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.

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National Institute of Allergy and Infectious Diseases (NIAID)
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Immunological Sciences Study Section (IMS)
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Children's Hospital Boston
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