IgE antibody plays an important role in allergic diseases. IgE synthesis by B-cells requires two signals. The first signal is delivered by the cytokines IL-4 or IL-13 which target the Ce gene for switch recombination. The second signal is delivered by interaction of the B-cell surface antigen CD40 with its ligand (CD40L) and activates deletional switch recombination. The investigators studies indicate that protein tyrosine kinases play an important role in CD40 mediated class switching. Recently, two members of the TNF receptor associated family of proteins, TRAF-2 and TRAF-3, were found to be associated with CD40. The investigators have also demonstrated that Jak3 is associated with CD40 and that both Jak3 and STAT-3 are activated upon CD40 ligation. They hypothesize that the Jak-STAT and TRAF signaling pathways activated by CD40 may synergize to induce switch recombination. The investigators propose to examine the following: I. Interplay between CD40, Jak3 and TRAF proteins. They will study a) the structural interactions between CD40, Jak3 and TRAF proteins, b) the biochemical interactions between Jak3 and TRAF proteins and c) the role of Jak3 in CD40 mediated cellular responses in vitro. CD40 mediated biochemical, gene induction and cellular events will be examined in B-cells from Jak3 deficient patients and in B-cells transfected with mutant chimeric CD8:CD40 receptors that fail to associate with Jak3. II. Role of Jak3 in CD40 mediated IgE isotype switching. The investigators will study CD40 mediated IgE isotype switching in a) Jak3 deficient B-cells and b) CD40 mutant transgenic mice with disrupted CD40-Jak3 association. III. Role of TRAF-3 in CD40 mediated IgE isotype switching. The investigators will study CD40 mediated IgE isotype switching in a) TRAF-3-/- mice and b) CD40 mutant transgenic mice with disrupted CD40-TRAF-3 association.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI031136-08
Application #
2882167
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Plaut, Marshall
Project Start
1992-03-01
Project End
2002-02-28
Budget Start
1999-03-01
Budget End
2000-02-29
Support Year
8
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Ozcan, Esra; Rauter, Ingrid; Garibyan, Lilit et al. (2011) Toll-like receptor 9, transmembrane activator and calcium-modulating cyclophilin ligand interactor, and CD40 synergize in causing B-cell activation. J Allergy Clin Immunol 128:601-9.e1-4
Jabara, Haifa H; Angelini, Federica; Brodeur, Scott R et al. (2011) Ligation of CD46 to CD40 inhibits CD40 signaling in B cells. Int Immunol 23:215-21
Jabara, Haifa H; Weng, Yu; Sannikova, Tatyana et al. (2009) TRAF2 and TRAF3 independently mediate Ig class switching driven by CD40. Int Immunol 21:477-88
Jabara, Haifa H; Chaudhuri, Jayanta; Dutt, Shilpee et al. (2008) B-cell receptor cross-linking delays activation-induced cytidine deaminase induction and inhibits class-switch recombination to IgE. J Allergy Clin Immunol 121:191-196.e2
Castigli, Emanuela; Wilson, Stephen A; Elkhal, Abdallah et al. (2007) Transmembrane activator and calcium modulator and cyclophilin ligand interactor enhances CD40-driven plasma cell differentiation. J Allergy Clin Immunol 120:885-91
Orange, Jordan S; Levy, Ofer; Geha, Raif S (2005) Human disease resulting from gene mutations that interfere with appropriate nuclear factor-kappaB activation. Immunol Rev 203:21-37
Castigli, Emanuela; Wilson, Stephen A; Scott, Sumi et al. (2005) TACI and BAFF-R mediate isotype switching in B cells. J Exp Med 201:35-9
Jabara, Haifa H; Geha, Raif S (2005) Jun N-terminal kinase is essential for CD40-mediated IgE class switching in B cells. J Allergy Clin Immunol 115:856-63
Dedeoglu, Fatma; Horwitz, Bruce; Chaudhuri, Jayanta et al. (2004) Induction of activation-induced cytidine deaminase gene expression by IL-4 and CD40 ligation is dependent on STAT6 and NFkappaB. Int Immunol 16:395-404
Orange, Jordan S; Jain, Ashish; Ballas, Zuhair K et al. (2004) The presentation and natural history of immunodeficiency caused by nuclear factor kappaB essential modulator mutation. J Allergy Clin Immunol 113:725-33

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