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Targeting the Extracellular Membrane-Proximal Domain of Membrane-Bound IgE by Passive Immunization Blocks IgE Synthesis In Vivo¹

Stefan Feichtner^2,*, Daniela Inführ^2,*, Gertrude Achatz-Straussberger^*, Doris Schmid^*, Alexander Karnowski, Marinus Lamers, Claudio Rhyner, Reto Crameri and Gernot Achatz^3,*

^* Department of Molecular Biology, University of Salzburg, Salzburg, Austria; Walter and Eliza Hall Institute for Medical Research, Victoria, Australia; Max-Planck-Institute for Immunobiology, Freiburg, Germany; and Swiss Institute of Allergy and Asthma Research, Davos, Switzerland

The classical allergic reaction starts seconds or minutes after Ag contact and is committed by Abs produced by a special subset of B lymphocytes. These Abs belong to the IgE subclass and are responsible for Type I hyperreactivity reactions. Treatment of allergic diseases with humanized anti-IgE Abs leads primarily to a decrease of serum IgE levels. As a consequence, the number of high-affinity IgE receptors on mast cells and basophils decreases, leading to a lower excitability of the effector cells. The biological mechanism behind anti-IgE therapy remains partly speculative; however, it is likely that these Abs also interact with membrane IgE (mIgE) on B cells and possibly interfere with IgE production. In the present work, we raised a mouse mAb directed exclusively against the extracellular membrane-proximal domain of mIgE. The interaction between the monoclonal anti-mIgE Ab and mIgE induces receptor-mediated apoptosis in vitro. Passive immunization experiments lead to a block of newly synthesized specific IgEs during a parallel application of recombinant Bet v1a, the major birch pollen allergen. The decrease of allergen-specific serum IgE might be related to tolerance-inducing mechanisms stopping mIgE-displaying B cells in their proliferation and differentiation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Austria Science Foundation Projects P-19017 and T166 (Hertha Firnberg Fellowship) and the Austrian National Bank (Oesterreichische Nationalbank Grant 11710), Christian Doppler Laboratory for Allergy Diagnosis and Therapy, the Swiss National Science Foundation (Grant 310000-114634/1), and the OPO-Pharma Foundation, Zürich.

² S.F. and D.I. contributed equally to this work.

³ Address correspondence and reprint request to Dr. Gernot Achatz, University of Salzburg, Department of Molecular Biology, Hellbrunnerstrasse 34, A-5020 Salzburg, Austria. E-mail address: gernot.achatz{at}sbg.ac.at

⁴ Abbreviations used in this paper: mIgE, membrane IgE; EMPD, extracellular membrane-proximal domain; KLH, keyhole limpet hemocyanin; RT, room temperature; RBL, rat basophilic lymphocyte; SPRA, surface plasmon resonance analysis.

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