Somatic Hypermutation and Affinity Maturation
Author(s): David Dorward, Hannah McManus and Genevieve McMahon
By the end of this CAL you should understand:
- how the BCR is coded for.
- the processes which are used to introduce variety into the gene product; somatic hypermutation.
- affinity maturation and its role in the development of a more efficient immune response.
- how this links to the activity of the germinal centre.
Introduction Part 1 of 4
Somatic Hypermutation Part 2 of 4
You may have wondered while making your way through the ‘Germinal Centre’ section exactly how B cells change their antigen specificity. B cells have developed a clever mechanism of introducing target mutations into their B cell receptor gene sequence while cycling through the germinal centre, leading to a change in receptor specificity. This process is given the fancy name of ‘somatic hypermutation’.
The B cell receptor (BCR) is coded for by different gene regions, named the ‘V’, ‘D’ and ‘J’ regions. The one we are concerned with here is the ‘V’ region; this is the region which codes for the variable part of the receptor and hence determines what antigen the receptor will bind to.
During somatic hypermutation, point mutations are introduced into this variable region. This is done by an enzyme with the complicated name of ‘Activation-induced cytidine deaminase’, or more simply ‘AID’. AID is only expressed in activated B cells, and hence somatic hypermutation only occurs after B cells have been activated by a helper T cell. AID initiates mismatch repair and base excision repair pathways in the DNA of the V region during transcription, altering the DNA sequence by working alongside other enzymes such as DNA polymerases and mismatch repair proteins (remember your genetics?!).
The reason this process is given the name of ‘hypermutation’ is that these mutations happen at a very high rate, resulting in mutant B cell receptors appearing on B cell surfaces. These are then filtered out or selected for by affinity maturation.
Affinity Maturation Part 3 of 4
We have discussed somatic hypermutation, a process where point mutations create B cells which differ subtly from each other in specificity for antigen. As these mutations change the ability for the B cell receptors to bind antigen, they change the fate of each B cell within the germinal centre. Through chance alone, most of these recombinations have a negative effect on antigen binding and lead these B cells to die by apoptosis as they can’t compete with their ‘better-matched’ colleagues. These dying cells are quickly engulfed by resident macrophages, creating ‘tingible body macrophages’ which are a characteristic feature of germinal centres.
The selection process determining which cells meet this fate appears to occur in stages. It is believed somatic hypermutation occurs in the dark zone of the germinal centre, but when centroblasts stop proliferating and develop instead into centrocytes they increase their expression of certain surface receptors and move towards the light zone.
The light zone is an area which is full of FDCs expressing antigen. This allows the mutated B cells to test out their receptor binding properties – if the new receptor can still bind the antigen, a survival signal is sent allowing the B cell to cycle through the process somatic hypermutation again. This is known as the cyclic re-entry model of B cell maturation. At each stage new B cells have to compete for antigen with their predecessors, meaning they only survive if their receptor is better fitted to the antigen than before.
Over time, this whole process leads to selected B cells having an increased affinity for their antigen. Of course, it’s not quite this simple, and to truly survive not only do B cells have to interact with antigen on FDCs but they also need prolonged contact with T follicular helper cells. This is done through a special ligand:receptor interaction; B cells express a ligand called ICOS ligand (ICOSL), which co-stimulates the T follicular helper cell through its ICOS receptor. This causes the T cell to upregulate a ligand which binds to CD40 on the B cell, promoting B cell survival by inhibiting apoptosis.
Conclusion Part 4 of 4
The B Cell Receptor is a massively variable molecule which can change through generations of B cell clones via the process of somatic hypermutation. Affinity maturation is the subsequent process which selects B cells based on these changes to the receptor conformation, selecting the most avidly binding receptors to enhance the immune response and ultimately provide memory. This occurs within the dark and light zones of the germinal centre through interactions with FDCs and T follicular helper cells presenting antigen.