Hyper IgM syndrome

Hyper IgM syndrome is a problem where B cells are unable to undergo antibody class-switching, meaning that they can produce IgM antibodies, or immunoglobulins, but struggle to produce other types of antibodies, and that leaves individuals at risk for certain infections.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.

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 constant region, 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 antibody class 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 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 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 get 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 IgG free producing plasma cell, and if a lot is cut out, the result might be an IgE antibody producing plasma cell.

Hyper IgM syndrome can be caused by a variety of genetic defects, which make the B cells unable to undergo class switching.

There are several subtypes of hyper IgM syndrome. The most common is Type 1, which is an X-linked recessive disease of the CD40 ligand gene, otherwise known as CD40LG, which affects T cells’ ability to stimulate B cells and activate them.

Type 2 is an autosomal recessive disease in which there’s a mutation in an enzyme that helps with class switching in the B cells.

Type 3 is an autosomal recessive mutation in the CD40 gene affecting B cells, so that they’re unable to be activated by T cells.

Type 4 is again thought to be related to a mutation in an enzyme that helps with class switching in the B cells, but the exact defect here is unknown.

Lastly, there’s type 5, which is once again, caused by a mutation in an enzyme involved in B cell class switching. Ultimately, individuals with Hyper IgM syndrome are predisposed to certain infections including fungi, like Pneumocystis jirovecii, which causes pneumonia, protozoa like cryptosporidium, which infects the biliary tract and causes chronic diarrhea and malabsorption, viruses like cytomegalovirus, which which often causes a viral pneumonia or viral hepatitis, and encapsulated bacteria, like Streptococcus pneumoniae, which can cause otitis media, sinusitis, and bacterial pneumonia.The symptoms of hyper IgM are related to the chronic infections that a person develops, and the diagnosis is based on finding low levels of IgG, IgA, IgE, and IgD antibodies with a normal or elevated IgM level.

Usually there’s a family history of the disease, and in the majority of cases flow cytometry or genetic testing can confirm that there’s a mutated CD40 ligand.Treatment includes infusions of immunoglobulin pooled from lots of donors, which helps provide passive immunity that can help the immune system fight off pathogens.

Because of the risk of Pneumocystis jirovecii infection, individuals are often prophylactically treated with the antibiotic trimethoprim-sulfamethoxazole.

In some instances, a bone marrow transplant can be done to establish a normal immune system.All right, as a quick recap...

Hyper IgM Syndrome is characterized by a defect in the ability of B cells to undergo antibody class-switching, meaning that they can produce IgM antibodies, but not IgG, IgA, IgE, or IgD.

The most common cause is an X-linked recessive genetic defect of the CD40 ligand, leaving helper T cells incapable of initiating antibody class-switching in B cells.

Affected individuals experience recurrent infections with Pneumocystis jirovecii, cryptosporidium, cytomegalovirus, and encapsulated bacteria, like Streptococcus pneumoniae, and may require infusions of antibodies produced by other people in addition to antibiotics.

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