What Is Somatic Hypermutation?

Somatic hypermutation (SHM) is a mechanism by which the immune system adapts in order to recognize antigens that it has not previously encountered. This mechanism is the predominant method in humans and enables the cells of the immune system to diversify their receptors by promoting mutation in the variable regions of the immunoglobulin genes. These regions form the antibody-antigen binding sites and contribute to the specificity capabilities of each antibody, allowing for particular antigen recognition.

When a foreign antigen, such as a microbe, comes into contact with the immune system, it is identified as unfamiliar by the B cells. The B cells are then activated and stimulated to proliferate. During this proliferation, the immunoglobulin variable region DNA is transcribed and translated at very high rate, approximately 10⁵-10⁶ times faster than normal mutation. This somatic hypermutation allows a rapid response that is essential to an efficient immune system.

Somatic hypermutation is thought to be achieved by the deamination of the cytosine base in the DNA by activation-induced deaminase (AID), converting it from deoxycytidine to deoxyuracil and resulting in new DNA. This new DNA contains a uracil-guanine mismatch, because uracil normally occurs in RNA, where it is paired with adenine, and guanine is normally paired with cytosine in DNA. Correction of this mutation occurs through removal by a high-fidelity DNA repair enzyme, uracil-DNA glycosylase (UNG₂) followed by the synthesis of new DNA strands by DNA polymerase. This process, however, is error-prone and can result the substitution of incorrect nucleobases at the original site of deamination or the adjacent base pairs. This creates a "hot spot" that is vulnerable to insertion and deletion mutations.

The results of the somatic hypermutation are then transcribed and translated, resulting in large numbers of B cells that carry varying receptors and specificity, as coded by the hypermutated regions. Those B cells with antibodies that display the greatest affinity for the antigen that originally stimulated proliferation will then differentiate into plasma cells that will produce the corresponding, affinity-specified antibody, as well as into memory B cells. These differentiations and affinity maturation will subsequently allow the immune system to produce a greater, more effective response if the antigen is encountered in the future.

Somatic hypermutation occurs in individual immune cells, so it is transmitted only within that one particular cell line. Furthermore, mutations are not passed down to any offspring. Problems can arise, however, because somatic hypermutation also involves cells that auto-select against the organisms' own cells. If there is a failure in this process, an autoimmune response might be provoked.