Somatic hypermutation (orSHM) is acellular mechanism by which theimmune system adapts to the new foreign elements that confront it (e.g.microbes). A major component of the process ofaffinity maturation, SHM diversifiesB 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.[1] Somatic hypermutation involves a programmed process ofmutation affecting the variable regions ofimmunoglobulin genes. Unlikegermline mutation, SHM affects only an organism's individualimmune cells, and the mutations are not transmitted to the organism'soffspring.[2] Because this mechanism is merely selective and not precisely targeted, somatic hypermutation has been strongly implicated in the development ofB-cell lymphomas[3] and many other cancers.[4][5]
When a B cell recognizes an antigen, it is stimulated to divide (orproliferate). During proliferation, theB-cell receptorlocus undergoes an extremely high rate ofsomatic mutation that is at least105–106 fold greater than the normal rate of mutation across the genome.[2] Variation is mainly in the form ofsingle-base substitutions, with insertions and deletions being less common. These mutations occur mostly at "hotspots" in theDNA, which are concentrated inhypervariable regions. These regions correspond to thecomplementarity-determining regions; the sites involved in antigen recognition on the immunoglobulin.[6] The "hotspots" of somatic hypermutation vary depending on the base that is being mutated. RGYW (i.e. A/G G C/T A/T) for a G, WRCY for a C, WA for an A and TW for a T.[7][8] The overall result of the hypermutation process is achieved by a balance between error-prone and high fidelity repair.[9] This directed hypermutation allows for the selection of B cells that express immunoglobulin receptors possessing an enhanced ability to recognize and bind a specific foreignantigen.[1]
The mechanism of SHM involvesdeamination ofcytosine touracil in DNA by the enzymeactivation-induced cytidine deaminase, or AID.[10][11] A cytosine:guanine pair is thus directly mutated to a uracil:guanine mismatch. Uracil residues are not normally found in DNA, therefore, to maintain the integrity of the genome, most of these mutations must be repaired by high-fidelitybase excision repairenzymes. The uracil bases are removed by the repair enzyme,uracil-DNA glycosylase,[11] followed by cleavage of the DNA backbone by apurinic endonuclease. Error-prone DNA polymerases are then recruited to fill in the gap and create mutations.[10][12]
The synthesis of this new DNA involves error-proneDNA polymerases, which often introduce mutations at the position of the deaminated cytosine itself or neighboringbase pairs. The introduction of mutations in the rapidly proliferating population of B cells ultimately culminates in the production of thousands of B cells, possessing slightly different receptors and varying specificity for the antigen, from which the B cell with highestaffinities for the antigen can be selected. The B cells with the greatest affinity will then be selected to differentiate intoplasma cells producingantibody and long-livedmemory B cells contributing to enhanced immune responses upon reinfection.[2]
The hypermutation process also utilizes cells that auto-select against the 'signature' of an organism's own cells. It is hypothesized that failures of this auto-selection process may also lead to the development of anauto-immune response.[13]
In birds which have a very limited number of genes available to V(D)J recombination,gene conversion between pseudogenic V segments and the currently-active V segment occur with SMH, thereby introducing extra diversity. Mammals such as cattle, sheep, and horses have a sufficiently large selection for V(D)J, but they also perform somatic gene conversion. This kind of gene conversion is also started by the AID enzyme, leading to a double-strand break, which is then repaired by using other V or pseudogenic-V segments as templates. Humans are not known to perform such gene conversion, except for one report of indirect evidence.[14]
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