Somatic hypermutation (or SHM) is a mechanism inside cells that is part of the way the immune system adapts to the new foreign elements that confront it (for example, microbes). SHM diversifies the receptors used by the immune system 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 of mutation affecting the variable regions of immunoglobulin genes. Unlike germline mutation, SHM affects only individual immune cells, and the mutations are not transmitted to offspring.[2]
Mistargeted somatic hypermutation is a likely mechanism in the development of B-cell lymphomas.[3]
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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.[2] 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, known as hypervariable regions. These regions correspond to the complementarity determining regions; the sites involved in antigen recognition on the immunoglobulin.[4] The exact nature of this targeting is poorly understood, although is thought to be controlled by a balance of error-prone and high fidelity repair.[5] 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.[1]
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.[6][7] A cytosine:guanine pair is thus directly mutated a 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-fidelity DNA mismatch repair enzymes. The uracil bases are removed by the repair enzyme, uracil-DNA glycosylase.[7] Error-prone DNA polymerases are then recruited to fill in the gap and create mutations.[6][8]
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 neighboring base pairs. During B cell division the immunoglobulin variable region DNA is transcribed and translated. 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 highest affinities for the antigen can be selected. The B cells with the greatest affinity will then be selected to differentiate into plasma cells producing antibody and long-lived memory 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 an auto-immune response.
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