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Hypomorphic mutations in the zinc finger domain of NF-kappaB essential modulator (NEMO) cause X-linked hyper-IgM syndrome with ectodermal dysplasia (XHM-ED). Here we report that patient B cells are characterized by an absence of Ig somatic hypermutation (SHM) and defective class switch recombination (CSR) despite normal induction of activation-induced cytidine deaminase (AID) and Iepsilon-Cepsilon transcripts. This indicates that AID expression alone is insufficient to support neutralizing antibody responses. Furthermore, we show that patient B cells stimulated with CD40 ligand are impaired in both p65 and c-Rel activation, and whereas addition of IL-4 can enhance p65 activity, c-Rel activity remains deficient. This suggests that these NF-kappaB components have different activation requirements and that IL-4 can augment some but not all NEMO-dependent NF-kappaB signaling. Finally, using microarray analysis of patient B cells we identified downstream effects of impaired NF-kappaB activation and candidate factors that may be necessary for CSR and SHM in B cells.

Specific NEMO mutations impair CD40-mediated c-Rel activation and B cell terminal differentiation