Somatic hypermutation and affinity maturation

Definitions & Key takeaways

Somatic hypermutation and affinity maturation are two mechanisms by which the immune system can adapt to better recognize and neutralize pathogens. Somatic hypermutation is a cellular mechanism by which the immune system adapts to the new foreign elements that confront it (e.g. microbes), whereas affinity maturation refers to the process of increasing the specificity and strength of the interaction between an antibody and its target antigen to increase the effectiveness of the immune response.

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The immune response is highly specific for each invader. And that's because the cells of the adaptive immune response have receptors that differentiate one pathogen from another by their unique parts called antigens.
The key cells of the adaptive immune response are the lymphocytes. The B and T cells which have unique antigen receptors known as the B cell receptor or BCR and T cell receptor or T CR respectively.
Both B cells and T cells undergo a process called VD J rearrangement to generate a massively diverse set of receptors. B cells can further enhance the diversity of their BCR repertoire using a process called somatic hypermutation.
And the result is that the cells that emerge will have a stronger and more specific response to the antigen. And this is called affinity maturation.
Now remember that the B cell receptor is essentially an antibody except that it's attached to the surface of the B cell.
And each B cell receptor or antibody has two general parts. The variable region which binds antigen and the constant region which determines the specific antibody class IgM IgG IGA IgD or IgE.
First, let's start with the activation of B cells which occurs when a foreign antigen binds and crosslinks adjacent BCR S, thereby triggering a cascade of events that help B cells proliferate and differentiate once activated.
The B cell internalizes the antigen and presents a piece of it on a major histocompatibility complex class two molecule or MHC class two for short at some point along comes a CD four positive helper T cell that binds to the presented antigen.
When this interaction occurs, the T cell expresses a protein called CD 40 ligand on its surface which binds to the CD 40 receptor on the B cell.
This triggers a series of events that eventually result in the activation of the enzyme called activation induced cytidine deaminase or aid for short.
This enzyme is only found in B cells and allows them to make cuts in the DNA causing the B cell to class switch from I GM to GG IG A or I GE.
At the same time, the T cells secrete cytokines that bind cytokine receptors on the B cell providing specific instructions on what class of antibody it should start producing because of the role that aid plays in class switching.
People who lack aid suffer from a condition known as hyper IgM immunodeficiency where they have a hard time making antibodies other than I GM.
The most common cause of this condition is an excellent recessive genetic defect of the CD 40 ligand that leaves helper T cells incapable of binding CD 40 receptors on B cells.
In addition to promoting class switching aid also leads to somatic hypermutation. Somatic hypermutation only happens in activated B cells, not T cells and primarily occurs in the germinal centers of the lymph nodes and spleen.
You see aid can only bind to single stranded DNA. So it's really only able to target genes that are being actively transcribed during the rapid proliferation phase that occurs following B cell activations.
The way the aid enzyme works is turning a cytidine into a uridine in the DNA. Now keep in mind that uridine is completely foreign to DNA and typically only found in RNA.
And uridine can't properly bind to the guanazine nucleoside on the opposite DNA strand. As a result, the cell tries to fix this mistake in the DNA in one of two ways, either mismatch repair or base excision repair in mismatch repair, the mismatch repair proteins, MS H two and MS H six, Wu Shin to fix the DNA before transcription is complete.
They kind of do this like the pit crew at a NASCAR race trying to quickly fix a car on lap 40 out of 100 MS H two and MS H six recruit nucleases which remove the uridine and several adjacent nucleotides from the DNA and then DNA polymerase comes in to help replace the nucleotides.
This process is extremely error prone and tends to introduce mutations into the DNA. The other option is base excision repair, which is where the enzyme uracil DNA glycosylase removes the uracil base from the uridine and typically in the next round of DNA replication, a random nucleotide is inserted into the opposite DNA strand by DNA polymerase once again, leading to a mutation.
And these random mutations mean the daughter cells of the initial B cell may have a very different antigen specificity than their mother cell.
Now, even though random mutations in a gene are usually a problem mutations in the variable region of the BCR are actually a really good thing.
That's because the changes affect how strongly the BCR binds to the antigen, its affinity for the antigen. And since the B cells will eventually become plasma cells that secrete antibodies, this process affects the antibody affinity for antigen.
While some daughter cells have mutations in their BCR that increase the affinity for antigen, others have mutations that decrease it.
If A B cells affinity is so low that it doesn't respond to the antigen anymore, then the B cell will simply stop getting activated and will die out over time.
Meanwhile, other cells will get a stronger and stronger affinity over the generations. And this is what leads to affinity maturation.
It's really like natural selection on a cellular level sped up so that we see changes happening over days instead of over thousands of years while all of this is happening, keep in mind that there's an immune response taking place and that there's initially lots of antigen floating around over time as the immune system clears away more and more of the infection, there's less antigen left for this process of affinity maturation.
That means that only the BCR S with the highest affinity for the antigen will be able to bind to the small amount that's floating around.
In other words, as antigen is removed, it helps to also promote only the daughter cells with BCR that have the strongest ability to bind the antigen and mount a response against it.
All right, as a quick recap somatic hypermutation only occurs in B cells which express the enzyme aid aid is able to make small mutations directly in the antigen binding site of the BCR which get expressed in the daughter cells of a rapidly proliferating cell.
These changes in the variable region change the affinity or strength that the BCR has for its antigen. As antigen becomes limited B cells with the lowest affinity will die off first making it.
So that only those B cells with the strongest affinity for the antigen remain. This process is called affinity maturation.