title: c-Rel plays a key role in deficient activation of B cells from a non-X-linked hyper-IgM patient.
abstract: Our previous results demonstrated that B cells from a patient (pt1) with non-X-linked hyper-IgM syndrome (HIGM) possess an atypical CD23(lo) phenotype that is unaffected by CD40-mediated activation. To investigate the molecular mechanism underlying defective CD23 expression in pt1 B cells, we used lymphoblastoid cell lines that express LMP1 under the control of a tetracycline-inducible promoter (LCL(tet)). Our analysis revealed that the CD23(lo) phenotype in the pt1-LCL(tet) cells is a direct consequence of diminished CD23 transcription. We demonstrate a marked decrease in c-Rel-containing complexes that bind to the proximal CD23a/b promoters in pt1-LCL(tet) extracts, resulting from an overall lower expression of c-Rel in pt1-LCL(tet) cells. Analysis of c-Rel mRNA revealed relatively equal amounts in pt1-LCL(tet) and control LCL(tet) cells, indicating that diminished c-Rel protein expression is unrelated to decreased transcription. Finally, a critical role for c-Rel in CD23 regulation was demonstrated by effectively altering c-Rel expression that resulted in the direct modulation of CD23 surface expression. Collectively, these findings demonstrate that low levels of c-Rel are the underlying cause of aberrant CD23 expression in pt1 B cells and are likely to play a critical role in the pathophysiology of this form of HIGM.
authors.affiliation: Dept of Cell Biology and Neuroscience, Nelson Biological Laboratories, Rutgers, The State University of New Jersey, 604 Allison Rd, Piscataway, NJ 08854, USA.
authors.forename: Kristina T
authors.initials: KT
authors.lastname: Lu
authors.forename: Frank L
authors.initials: FL
authors.lastname: Sinquett
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Dryer
authors.forename: Charles
authors.initials: C
authors.lastname: Song
authors.forename: Lori R
authors.initials: LR
authors.lastname: Covey
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D002461:Cell Line, Transformed; D005786:Gene Expression Regulation; D006801:Humans; D053307:Hyper-IgM Immunodeficiency Syndrome, Type 1 / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D011401:Promoter Regions, Genetic; D020569:Proto-Oncogene Proteins c-rel / Q000096:biosynthesis* / Q000235:genetics; D017455:Receptors, IgE / Q000096:biosynthesis* / Q000235:genetics; D013577:Syndrome; D014158:Transcription, Genetic
chemical_list: D020569:Proto-Oncogene Proteins c-rel; D017455:Receptors, IgE