Submitted March 9, 2006
Accepted July 25, 2006
c-Rel plays a key role in deficient activation of B cells from a non-X-linked hyper IgM patient
Kristina T Lu, Frank L Sinquett, Rebecca L Dryer, Charles Song, and Lori R Covey*
Rutgers University, The State University of New Jersey, Piscataway, NJ, USA
Harbor General Hospital, UCLA, Torrance, CA, USA
* Corresponding author; email: covey{at}biology.rutgers.edu.
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 utilized 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 relative equal amounts in pt1- 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 which resulted in the direct modulation of CD23 surface expression. Collectively, these findings demonstrate that low levels of c-Rel is the underlying cause of aberrant CD23 expression in pt1 B cells and is likely to play a critical role in the pathophysiology of this form of HIGM.
