Somatic hypermutation and affinity maturation

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 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.

First, let’s start with the activation of B cells, which occurs when a foreign antigen binds and cross-links adjacent BCRs, 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 II molecule, or MHC-class II for short. At some point, along comes a CD4+ helper T cell that binds to the presented antigen.

When this interaction occurs, the T cell expresses a protein called CD40 ligand on its surface, which binds the CD40 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 IgM to IgG, IgA, or IgE.

At the same time, the T cell secretes 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 IgM. The most common cause of this condition is an X-linked recessive genetic defect of the CD40 ligand that leaves helper T cells incapable of binding CD40 receptors on B cells.