Everything about Hypermutation totally explained
Somatic hypermutation (or SHM) is a mechanism inside
cells that's part of the way the
immune system adapts to the new foreign elements which confront it (for example,
microbes). SHM diversifies the receptors that the immune system uses 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 many other types of
mutation, SHM affects only individual
immune cells, and the mutations are not transmitted to
offspring.
Targets
When a
B cell recognizes an antigen, it's stimulated to divide (or
proliferate). During proliferation, the
B cell receptor locus undergoes an extremely high rate of
somatic mutation, that's at least
105-106 fold greater than the normal rate of mutation across the genome. 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.
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. 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.
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 long-lived
plasma cells producing
antibody and
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. It is hypothesized that failures of this auto-selection process may also lead to the development of an
auto-immune response.
Further Information
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