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Somatic Hypermutation (or SHM) is a cellular mechanism that occurs during an adaptive immune response and serves to diversify the antigen specific receptor repertoire of the immune systems, throughout the lifetime of an organism.
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Targets
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. [ ]
The mutations that occur are mainly single base substitutions, with occasional insertions and deletions, and occur at “hotspots” located throughout DNA that encodes the immunoglobulin variable region.[Li, Ziqiang, Caroline J. Woo1, Maria D. Iglesias-Ussel, Diana Ronai and Matthew D. Scharff. (2004) ''The generation of antibody diversity through somatic hypermutation and class switch recombination''Full Text (html) Genes & Development 18:1-11.] 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.
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Mechanism
Experimental evidence supports the view that the mechanism of SHM involves deamination of cytosine to uracil in DNA by an enzyme called Activation-Induced (Cytidine) Deaminase, or AID.[Diaz, Marilyn ''Somatic Hypermutation'' National Institute of Environmental Health Sciences.] [Larson, Erik D and Nancy Maizels (2004) ''Transcription-coupled mutagenesis by the DNA deaminase AID'' Full Text (html) Genome Biol.; 5(3):211.] A cytosine:guanine pair is thus directly mutated a uracil:guanine mismatch. Deamination of cytosine, and the production of uracil:guanine mismatches, occurs frequently each day and in each mammalian cell.[ 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-fidelity DNA mismatch repair enzymes. The uracil bases are removed by the repair enzyme, uracil-DNA glycosylase.][ New DNA synthesis then recreates the proper cytosine:guanine duplex. ][Neuberger, Michael "Immunity and DNA deamination MRC Laboratory of Molecular Biology]
The synthesis of this new DNA involves error-prone DNA polymerases, which often introduce mutations either at the position of the deaminated cytosine itself or neighbouring base pairs. During B cell division the immunoglobulin variable region DNA is transcribed and translated. The introduction of mutations 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 highest affinities for the antigen can be selected. The B cells with the greatest affinity will then be selected to differentiate into memory B cells, contributing to enhanced immune responses upon reinfection.[ ]
The hypermutation process also utilizes cells that auto-select against the 'signature' of an organism's own cells. Failures of this auto-selection process may lead to the development of an auto-immune response.
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See also
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