Antibody Class Switching
Author(s): David Dorward, Genevieve McMahon and Hannah McManus
Class switching is the process whereby an activated B cell changes its antibody production from IgM to either IgA, IgG, or IgE depending on the functional requirements.
By the end of this CAL you should understand:
- the basic structure and function of an antibody.
- the different classes of antibodies and the general functions of each.
- how class switching occurs and what triggers this to happen.
- the purpose of class switching in the grand scheme of the immune response.
Introduction - what is an antibody class? Part 1 of 11
An antibody class is determined by the heavy chain of the antibody.
Let’s take a quick look at the structure of an antibody to find out what this means:
- Antibodies are found in a general ‘Y’ shaped arrangement, with two heavy and two light chains
- You can see that the light chains are each made up of a constant and variable region
- Each of the heavy chains is made up of a variable region, and three constant segments
- The variable regions of the heavy and light chains come together to form two identical paratopes for antigen binding
- The constant heavy chain segment create the Fc region, which is vital for binding to Fc receptors on other cell types and mediating antibody functions
- Changes in this region by class switching will, therefore, alter the functional abilities of the antibody without altering the specificity of the paratope.
What are the main classes of antibody? Part 2 of 11
There are five classes of antibody that B cells can express – IgA, IgD, IgE, IgG and IgM. Class expression depends on a variety of stimuli and the experience of the cell.
Each antibody class has its own specific function within an immune response as we will discuss in a moment, other than IgD whose function is not yet understood.
IgD is expressed by naïve B cells alongside IgM, and this expression is lost following activation.
However, as you can see below. each of the other antibody classes has a distinct structure and function within the immune response.
IgM Part 3 of 11
IgM is the antibody class which predominates in the early stages of an immune response as it is the first to be produced.
Although all antibodies are comprised of the same basic structure, some are capable of forming polymers to increase their functionality. IgM is an example of this and is often found in the blood in a pentameric structure which increases the surface area and the number of sites for antigen binding. IgM is therefore particularly good at trapping and neutralising antigen, and also activating complement, but is less good at ADCC and opsonisation.
IgG Part 4 of 11
IgG is a class of antibody which can be further subdivided into four subclasses (IgG1-4), all of which exist as monomers.
IgG is also the only class of antibody which is capable of crossing the placenta, conferring early protective immunity in the foetus.
IgA Part 5 of 11
IgA also exists in a polymeric form, as it is capable of forming dimers. These dimers are generally found in the gut and at other mucosal surfaces, and so are specially designed for antigen trapping and neutralisation at these surfaces, allowing invading pathogens to be flushed out of the body without causing harm.
IgA is poor at activating complement and ADCC which is also very logical, as these are highly inflammatory processes which would cause more damage in these mucosal areas than the pathogen itself, and so a neutralising approach is preferred.
IgE Part 6 of 11
IgE is the final class of antibody, which is found as a monomer and is often bound to Fc receptors on mast cells, basophils and eosinophils.
It has a prominent role in allergy responses, as well as in parasite infections.
Part 7 of 11
So, let’s summarise all of those different antibodies and their roles in immunity…
So how do we go about class switching? Part 8 of 11
As we’ve already discussed, the class of antibody produced by a B cell is determined by which heavy chain constant region gene is being expressed. So a process needs to occur whereby this constant region gene is swapped from μ (IgM) to one of the other isotypes, without altering the variable heavy chain gene expression.
This is done by a process called class switch recombination and is an irreversible process. Repetitive areas of DNA known as ‘switch regions’ are found in the introns upstream of each isotype gene, which is used to guide AID and other enzymes to the site. These then create nicks in the DNA sequence, allowing the μ genes to be excised and then a repair enzyme to come along and join the VDJ segment back on to the new constant region.
What determines which class of antibody is expressed? Part 9 of 11
Class expression depends on the environment the B cell finds itself in after activation.
CD4 T cells in the area produce cytokines which help to skew the immune response to the most appropriate type of response, so these cytokines interact with the B cells and cause them to favour a particular antibody class. For example, at mucosal surfaces, CD4 T cells will often produce TGFβ which drives the B cells present to produce IgA, whereas in allergy or during parasite infection there is a large amount of IL-4 and IL-13 which skew towards IgE production.
The pathogens involved may also send signals which the B cells can use to decide which class of antibody would be best to produce, as well as by informing the CD4 T cell response.
Significance of antibody class Part 10 of 11
We’ve already discussed the fact that the functional properties of an antibody are conferred by the constant regions of the heavy chain, whilst the antigen binding ability is determined by the paratope produced by the variable light and heavy chain regions together.
But what does the heavy chain actually do?
Well, as you can see from the picture above, the constant regions of the heavy chain come together to form the Fc portion of the antibody. This is the area of the antibody that interacts with other immune cells, and hence has a huge impact on the effect on the resulting response. Most immune cells carry Fc receptors, which bind this portion of the antibody and therefore react to the presence of the antigen through a variety of mechanisms.
The special functions of each antibody are therefore partially determined by which Fc receptor they bind to. There are various subtypes of these receptors to increase the specificity of this response; for example, Fcγ for IgG, Fcε for IgE, Fcα for IgA and Fcα/µ for IgM/IgA. Not only does binding to these various receptors lead to different outcomes, but the expression of these receptors on particular cell types also helps to further hone the response.
This restricted distribution pattern also plays a huge role in conferring the type of response produced. Mast cells are a particularly good example. They express high-affinity Fcε receptors to encourage IgE binding that leads to degranulation of these cells. This attracts other immune cells such as eosinophils and basophils to the site, which is of particular importance in combating parasitic infections.
Conclusion Part 11 of 11
Class switching is a process which takes place in B cells to alter the class of antibody produced during an immune response from IgM to one of the other classes.
This is a pivotal process that allows the response to become tailored to the particular infection that is present, allowing it to be tackled more efficiently whilst preserving the surrounding tissues where possible.
Each class of antibody, therefore, has its own strengths and functions, including opsonisation, ADCC and neutralisation, which confer their optimal use.
The choice of antibody is dictated by the infecting pathogen, as well as signals from surrounding immune cells, and occurs via an irreversible process called class switch recombination.