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Allergen cleavage by effector cell-derived proteases regulates allergic inflammation

Ingrid Rauter^*, Maria-Theresa Krauth, Sabine Flicker^*, Anna Gieras^*, Kerstin Westritschnig^*, Susanne Vrtala^*, Nadja Balic, Susanne Spitzauer, Johannes Huss-Marp, Knut Brockow, Ulf Darsow, Johannes Ring, Heidrun Behrendt, Hans Semper, Peter Valent and Rudolf Valenta^*,1

^* Division of Immunopathology, Department of Pathophysiology, Center for Physiology and Pathophysiology, Medical University of Vienna, Austria;

Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria;

Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Austria; and

ZAUM–Center for Allergy and Environment, Division of Environmental Dermatology and Allergy GSF/TUM, Department of Dermatology and Allergy, Technical University of Munich, Germany

¹Correspondence: Division of Immunopathology, Department of Pathophysiology, Center for Physiology and Pathophysiology, Medical University of Vienna, General Hospital Vienna, 3Q, Waehringer Guertel 18–20, A-1090 Vienna, Austria. E-mail: rudolf.valenta{at}meduniwien.ac.at

ABSTRACT

The key event of allergic inflammation, allergen-induced crosslinking of mast cell-bound IgE antibodies, is accompanied by release of inflammatory mediators, cytokines, and proteases, in particular ß-tryptase. We provide evidence that protease-mediated cleavage of allergens represents a mechanism that regulates allergen-induced mast cell activation. When used in molar ratios as they occur in vivo, purified ß-tryptase cleaved major grass and birch pollen allergens, resulting in defined peptide fragments as mapped by mass spectrometry. Tryptase-cleaved allergens showed reduced IgE reactivity and allergenic activity. The biological relevance is demonstrated by the fact that lysates from activated human mast cells containing tryptase levels as they occur in vivo cleaved allergens. Additionally, protamine, an inhibitor of heparin-dependent effector cell proteases, augmented allergen-induced release of mediators from effector cells. Protease-mediated allergen cleavage may represent an important mechanism for terminating allergen-induced effector cell activation.—Rauter, I., Krauth, M.-T., Flicker, S., Gieras, A., Westritschnig, K., Vrtala, S., Balic, N., Spitzauer, S., Huss-Marp, J., Brockow, K., Darsow, U., Ring, J., Behrendt, H., Semper, H., Valent, P., Valenta, R. Allergen cleavage by effector cell-derived proteases regulates allergic inflammation.

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