c-Rel plays a key role in deficient activation of B cells from a non–X-linked hyper-IgM patient

• Published in: Blood 2006-12, Vol.108 (12), p.3769-3776
• Main Authors: Lu, Kristina T., Sinquett, Frank L., Dryer, Rebecca L., Song, Charles, Covey, Lori R.
• Format: Article
• Language: English
• Subjects: B-Lymphocytes - metabolism; B-Lymphocytes - pathology; Biological and medical sciences; Cell Line, Transformed; Gene Expression Regulation; Humans; Hyper-IgM Immunodeficiency Syndrome, Type 1 - genetics; Hyper-IgM Immunodeficiency Syndrome, Type 1 - metabolism; Hyper-IgM Immunodeficiency Syndrome, Type 1 - pathology; Hyper-IgM Immunodeficiency Syndrome, Type 1 - physiopathology; Immunobiology; Immunodeficiencies. Immunoglobulinopathies; Immunoglobulinopathies; Immunopathology; Medical sciences; Promoter Regions, Genetic; Proto-Oncogene Proteins c-rel - biosynthesis; Proto-Oncogene Proteins c-rel - genetics; Receptors, IgE - biosynthesis; Receptors, IgE - genetics; Syndrome; Transcription, Genetic
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2006-03-008839

Our previous results demonstrated that B cells from a patient (pt1) with non–X-linked hyper-IgM syndrome (HIGM) possess an atypical CD23lo 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 (LCLtet). Our analysis revealed that the CD23lo phenotype in the pt1-LCLtet 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-LCLtet extracts, resulting from an overall lower expression of c-Rel in pt1-LCLtet cells. Analysis of c-Rel mRNA revealed relatively equal amounts in pt1-LCLtet and control LCLtet 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.