Somatic hypermutation

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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.^[1] Somatic hypermutation involves a programmed process of mutation affecting the variable regions of immunoglobulin genes. Unlike many other types of mutation, SHM affects only individual immune cells, and the mutations are not transmitted to the offspring.^[1]

1 Targets
2 Mechanism
3 See also
4 References

[edit] 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. ^[1] 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.^[2] 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.

[edit] Mechanism

Chemical structure of cytosine

Chemical structure of uracil

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.^[3] ^[4] 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.^[4] 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.^[4] New DNA synthesis then recreates the proper cytosine:guanine duplex. ^[5]

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 long-lived plasma cells producing antibody and memory B cells contributing to enhanced immune responses upon reinfection.^[1]

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.