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

Blood. 2006 Dec 1;108(12):3769-76. doi: 10.1182/blood-2006-03-008839. Epub 2006 Aug 8.

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.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • B-Lymphocytes / metabolism*
  • B-Lymphocytes / pathology
  • 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
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-rel / biosynthesis*
  • Proto-Oncogene Proteins c-rel / genetics
  • Receptors, IgE / biosynthesis*
  • Receptors, IgE / genetics
  • Syndrome
  • Transcription, Genetic

Substances

  • Proto-Oncogene Proteins c-rel
  • Receptors, IgE