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Somatic hypermutation and affinity maturation

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Somatic hypermutation and affinity maturation

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Somatic hypermutation and affinity maturation

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USMLE® Step 1 style questions USMLE

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An activated B cell located in the spleen binds an antigen and is activated via cytokines from a nearby T cell. An enzyme is then expressed in the B cell, which causes random nucleotides to be changed in the B cell receptor variable region. Subsequent generations of daughter cells of this B cell develop progressively stronger binding to this antigen. Which of the following correctly describes this process?  

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Content Reviewers:

Rishi Desai, MD, MPH

The immune response is highly specific for each invader, and that’s because the cells of the adaptive immune response have unique receptors that can differentiate friendly bacteria from deadly pathogens 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 TCR respectively.

Both B cells and T cells undergo a process called VDJ 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.

When B cell receptors are initially created it’s done in the absence of antigen.

Somatic hypermutation only happens in activated B cells, and not in T cells.

This happens at sites where B cells are activated and T cells are also present- basically in germinal centers within lymph nodes and the spleen.

When B cells receive antigen stimulation by crosslinking their BCRs, they express the molecule CD40 on their surface.

Nearby helper T cells with a CD40 ligand then come along and the CD40-CD40 ligand interaction makes the B cell upregulated cytokine receptors.

The T cell then sends out cytokines which bind to these receptors, and cause various changes within the activated B cell.

One key change is activation of the enzyme Activation Induced cytidine deaminase or AID - an enzyme that’s only found in B cells.

AID allows the B cell to make cuts in the DNA, causing the B cell to class switch from IgM to IgG, IgA, or IgE depending on the cytokines it receives from the T cell.

Because of the role that AID plays in class switching, people who lack AID suffer from a type of Hyper IgM immunodeficiency where they have a hard time making antibodies other than IgM.

In addition to promoting class switching, AID also leads to somatic hypermutation.

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 activation.

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 guanosine 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.

Summary
Somatic hypermutation (SHM) is a cellular mechanism by which the immune system adapts to the new foreign elements that confront it (e.g. microbes), as seen during class switching. A major component of the process of affinity maturation, SHM diversifies B cell receptors used 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.