Since it's random, what kinds of rearrangements do they make?

Non-productive rearrangements which do not translate as functional Ig chain; these occur frequently Productive rearrangements translate complete and functional Ig chain; but these occur infrequently

Case Study: Dennis Fawcett

Okay

Self antigens that are soluble proteins often carry only one copy of an epitope and cannot be addressed by receptor editing

Okay

You better know those phases

Okay

Self-reactive B cells in peripheral tolerance are removed by what?

Peripheral Tolerance

When the pre-B-cell receptor is made, what does the B-cell do to the functional u chain inside of it?

Prevents making more than one functional u chain

What is the first recognizable B-cell progenitor

Pro-B cell

He has Pneumocystic jirovecii pneumonia Fungus disease People usually don't get if they have good immune systems. Therefore, he's having trouble with phagocytosis. Shows very low IgG, IgA and elevated IgM Does not respond to vaccinations His T-cells DO NOT react with CD40 because his T-cells do not have CD40L. T cells are suppose to interact with CD40 on B-cells so activate T cells and make B-cells produce antibodies Also have no Germinal Centers in the lymph nodes which is where B-cells mature.

Really?

Yes, B-cells develop in the bone marrow. But where do they actually mature?

Secondary lymphoid Tissue

What is the Pro-B cell capapble of

Self-renewal

Therefore, the living B-cells are what?

Self-tolerant

Basically, RAD will rearrange the genes based on a list. So it first rearranges k gene on first chromosome. If it works, the cell will express u and k IgM If it does not work works, it rearranges k gene on second chromosome. If THAT works, it'll express the u and k IgM If second one fails, the RAD will give up on k and go to rearrange the tepee gene. It follows the same pattern with apoptosis if all 4 attempts fail.

So that's what they mean by superseding further gene rearrangements?

B-cell development is stimulated by bone marrow what cells?

Stromal cells

The property of the heavy chain's ability to combine with the light chain depends on what?

Surrogate light chain which checks the heavy chain to form a pre-B-cell receptor that signals maturation of the pro-B-cell to a pre-B-cell

There are special B-cells that arise early in embryonic development. What are they and why are they special?

The B-1 cells and they express CD5 which are usually found on T-cells

Why inefficient?

The N and P nucleotides are being randomly added. It's random and imprecise in fact

Why is the production of this u heavy chain important?

The b cell survival depends on the u heavy chain's ability to combine with the light chain

In a general summary, there are 2 main checkpoints in the development of B-cells in the bone marrow. What are the checkpoints?

The first checkpoint is the formation of pre-B-cell receptor within the cell. This is to determine a functional heavy chain The second checkpoint is the formation of regular B-cell receptor that is expressed on the surface of the cell. This determines a functional light chain

When it works, the now does what?

The heavy chain gene will stop rearranging. Then cells will divide several times to form large pre-B-Cells

In Pro-B cell development, what is the progenitors of all the blood cells?

The hematopoietic stem cell

Okay, but there are phases to development within the bone marrow How many phases are there?

There are 6 phases

What happens to self-reacting B cells in the BONE MARROW and PERIPHERAL CIRCULATION that encounter an antigen.

They are prevented from maturing

Stromal cells have 2 important functions. What are they?

They create specific contacts with developing B cells using adhesion molecules and their ligands They produce growth factors that interact with receptors on maturing B cells Ex: Stem-cell factor (SCF) and IL-7

If a B-cell bind to a self-antigen, they release negative signals. This means they are NEGATIVELY SELECTED. What happens to them now?

They die by apoptosis

How does having 2 copies help?

They increase the chance of productive rearrangement

Large pre-B cell

VDJ rearranged, u heavy chain made

In summary, Early pro-B cells have 2 copies of heavy chain locus. first, they undergo H-chain rearrangement. Afterwards, D-J rearrangement needs to be productive rearrangement on both chromosomes. In late pro B-cells productive rearrangement needs to be done on etiher the first or second V-DJ regions (nothice the region changed) If productive rearrangement didn't occur, then the cell goes through apoptosis

Yep

Receptor energy, apoptosis, Anergy assures that B-cells leaving the bone marrow display what?

central tolerance