Mast cell–derived proteases control allergic inflammation through cleavage of IgE Ingrid Rauter, PhD, Maria-Theresa Krauth, MD, Kerstin Westritschnig,

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Mast cell–derived proteases control allergic inflammation through cleavage of IgE Ingrid Rauter, PhD, Maria-Theresa Krauth, MD, Kerstin Westritschnig, MD, Friedrich Horak, MD, Sabine Flicker, PhD, Anna Gieras, MSc, Andreas Repa, MD, Nadja Balic, Susanne Spitzauer, MD, Johannes Huss-Marp, MD, Knut Brockow, MD, Ulf Darsow, MD, Heidrun Behrendt, MD, Johannes Ring, MD, Franz Kricek, PhD, Peter Valent, MD, Rudolf Valenta, MD Journal of Allergy and Clinical Immunology Volume 121, Issue 1, Pages 197-202 (January 2008) DOI: 10.1016/j.jaci.2007.08.015 Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Tryptase cleaves IgE and abolishes binding of IgE to allergen. A, Nitrocellulose-blotted human IgE treated with (+) or without (−) tryptase was stained with anti-human IgE antibodies. Molecular weights (in kilodaltons) are displayed. B and C, Birch pollen allergen (Bet v 1)–specific human IgE was treated with (+) or without (−) tryptase (molar ratios: solid column, tryptase:IgE = 1:20; open column, tryptase:IgE = 1:40) and reacted with ELISA plate–bound Bet v 1 or the grass pollen allergen Phl p 5. OD values (y-axis) correspond to bound IgE detected with 2 different monoclonal anti-IgE antibodies (Fig 1, B: Pharmingen; Fig 1, C: LE-27). D, Plate-bound Bet v 1–specific IgE treated with (IgE +) or without (IgE −) tryptase and tryptase alone were incubated with Bet v 1, and bound Bet v 1 was detected with rabbit anti-Bet v 1 antibodies. OD values (y-axis) correspond to bound Bet v 1–specific rabbit antibodies. Journal of Allergy and Clinical Immunology 2008 121, 197-202DOI: (10.1016/j.jaci.2007.08.015) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Tryptase-exposed IgE does not bind to FcɛRI. A, IgE was treated with (IgE +) or without (IgE −) tryptase. The reactants or buffer alone reacted with the ELISA plate–immobilized α-chain of FcɛRI, and bound IgE was detected with a monoclonal anti-IgE antibody. OD values (y-axis) correspond to captured and intact IgE. B, Preferential cleavage of IgE by tryptase. The α-chain was treated with (open bars) or without (solid bars) tryptase, and the reactants were coated on ELISA plates and exposed to IgE treated with (IgE +) or without (IgE −) tryptase or buffer alone (B). Amounts of bound IgE correspond to OD values (y-axis). C, FcɛRI-bound IgE is cleaved by tryptase. IgE/α-chain complexes were treated with (IgE α-chain +) or without (IgE α-chain −) tryptase. The reactants were coated on ELISA plates, and intact IgE was detected. OD values (y-axis) correspond to bound IgE. Journal of Allergy and Clinical Immunology 2008 121, 197-202DOI: (10.1016/j.jaci.2007.08.015) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Mast cell lysates cleave IgE. A, IgE was exposed to different reactants (lane 1, buffer; lane 2, leupeptin; lane 3, mast cell lysate; lane 4, mast cell lysate plus leupeptin) blotted onto nitrocellulose and detected with anti-human IgE antibodies. B, Purified human mast cells (duplicate wells) were loaded with IgE and either activated with calcium ionophore (lanes 1, 2, 5, and 6) or not (lanes 3, 4, 7, and 8). Supernatants (SN) and cellular extracts (E) were analyzed by means of Western blotting for the presence of IgE. Molecular weights (in kilodaltons) are displayed. Journal of Allergy and Clinical Immunology 2008 121, 197-202DOI: (10.1016/j.jaci.2007.08.015) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Protamine augments IgE-dependent allergic inflammation in vivo. A, Box plot representation of late-phase allergic skin inflammation (y-axis, in square centimeters) in a group of 12 allergic patients challenged with pollen allergens and 2 nonallergic persons challenged with anti-IgE after pretreatment with protamine (a) or NaCl (b). Non–IgE-dependent late-phase reactions (LPR) after challenge with codeine after pretreatment with protamine (c) or NaCl (d) in the same group of individuals are also shown. Mean values and outliers are indicated. B, An allergic patient and a nonallergic subjects underwent skin prick tests with allergen (+) or PBS (−). Nitrocellulose-blotted skin blister fluids obtained from the application sites were analyzed by means of Western blotting for the presence of IgE. Molecular weights (in kilodaltons) are shown. Journal of Allergy and Clinical Immunology 2008 121, 197-202DOI: (10.1016/j.jaci.2007.08.015) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions