An 18-month-old girl is brought to the pediatrician because of recurrent upper respiratory tract infections.She has a fever,labored breathing,and a dry cough.Diagnostic tests confirm infection with Pneumocystis jiroveci.Serum studies are remarkable for negligible levels of IgG and IgA in the presence of high concentrations of IgM.The family history is unremarkable;in particular,the patient's three older brothers are in excellent health.This patient most likely carries a mutation in which of the following molecules?

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The patient's clinical presentation is consistent with hyper-IgM syndrome,which is associated with defective switching of B cells to the IgG and IgA isotypes.Whereas IgG and IgA levels may be undetectable in blood,IgM titers are often concomitantly increased.The molecular defect arises from impaired interaction between CD40L on T cells and CD40 on B cells;thus T cells cannot provide B cells with the stimulatory signals required for heavy chain isotype switching.Patients also show defects in cell-mediated immunity,since CD40 ligand-receptor interactions are important for T cell-dependent activation of macrophages.These patients therefore are particularly susceptible to infection by the opportunistic intracellular microbe Pneumocystis jiroveci.Because this patient is a girl with healthy brothers and maternal uncles,she is unlikely to have X-linked hyper-IgM syndrome,which is caused by mutations in CD40L (expressed on T cells).Rather,she is more likely to carry a rare mutation in CD40 (expressed on B cells),which results in hyper-IgM syndrome with an autosomal recessive pattern of inheritance.

An 18-Month-Old Girl Is Brought to the Pediatrician Because of Recurrent