Class Switching

 Upon stimulation with an immunogen, the circulating antibodies belong first to the IgM isotype, before being replaced by immunoglobulins of another class (most frequently an IgG in the bloodstream). This phenomenon is known as isotype switching (or switch) and is the consequence of a gene rearrangement that takes place in the centrocytes, located in the light zone of the germinal center. As a result, the V–D–J rearranged section of the mature B cell, which was initially associatedwith a Cm constant region to make a complete m chain, will now become associated with the constant region of another isotype. This gene rearrangement involves recognition sequences termed “switch regions” that are located at 5′ of each constant CH gene (with the exception of the d chain gene). These regions are very similar in sequence and are presumably recognized by an enzyme system, which has not been identified to date, but does not involve recombinase. As a result of this recombination event, the portion of DNA localized between the two switch regions concerned is deleted. The light-chain genes are not affected by the isotype switching, so the antibody combining site is unaffected. In other words, isotype switching has changed the Ig isotype without modifying the specificity of the cell. It has simply conferred on the antibody a distinct biological function, which will amplify the physiological action of the immune system in a number of ways, such as to fight more appropriately against pathogens, ensure fetal protection through transplacental transfer, be expressed in secretions, and so on, depending upon the selected isotype. Isotype switching is another example of a mechanism that necessitates interaction between T cells and B cells and makes use of two sets of molecules. One involves CD40 ligand (CD40-L) and CD40, expressed at the cell surfaces of T_H and B lymphocytes, respectively, and ensuring direct contact between the cells. The second signal is provided by the T_H cell and is a cytokine that is released as a soluble factor in the immediate proximity of the B cell. Depending upon the nature of the cytokine, and therefore on the type of interacting T cell, the switch mechanism will generate a discrete isotype. For example, secretion of interleukin-4 (IL-4) will favor a switch toward the IgE class, whereas transforming growth factor b1 will induce switching to IgA.