: The differentiation of IgM+ B cells into Ab secreting cells occurs in response to an array of signals provided by activated CD4+ T cells. A critical molecule in this regard is the CD40 ligand (CD154) expressed by activated T cells which through its cognate interaction with CD40 on B cells drives the proliferation and differentiation of antigen-activated IgM+ B cells. The relationship between proximal CD40 signaling events and downstream functions are not fully elucidated however, it is known that this multi-step process requires that activation of numerous signal transduction pathways. Our laboratory has had an ongoing interest in defining the early cytokine- and CD40-mediated signals required for class switch recombination (CSR) in human B cells. Although the critical roles of these signals in CSR are well recognized, the molecular mechanisms utilized by B cells to integrate these distinct classes of signals are poorly characterized. We have identified a B cell immunodeficiency that is distinguished by defective responses to CD40 and IL-4 signaling. B cells from a young female patient (pt#1) diagnosed with hyper-IgM syndrome have normal expression of CD40 but are clearly deficient in a subset of CD40- and IL-4-responsive functions including CD23 expression and early signals required for switch recombination. One intriguing characteristic of the patient B cells is that under specific in vitro conditions they regain """"""""functional responsiveness"""""""" and undergo switching in express downstream isotypes. We propose that the pt#1 defect is in an overlapping pathway important for both CD40- and IL-4-medicated B cell differentiation. To test this hypothesis, we propose to 1) identify signaling pathways that are directly affected by the pt#1 defect, 2) use CD23 and I-gamma promoter constructs to investigate transcription factor function, and 3) identify the defect using genetic complementation techniques. Completion of these studies should significantly increase our knowledge of how B cells utilize CD40 and IL-4 signaling cascades to activate CSR and B cell differentiation. Furthermore, results from these proposed experiments should increase our understanding of hyper-IgM syndrome by identifying a novel gene involved in the pathogenesis of this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI037081-06A2
Application #
6472557
Study Section
Immunobiology Study Section (IMB)
Program Officer
Mallia, Conrad M
Project Start
1995-09-15
Project End
2007-02-28
Budget Start
2002-03-01
Budget End
2003-02-28
Support Year
6
Fiscal Year
2002
Total Cost
$130,328
Indirect Cost
Name
Rutgers University
Department
Anatomy/Cell Biology
Type
Schools of Arts and Sciences
DUNS #
038633251
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
Matus-Nicodemos, Rodrigo; Vavassori, Stefano; Castro-Faix, Moraima et al. (2011) Polypyrimidine tract-binding protein is critical for the turnover and subcellular distribution of CD40 ligand mRNA in CD4+ T cells. J Immunol 186:2164-71
Sinquett, Frank L; Dryer, Rebecca L; Marcelli, Valentina et al. (2009) Single nucleotide changes in the human Igamma1 and Igamma4 promoters underlie different transcriptional responses to CD40. J Immunol 182:2185-93