In the absence of specific antigen, mature B cells survive in the peripheral circulation for only a few days. Cells which do not encounter antigen within this period of time undergo apoptosis. This is necessary in order to maintain an optimal # of B lymphocytes in the peripheral circulation.
Most B cell antigens are T dependent. In other words, the B cell requires direct contact by Th lymphocytes as well as exposure to Th lymphocyte cytokines in order to be fully activated.
There are a few T independent antigens. One of the best known examples of a T independent antigen is LPS (lipopolysaccharide). At low concentrations, LPS stimulates the production of specific antibodies (LPS-specific) but at high concentrations it can cause the polyclonal activation of B cells. The polyclonal activation of B cells leads to the proliferation and differentiation of large numbers of B cells, regardless of their antigen specificity.
Bacterial cell wall polysaccharides and bacterial flagellin can also serve as T independent antigens. The cell wall polysaccharides are characterized by possessing repetitive monosaccharide subunits while the bacterial flagellin is a repetitive polymeric protein. It is believed that these repetitive antigens stimulate B cells by extensively cross-linking membrane-bound Ig. The antibody response to these antigens is specific. This process does not require direct T cell contact but does require the presence of certain T cell cytokines.
The antibody response to T independent antigens is typically weaker, there are no memory B cells produced, and only IgM is produced (due to the lack of heavy class switching).
As stated previously, most antigens are T dependent and B lymphocytes require the direct participation of Th lymphocytes for full activation and differentiation to plasma cells.
The events which lead to activation and further differentiation of the B cell are given below:
1) Specific antigen binds to mIg (membrane-bound Ig) leading to the mIg cross-linkage.
[membrane signal transduced by Ig-alpha/Ig-beta]
2) The antigen is then internalized by receptor mediated endocytosis.
3) Increased expression of Class II MHC and B-7 occurs ---- providing for enhancement of the antigen presenting capability of the B cell.
4) Processed peptide + Class II MHC appears on the surface of the B cell within 30-60 minutes following the initial encounter with antigen. The B cell can now present peptide + Class II MHC to a specific Th lymphocyte.
5) A Th cell/B cell conjugate forms as the TcR binds to the peptide + Class II MHC and B7 binds to CD28 on the Th lymphocyte.
6) The CD40L (CD40 ligand) is now expressed on the surface of the Th lymphocyte.
7) CD40 on the B cell binds specifically to CD40L on the Th cell. (CD40 belongs to a family of cell surface proteins that are known to regulate cell proliferation and PCD (programmed cell death). At this point the B cell is "rescued" from apoptosis.
8) There is now a directional release of cytokines from the Th cell. [Th cytokines that have been shown to be important in providing the signal which leads to the proliferation of B cells are IL-2, IL-4, and IL-5].
9) B cell and Th cell separate, and B cell proliferates.
As the activated B cell proliferates, several differentiation events can occur:
formation of plasma cells
formation of memory B cells
heavy class switching
affinity maturation
These differentiation events occur within germinal centers of the secondary lymphoid organs and require signals provided by T helper lymphocytes.
All isotypes of mIg have very short cytoplasmic tails. Both mIgM and mIgD have a cytoplasmic domain which is only 3 amino acids in length. The cytoplasmic tails of mIg are too short to be able to associate with intracellular signaling molecules. So.... the question is, how can mIg mediate an activating signal after binding to antigen?
We now know that mIg is always associated with the Ig-alpha/Ig-beta heterodimer collectively forming what has been termed the B cell receptor complex (BCR).
Two molecules of this heterodimer associate with one mIg to form a single BCR. The Ig-alpha/Ig-beta heterodimer carries out the signal transducing fuction of the complex. The Ig-alpha chain has a long cytoplasmic domain containing 61 amino acids while the Ig-beta chain has a long cytoplasmic domain containing 48 amino acids.
See figure of BCR in text.
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