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Specific NEMO mutations impair CD40-mediated c-Rel activation and B cell terminal differentiation
Ashish Jain, … , Steven Holland, Jonathan M.J. Derry
Ashish Jain, … , Steven Holland, Jonathan M.J. Derry
Published December 1, 2004
Citation Information: J Clin Invest. 2004;114(11):1593-1602. https://doi.org/10.1172/JCI21345.
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Article Immunology

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

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Abstract

Hypomorphic mutations in the zinc finger domain of NF-κB 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 Iε-Cε 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-κB components have different activation requirements and that IL-4 can augment some but not all NEMO-dependent NF-κB signaling. Finally, using microarray analysis of patient B cells we identified downstream effects of impaired NF-κB activation and candidate factors that may be necessary for CSR and SHM in B cells.

Authors

Ashish Jain, Chi A. Ma, Eduardo Lopez-Granados, Gary Means, William Brady, Jordan S. Orange, Shuying Liu, Steven Holland, Jonathan M.J. Derry

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Genes from XHM-ED B cells that show abnormal regulation in response to C...

Genes from XHM-ED B cells that show abnormal regulation in response to CD40L plus IL-4


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