title: Specific NEMO mutations impair CD40-mediated c-Rel activation and B cell terminal differentiation.
abstract: 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.
authors.affiliation: Laboratory of Host Defense, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland 20892, USA. ajain@niaid.nih.gov
authors.forename: Ashish
authors.initials: A
authors.lastname: Jain
authors.forename: Chi A
authors.initials: CA
authors.lastname: Ma
authors.forename: Eduardo
authors.initials: E
authors.lastname: Lopez-Granados
authors.forename: Gary
authors.initials: G
authors.lastname: Means
authors.forename: William
authors.initials: W
authors.lastname: Brady
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Orange
authors.forename: Shuying
authors.initials: S
authors.lastname: Liu
authors.forename: Steven
authors.initials: S
authors.lastname: Holland
authors.forename: Jonathan M J
authors.initials: JM
authors.lastname: Derry
mesh_terms: D000293:Adolescent; D000328:Adult; D001402:B-Lymphocytes / Q000166:cytology / Q000502:physiology*; D019013:CD40 Antigens / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics* / Q000276:immunology*; D002454:Cell Differentiation / Q000502:physiology*; D002675:Child, Preschool; D003564:Cytidine Deaminase; D043525:Cytosine Deaminase / Q000235:genetics / Q000378:metabolism; D004476:Ectodermal Dysplasia / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation; D006801:Humans; D006942:Hypergammaglobulinemia / Q000235:genetics / Q000276:immunology; D051550:I-kappa B Kinase; D017578:Immunoglobulin Class Switching / Q000235:genetics; D007136:Immunoglobulins / Q000097:blood; D015847:Interleukin-4 / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D016328:NF-kappa B / Q000276:immunology; D020569:Proto-Oncogene Proteins c-rel / Q000235:genetics / Q000276:immunology*; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics; D013577:Syndrome; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D019013:CD40 Antigens; D002352:Carrier Proteins; C491731:IKBKG protein, human; D007136:Immunoglobulins; D016328:NF-kappa B; D020569:Proto-Oncogene Proteins c-rel; D015847:Interleukin-4; D051550:I-kappa B Kinase; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D043525:Cytosine Deaminase; D003564:Cytidine Deaminase