Which immunoglobulin deficiency syndrome is caused by defective CD40 ligand, resulting in failure of class-switch recombination and high IgM with low other isotypes?

• A. Hyper-IgM syndrome (CD40 ligand deficiency)
• B. Common variable immunodeficiency
• C. X-linked agammaglobulinemia
• D. Selective IgA deficiency

Answer: (A)

The essential idea is that switching the class of antibody B cells produce requires a signal from helper T cells through CD40 and its ligand. When CD40 ligand is defective, B cells cannot receive that signal, so they cannot perform class-switch recombination. They end up making mainly IgM and have very low levels of other isotypes like IgG, IgA, and IgE. That pattern—normal or high IgM with low IgG/IgA/IgE—defines Hyper-IgM syndrome caused by CD40L (CD40 ligand) deficiency. This arises from impaired T–B cell cooperation in germinal centers, leading to poor affinity maturation and limited antibody diversity, which underlies the recurrent bacterial infections and opportunistic infections seen in this condition.

Other choices don’t fit this pattern: X-linked agammaglobulinemia involves a failure to develop B cells due to BTK mutation, so all immunoglobulins are low; common variable immunodeficiency shows hypogammaglobulinemia with variable, not specifically CD40L–driven CSR defects; selective IgA deficiency is isolated IgA loss with normal other isotypes.