B-Lymphocytes
The function of B-lymphocytes is to produce antibody. The B-cell itself has no direct activity against pathogens. The production of antibodies is a complex process and is discussed in the section on antibodies. These two sections should be read together. B-lymphocytes are derived from the lymphoid progenitor cell and their development begins in the foetal liver and continues in the bone marrow.
An important concept for all lymphocytes is the elimination of self-reactive cells. Both B- and T- lymphocytes are antigen-specific. Each individual lymphocyte can produce a massive immune response to that antigen. Obviously this is a vital process in fighting infection but if this reaction is induced to self-antigens (i.e. antigens found on host cells) it would be extremely deleterious. This is the basis of auto-immune disease. For the most part auto-immune disease is avoided because lymphocytes that are self-reactive are eliminated in an early stage. In the case of B-cells this happens as soon as the immunoglobulin molecule is expressed on the surface of the immature B-cell, whilst still in the bone marrow.
B-lymphocyte development
There are five recognised stages in the development of the B-lymphocyte: Stem Cell, Early pro-B cell, Late pro-B cell, Pre B cell and the Immature B cell. These stages correspond to the rearrangement of the immunoglobulin genes necessary to produce functioning immunoglobulin. If at any stage a functioning molecule is not produced, the cell undergoes apotosis (programmed cell death). As a consequence, only functioning B lymphocytes (those producing functioning immunoglobulin) become mature B cells.
1. As stated in the section on antibodies, the heavy chain rearrangement occurs first. In the early pro-B cell the DH and JH segments are joined on both copies of the heavy gene. As the joining of these segments involves the random insertion of nucleotides (P- and N- nucleotides), there is a 2/3 chance of producing a frame-shift. If this occurs then the subsequent sequence is nonsense and a functioning heavy chain cannot be produced; if this happens the cell undergoes apoptosis. Thus the chances of producing an in-frame D-J joining is 1-(2/3 x 2/3) = 1-(4/9) = 5/9 = 0.56.
2. The next stage is the joining of the VH segment to the newly formed DJH. This occurs on one chromosome and then the other. This is important to ensure that the B-cell only produces a single allotype of immunoglobulin. Again the chances of producing an in-frame arrangement is 1/3. If it fails on one chromosome, the other will then undergo rearrangement. If it fails on the second chromosome the cell undergoes apoptosis. The chances of producing a functioning heavy chain at this point is 1/3 + 1/3 x 2/3 = 5/9 = 0.56. Once a functioning heavy chain is produced it is expressed on the cell surface with a special molecule named VpreBl 5. This is a surrogate light chain and takes the place of the light chain to make a ‘complete’ immunoglobulin. The cell then becomes a pre-B cell.
3. Kappa and lambda chains are functionally identical and thus the B cell has four chances to produce a functioning light chain. The k chain undergoes rearrangement first (one chromosome at a time). If it produces a functioning light chain the cell becomes an immature B cell. If the rearrangement of both k chains fails to produce a functioning light chain, the l chains undergo rearrangement (first one chromosome, then the other). Therefore the chances of producing a functioning light chain is 1-(2/3)4 = 1-(16/81)= 65/81 = 0.80
These steps are summarised below:
The stromal cell in the bone marrow is important at every step of this process. It interacts with the developing B-cell by various ligands. Once the immature cell is produced it encounters multivalent self-antigens. Any B-cell that binds to these will undergo apoptosis and hence self-reactive B-cells are eliminated.
Given that the overall chance of producing a functioning immunoglobulin is 0.56 x 0.56 x 0.82 = 0.25 and that any self-reactive cells are then eliminated, the production of B-lymphocytes is clearly a very wasteful process. However without the various contingencies (i.e. the presence of two types of light chain genes) and the fact that both chromosomes are used, the process would be far more inefficient.
The naïve B-cell is then released into the bloodstream. All lymphocytes circulate in the blood stream and in the lymphatic system. Lymph nodes play a vital role in ensuring that lymphocytes encounter the antigens of invading organisms.
Plasma Cells and Memory B Cells
When a naïve B-cell encounters an antigen (this occurs in secondary lymphoid organs such as lymph nodes) it is stimulated to grow and differentiate. It differentiates into two cell types: memory B-cells and plasma cells. At this point the plasma cell will secrete IgM as this is the native immunoglobulin type. Some of the plasma cells undergo isotype switching to produce IgG (or IgA or IgE). The plasma cells are short lived and die off after the infection has passed whereas the memory cell persist for many years or even for life. Memory cells also undergo isotype switching. In the event of a second infection by the same organisms the memory B-cells will respond to the infection by differentiating into plasma cells. At this point only IgG (or IgA or IgE) is produced. The T-helper cell plays an important role in stimulating the growth of B-cells and this is described in the section on T-helper cells and HIV.
