Immunoglobulins: proteins that play tag

This was originally written (by me) as a post on the PIA Discussion Boards, and has been modified to fit the format of the blog.

When going through the process of getting diagnosed, many people hear their specialist talking to them about immunoglobulin levels, IgA, IgM and IgG. What are they? Why are they important?

Introduction to Immunoglobulins

Immunoglobulins are also known as antibody, and they are the body's adaptive way of responding to infection - particularly to bacterial infection, although they also respond to both viral and parasite infections. You can see on the right that the general structure of an immunoglobulin is that of a Y shape.

At the tip of each arm is a variable binding site: the tips of antibodies produced by different plasma cells bind to different protein fragments known as antigens. Since every type of pathogen consists of different proteins, this means that antibodies are specific to that type of pathogen.

Antibodies "tag" pathogens so that cells in the immune system can recognise them. You can think of immunoglobulins as adapters which fit between the pathogen and the immune cell; this adaptation is known as opsonisation. For opsonisation to work, the tail of the Y is constant and is recognised by a number of different cells in the immune system.

When a "normal" person gets an infection, the first wave (primary response) of antibodies takes about 3 days to start production; the antibodies of the primary response are IgM (immunoglobulin M). IgM consists of a cluster of five Y-shaped antibodies joined by the bottom of the Y in the middle (a pentamer). Because each IgM pentamer has 10 binding sites, it's very effective at creating clusters of tagged pathogens which stimulates the immune response. In addition, IgM can also bind with key parts of the pathogen which prevent them being pathogenic; for example, antibodies against influenza virus or HIV actually prevent the virus entering the cells.

After about 10 days, antibody production switches to IgG. IgG consists of 4 subclasses, all of which are Y shaped, only some have longer tails than others. The tips of the arms consist of a binding site again, but the IgG binding sites tend to be even more accurately shaped to bind with the target pathogen. This secondary response is also the one which provides long-term immunity; when a "normal" person is re-exposed to the same pathogen, the body immediately starts producing the IgG it previously used to destroy the bug. Again, IgG works both by opsonising pathogens and/or blocking their entry into cells.

IgA is also a refined antibody (that is to say, it's part of the secondary response, not part of the primary response), and consists of two Y-shaped antibodys tied together at the tail (a dimer). Again, the tips are binding sites so an IgA antibody has 4 binding sites. However, IgA is secreted into the mucosa - that's the moist tissues lining the nose, mouth, throat, lungs and digestive tract - where it works by blocking pathogens seeking an opportunity to enter the body.

Immune Problems and Immunoglobulins

The most common form of primary immune deficiency (PID) is selective IgA deficiency (SIgAD), although the vast majority of people with SIgAD don't have any symptoms. In SIgAD, the person produces little or no IgA, and can therefore be susceptible to repeated respiratory and digestive tract infections, including sinusitis, tonsilitis, pharyngitis, laryngitis, oral ulcers, bronchitis, bronchiolitis, pneumonia, food poisoning, vomitting and diarrhoea (not an exhaustive list).

One of the most common forms of PID is common variable immunodeficiency (commonly known as CVID, but also known as hypogammaglobulinaemia or agammaglobulinaemia). In CVID, patients have little or no IgG and may have low levels of IgM or IgA. In CVID, low levels of IgM result in the body not mounting an effective initial response to an infection; low IgG results in the body's ongoing fight against pathogens being impaired. Low IgG and IgA may also mean that the body doesn't respond to vaccinations - although in some cases it responds to some types but not others (for example, it may not respond to pneumonia vaccine, but respond successfully to the tetanus vaccine).

A related form of PID is hyper-IgM syndrome, in which the body produces only IgM, and never moves onto a secondary response.

Treatment

IgG-deficient disorders benefit from immunoglobulin replacement therapy, such as SCIG and IVIG. IgG therapy is generally well tolerated (few people have reactions) and improves the quality of life substantially, reducing infections, joint pain and fatigue (all common symptoms of CVID). There is no point in replacing IgM as it is less efficient than IgG.

IgA is more complex and is currently not treatable directly. Having said that, there is research into nasal-spray IgA supplements at the moment. There is a question as to whether this will work or not because as the IgA is secreted into the mucus it gains an extra molecule which wraps itself around the IgA antibody - and it's possible this molecule is important for the antibody to work or not be degraded by other chemicals in the mucus. We can produce IgA in volume using various techniques, but the secretory component is a potential problem.