What is the most common cause of hyper IgM syndrome?

The most common cause of hyper IgM syndrome is related to defective CD40L (CD40 ligand) on T-helper (Th) cells. In a healthy immune response, CD40L is essential for the interaction between T cells and B cells. When CD40L on T-helper cells binds to CD40 on B cells, it activates the B cells to undergo class switch recombination. This process is crucial for the production of different immunoglobulin (Ig) classes, such as IgG, IgA, and IgE.

In hyper IgM syndrome, the defective expression or function of CD40L prevents proper class switching in B cells, which results in the overproduction of IgM and deficient levels of other immunoglobulin classes. This leads to a pronounced immunodeficiency, where the body has an inadequate response to pathogens due to the lack of sufficient amounts of IgG and IgA to combat infections effectively.

In contrast, increased IgA synthesis and excessive IgE production do not directly align with the pathological mechanism of hyper IgM syndrome, as they do not address the underlying defect in T-B cell interaction. Similarly, while underactive B-lymphocyte activation might seem related, it does not specifically account for the characteristic imbalance