Hypermutation somatique

Somatic hypermutation (or SHM) is a cellular mechanism by which the immune system adapts to the new foreign elements that confront it (e.g. microbes), as seen during class switching. A major component of the process of affinity maturation, SHM diversifies B cell receptors used to recognize foreign elements (antigens) and allows the immune system to adapt its response to new threats during the lifetime of an organism. Somatic hypermutation involves a programmed process of mutation affecting the variable regions of immunoglobulin genes. Unlike germline mutation, SHM affects only an organism's individual immune cells, and the mutations are not transmitted to the organism's offspring. Because this mechanism is merely selective and not precisely targeted, somatic hypermutation has been strongly implicated in the development of B-cell lymphomas and many other cancers. When a B cell recognizes an antigen, it is stimulated to divide (or proliferate). During proliferation, the B-cell receptor locus undergoes an extremely high rate of somatic mutation that is at least 105–106 fold greater than the normal rate of mutation across the genome. Variation is mainly in the form of single-base substitutions, with insertions and deletions being less common. These mutations occur mostly at "hotspots" in the DNA, which are concentrated in hypervariable regions. These regions correspond to the complementarity-determining regions; the sites involved in antigen recognition on the immunoglobulin. The "hotspots" of somatic hypermutation vary depending on the base that is being mutated. RGYW for a G, WRCY for a C, WA for an A and TW for a T. The overall result of the hypermutation process is achieved by a balance between error-prone and high fidelity repair. This directed hypermutation allows for the selection of B cells that express immunoglobulin receptors possessing an enhanced ability to recognize and bind a specific foreign antigen. The mechanism of SHM involves deamination of cytosine to uracil in DNA by the enzyme activation-induced cytidine deaminase, or AID.