Mutations in NF-κB essential modulator cause a class-switch–defective hyper-IgM syndrome in human subjects,20 as well as in p50 knockout mice.13, 44, 45 Haploinsufficiency of NF-κB might result in defective class-switch recombination because of poor expression of activation-induced cytidine deaminase, a gene regulated by NF-κB, which, when absent, is also associated with immunodeficiency.46 This evidence concerns the gene CD40 and hyper-IgM syndrome.