Explain why IgG is low and what CD40's role is? Why is a mutation in that gene a problem?

Question

Case Studies Tasks:

¹Daniel: Susan and Joe had a wonderful little boy named Daniel, but he had been having an awful lot of bacterial infections and he was barely a year old. It seemed that the antibiotics cleared up one bacterial respiratory infection only to have another follow shortly. The scary thing was that Daniel had just fought off a case of pneumonia caused

by Pneumocystis carnii, a fungal infection that was usually found in people with HIV. Waiting for the test

results of an HIV test for their little boy was one of the worst experiences ever. Thank goodness it came back negative.

However, it seemed that their troubles were just beginning. After this last lung infection, the fungal one, and

a negative HIV test, their doctor had ordered a number of other blood tests, including a genetic test that

Susan didn’t fully understand. Apparently the doctor was worried about Daniel’s immune system functions.

Susan had also met with a genetic counselor who collected a family history of any immune disorders. The

details were vague, but Susan’s mother, Helen, knew that one of her three brothers had died young from an

unexplained lung infection. Unfortunately, Grandma Ruth had passed away a few years ago, leaving them

with numerous unanswered questions. Susan and Joe had an appointment with their doctor that afternoon to go over the results. When they arrived Dr. Dresdner led them into an office where Ms. Henchey, the genetic counselor, waited. This can’t be good, thought Susan. The doctor began by explaining that they had analyzed Daniel’s blood and found that while he had normal levels of B cells and T cells, his antibody levels were anything but normal. The levels of

IgG, IgA, and IgE were very low, almost undetectable, and Daniel had abnormally high levels of IgM and IgD.

It appears that his immune system failed to undergo immunoglobulin isotype switching due to a CD40 ligand mutation in Daniel's DNA.

Answer 1

Hi Raven!

In a healthy immune system, B cells can sense invaders (bacteria, viruses, etc.) using IgM antibodies on their surface, ingest them, and then present a small chunk of the invader (antigen) on their surface using a Major Histone Compatibility (MHC) complex. CD4 helper T cells then come along and attach to the B cell in 2 important places: 1) the MHC which has the antigen presented on it, and 2) CD40 on the B cell which attaches to CD40 ligand on the CD4 helper T cell. When this happens, the CD4 cell releases cytokines (cellular messengers) which induce immunoglobulin isotype switching (ex. going from B cells producing IgM to producing IgG or IgA, etc.). Isotype switching allows our bodies to have a variety of immunoglobulins (IgM, IgG, IgA, etc.) to help prevent infections like the lung infections seen here.

As you can imagine, if the CD40 ligand is mutated and not working correctly, then we are unable to undergo immunoglobulin isotype switching and thus 1) IgG will be low and 1) we are going to be susceptible to all kinds of infections, particularly Pneumocystis, Histoplasma, Cryptosporidium. This clinical manifestation is called Hyper-IgM Syndrome and is typically X-linked recessive which explains the familial pattern of inheritance seen here.

Hopefully this was helpful! It is a complicated topic and takes quite a bit of thinking through. Let me know if you have any more questions!

Josiah