Question

It is believed a new transcription factor is expressed at the pre-pro-B-cell stage of development. How would you test this hypothesis? Explain the position of heavy- and light-chain rearrangement at this stage of development and how would you test it?

Answer 1

In adaptive immunity, the main function of the B cells is to secrete the antibodies that bind to the pathogens or the toxic products produced by the pathogens in the extracellular space of the body. The white blood cells, lymphocytes of the adaptive immunity have evolved to identify and fight against the broad range of pathogens. The immunoglobulins or Ig are the antigen-recognition molecules of the B cells. B cells produce these proteins in a wide range of the antigen specificities, each immunoglobulin produced by the B cells have a single specificity.

The BCR (B-cell receptor) is the membrane-bound immunoglobulin present on the surface of the B cell that serves as a receptor for the antigen. The terminally differentiated B cells, plasma cells secrete the immunoglobulin of the same antigen as an antibody. In adaptive immunity, the main function of the B cells is to secrete the antibodies that bind to the pathogens or the toxic products produced by the pathogens in the extracellular space of the body.

The development of the B cells begins in the liver of the fetus and continue throughout life in the bone marrow.  B cell officially develops completely when is eligible to express both L and chains present on its membrane. It is still immature because it can still be killed on coming in contact with the self-antigen until it can also express membrane IgD. The mature B cell traverses to the periphery and is activated by the antigen to become plasma cells that secrete antibody or a memory B cell that responds to the second exposure to antigen more quickly. The B cells that fail to complete the development undergo programmed cell death or apoptosis.

The B cell development begins when the stromal cells of bone marrow send signals to the lymphoid progenitor cells. The synthesis of the recombinase (RAG-2 and RAG-1) and TdT in CD34+ lymphoid progenitors is induced by the cytokines. The cells present on the H chain chromosome undergo D-J joining to become early pro-B cells. The expression of Class II MHC and CD45 (B220) also begins. The late pro-B cell stage is completed when the V segment is joined to the D-JH.

Pro-B cells transform into pre-B cells when chains are expressed by them with surrogate light chains present in the pre-B receptor. The pre-B receptor complex also contains signal transduction molecules. An antigen-binding signal is transmitted by the cytoplasmic tails of Ig heavy chains because they are very short to enter the cytoplasm. signal transduction molecules contain Immunoreceptor Tyrosine Activation Motifs (ITAMs) which phosphorylates due to the antigen-BCR binding. A cytoplasmic signaling cascade is initiated due to phosphorylation. The recombination of the H chain is stopped by the cell and it proliferates into a clone of B cells and all produce the same chains. This stage is called the large pre-B cell because resting cells are smaller than dividing cells.

After proliferation, small pre-B cells that are not dividing anymore undergo V-J joining on one L chain chromosome. The cell is known as an immature B cell when L chain is completely synthesized and expressed with chains present on the cell membrane. Immature B cells die in the bone marrow when it binds with the self antigen because they are extremely sensitive to antigen binding. Those B cells that are unable to bind self antigen are able to express chain and membrane IgD with their IgM when they are leaving the marrow and becoming mature naive B cells.

The defense provided by the B cells is known as antibody-mediated immunity because the activated B cells become plasma cells that form antibodies. It is also known as humoral immunity because the antibodies are found in the lymph or blood.

The B cells activate in the spleen or a lymph node when the specific antigen binds to its specific B-cell receptor (BCR). Thus, the activation is the process by which B cells get activated to produce its clones once the specific antigen binds to its BCR.

The B cells undergo clonal expansion and divide by mitosis several times soon after antigen binds to its BCR. B cells form many copies of itself and most of the clones transform into or become plasma cells, that circulate in the lymph and the blood. The plasma cells are greater than regular B cells because of the presence of an extensive network of RER (rough endoplasmic reticulum) for the production and secretion of the antibodies to a particular antigen on a larger scale.

Few cloned cells are transformed into memory cells which are critically important for long-term immunity. The second exposure of any antigen results in the quick division of the memory B cells that further give rise to more plasma cells that have the ability to produce the correct antibody rapidly.

The clonal selection theory explains the binding of the antigen with its specific receptor of only one type of T cell or B cell and then that T cell or B cell divides rapidly forming its clones.

The formation of the new plasma cells is ceased when the threat of the infection is passed. The already existing plasma cells undergo a cascade of particular cellular events and results in the destruction and death of the cell by the process of apoptosis.