Isolated primary immunoglobulin M deficiency

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Introduction0:00–0:15

In isolated primary immunoglobulin M deficiency, there’s a decrease in the number of IgM antibodies in the blood, while the levels of other types of antibodies remain normal.
Let’s take a look at how B cells end up secreting different types of antibodies. Each B cell is born in the bone marrow from a stem cell and develops its own B cell receptor, which sits on the cell surface.

Physiology0:15–4:18

The B cell receptor consists of two parts - a protein called CD79 that communicates with the rest of the cell and a membrane bound IgM or IgD antibody that can bind to an antigen.
An antigen is any substance recognized by that particular antibody. Each antibody has two identical light chains and two identical heavy chains that combine into a Y shape.
So this Y-shaped antibody’s got two arms with identical tips, which is called the variable region. This variable region contains an antigen binding domain that’s unique to that antibody.
Below the variable region, or toward the point where the arms meet, is the constant region where every member of an antibody class is identical – so all IgM antibodies have the same constand regions, but IgM and IgA constant regions are different.
And there are five classes of antibodies in total: IgM, IgG, IgA, IgE, and IgD class antibodies, and each one has a slightly different job.
For example, IgMs are part of B cell receptors, and are the first free-floating antibodies produced in an immune response.
They’re secreted as a pentamer, meaning there are five antibodies connected together, which provides many binding sites for grabbing antigens and taking them out of the blood.
Each antibody has complement protein binding sites on the heavy chains, so these IgM pentamers are also great at activating complement proteins, which help destroy and remove pathogens.
IgG antibodies stick to the surface of bacteria and viruses – and that prevents them from adhering to and infecting cells.
IgG also allows macrophages and neutrophils to grab and destroy the microbes. IgA antibodies line mucosal tissues like the gastrointestinal and respiratory tracts and stop microbes from invading in the first place.
IgE antibodies work with eosinophils to destroy parasites, and as for IgD antibodies, they’re also used in some B cell receptors, just like IgMs are, but their function as free-floating antibodies is still actually unclear.
Each B cell has over 100,000 B cell receptors spread across its surface, all of which bind the same unique antigen. When a B cell comes in contact with an antigen it recognizes, the B cell internalizes that antigen and then presents a piece of it on a major histocompatibility complex class II molecule, or MHC-class II for short.
Then, at some point, along comes a CD4+ helper T cell that binds to the presented antigen and when that happens, it expresses a protein called CD40 ligand on its surface.
The CD40 ligand attaches to a receptor on the B cell’s surface called CD40. This engagement is the key to activating B cells.
Often, the T cell also secretes cytokines like interferon gamma and different interleukins - which direct the B cell to providing the B cell with specific instructions as to what class of antibody it should start producing.
Some of these B cells turn into plasma cells which produce IgM, whereas other plasma cells undergo class-switching. Class-switching is the process of DNA segments being sliced, with pieces removed, and the remaining pieces stuck back together so that ultimately the gene itself encodes a different type of heavy chain.
If only some of the DNA is cut out, the result might be an IgG3 producing plasma cell, and if a lot is cut out, the result might be an IgE antibody producing plasma cell.

Pathology4:18–5:16

In isolated primary immunoglobulin M deficiency there’s a decrease - ranging from a slight decrease to being undetectable - in the level of free IgM circulating in the bloodstream while the levels of other antibodies remain normal.
This seems a bit strange because B cells have to make IgM antibodies before they can make antibodies of other classes. But it turns out that circulating B cells still have membrane-bound IgM on their surfaces – it’s just that there’s a decrease in the free-floating IgM antibodies.
The way this happens is unclear but one theory is that B cells are successfully activated and produce IgM antibodies, but the IgM antibodies are rapidly degraded after being secreted for some reason.
Another theory is that the problem may be with the B cells themselves, in that they may have trouble maturing and producing free IgM for some reason.
The range of symptoms begin in infancy and can vary widely – some individuals seem to be completely asymptomatic while others develop recurrent severe infections like sinusitis, diarrhea, and skin infections - in particular from encapsulated bacteria like Streptococcus pneumoniae and Haemophilus influenzae type B.

Symptoms5:16–5:49

These infections might progress to more severe conditions like meningitis and sepsis. Often, these individuals also suffer from allergic conditions like atopic dermatitis and asthma.

DIagnosis and treatment5:49–6:21

The diagnosis is based on having a history of recurrent infections and having normal levels of IgG, IgA, and IgE antibodies with a decreased IgM level.
Treatment is mainly aimed at treating concurrent conditions like atopic dermatitis and asthma, as well as using antibiotics to prophylax or treat infections.
Unfortunately, intravenous immunoglobulin infusions from a pool of plasma donors are ineffective, because they don’t contain much IgM.
All right, as a quick recap...In isolated primary immunoglobulin M deficiency there is a decrease in the level of free IgM circulating in the bloodstream while the levels of other antibody classes are still normal.

Review6:21–6:55

Symptoms can include recurrent infections as well as atopic dermatitis and asthma. Treatment can include prophylactic antibiotics, but intravenous immunoglobulin infusions are not typically helpful.