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What Is Somatic Hypermutation?

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  • Written By: Andrea Cross
  • Edited By: A. Joseph
  • Last Modified Date: 12 November 2016
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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.

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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.

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candyquilt
Post 3

Most of us have heard about auto-immune diseases right? This is when immune system cells attack the body's own cells instead of antigens.

For example, some types of thyroid disease are caused by this (Hashimato's) where the immune cells attack the cells of the thyroid gland and destroy them, causing the gland to stop functioning.

There are many such examples. There are different theories as to how this happens but it's most likely due to a somatic hypermutation gone wrong.

ZipLine
Post 2

@ysmina-- I'm not an expert on this topic. As far as I know, there are lots of different issues that can occur with the immune system causing it to function below optimum. It's definitely possible for this particular process to go wrong. Often times, doctors and scientists cannot identify the exact issue but they can easily tell that the immune system isn't responding when it should, responding abnormally or too slowly. So it would be difficult to know if your friend's immune system has issues with somatic hypermutation. Getting sick frequently and staying sick are definitely signs of a poorly functioning immune system.

ysmina
Post 1

I have a friend with a very weak immune system. He gets sick all the time and it takes a very long time for him to overcome the illness. He always needs medications but it still takes a while for his immune system to get to work.

Is it possible that his immune system cells are not doing somatic hypermutation correctly? Is it possible for this process to malfunction or fail?

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