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Probing the Ige-Binding Repertoire of Self-Antigens in Atopic Eczema

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Probing the Ige-Binding Repertoire of Self-Antigens in Atopic Eczema Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2009 Probing the IgE-Binding Repertoire of Self-Antigens in Atopic Eczema Zeller, S Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-31226 Dissertation Originally published at: Zeller, S. Probing the IgE-Binding Repertoire of Self-Antigens in Atopic Eczema. 2009, University of Zurich, Faculty of Science. Probing the IgE-Binding Repertoire of Self-Antigens in Atopic Eczema Dissertation zur Erlangung der naturwissenschaftlichen Doktorwürde (Dr. sc. nat.) vorgelegt der Mathematisch-naturwissenschaftlichen Fakultät der Universität Zürich von Sabine Zeller aus Deutschland Promotionskomitee Prof. Dr. Roland H. Wenger (Vorsitz) Prof. Dr. Reto Crameri (Leitung der Dissertation) PD Dr. Peter Schmid-Grendelmeier Zürich, 2009 Publications Original Articles 1. Zeller S, Rhyner C, Meyer N, Schmid-Grendelmeier P, Akdis CA, Crameri R. Exploring the repertoire of IgE-binding self-antigens associated with atopic eczema. Journal of Allergy and Clinical Immunology (accepted for publication) 2. Zeller S, Johansson C, Rhyner C, Scheynius A, Crameri R. The IgE-binding self- antigens tubulin-α and HLA-DR-α are overexpressed in the lesional skin of atopic eczema patients. Allergy (submitted) Review Article 1. Zeller S, Glaser AG, Vilhelmsson M, Rhyner C, Crameri R. Immunoglobulin-E- mediated reactivity to self-antigens: a controversial issue. International Archives of Allergy and Immunology 2008; 145:87-93. Table of contents 1 Acknowledgments ........................................................... 1 2 Summary ........................................................................ 2 3 Zusammenfassung .......................................................... 4 4 Abbreviations ................................................................. 6 5 Introduction ................................................................... 8 5.1 Historical background of allergy ............................................................................. 8 5.2 Hypersensitivity reactions and IgE-mediated allergy ............................................. 8 5.3 Immunological tolerance ...................................................................................... 11 5.4 Atopic diseases .................................................................................................... 16 5.5 Epidemiology of atopic diseases .......................................................................... 22 5.6 Allergens ............................................................................................................... 24 6 Aim of the thesis ........................................................... 31 7 Results ......................................................................... 32 7.1 Exploring the repertoire of IgE-binding self-antigens associated with atopic eczema ................................................................................................................. 32 7.2 The IgE-binding self-antigens tubulin-α and HLA-DR-α are overexpressed in the lesional skin of atopic eczema patients ................................................................ 57 8 Final Discussion ............................................................ 65 8.1 Identification of a broad spectrum of self-antigens associated with atopic eczema ................................................................................................................. 66 8.2 Production of recombinant self-antigens .............................................................. 66 8.3 Immunological characterization of recombinant self-antigens ............................. 67 8.4 Dermal expression of self-antigens ...................................................................... 69 8.5 IgE-mediated Reactivity to Self-Antigens: A Controversial Issue ........................ 70 8.6 Conclusion and Outlook ....................................................................................... 78 8.7 Statement of contribution to publications ............................................................. 79 9 References .................................................................... 80 10 Curriculum Vitae .......................................................... 100 Acknowledgments 1 Acknowledgments Firstly, I would like to thank Prof. Dr. Reto Crameri, who supervised the present thesis, for his continuous support, for sharing his great knowledge, good discussions, and new ideas. I like to express my gratitude to the members of the “Promotionskomitee”, Prof. Dr. Roland Wenger, Prof. Dr. Reto Crameri, and PD Dr. Peter Schmid-Grendelmeier, for accepting the responsibility for my PhD thesis and Prof. Dr. Thomas Werfel for critically reading this dissertation. In particular, I thank PD Dr. Peter Schmid-Grendelmeier for his support, his enthusiasm, and good collaborations. I like to express my thanks to Prof. Dr. Annika Scheynius for welcoming me in her group in the Karolinska Institute in Stockholm. I highly appreciate her support and the practical help of Catharina Johansson and Anna Andersson. I cordially thank all the present and former members of the department of Molecular Allergology, Claudio Rhyner, Michael Weichel, Andreas Glaser, Anna Schaffartzik, Philippe Indermitte, and Monica Vilhelmsson for their practical help during work and their friendship. Moreover, my appreciation goes to Nadia Ouaked, Sven Klunker, Kerstin Siegmund, Norbert Meyer, Carmela Tognala, Daniela Bert and all the other co-workers of the SIAF as well as Annarös Zentner. Thank you for creating such an enjoyable working atmosphere and for all the great moments in Davos! My special thanks go to Prof. Dr. Cezmi A. Akdis, director of the Swiss Institute of Allergy and Asthma research (SIAF), as well as Prof. Dr. Kurt Blaser, former director of the institute, for the opportunity to write a PhD thesis at the SIAF. Finally, I like to thank my family for their generosity, full confidence, and loving support. This work was financially supported by the Swiss National Science Foundation grants 31- 63381.00/2 and 310000-114634/1 and by the OPO-Pharma Foundation, Zürich. The research stay in the Karolinska Institute was financed by a fellowship from the European Molecular Biology Organization (EMBO), grant ASTF 351.00-2007. 1 Summary 2 Summary Atopic eczema is the most common chronic inflammatory skin disease, affecting 10-20% of children and 1-3% of adults in industrialized countries. Various genetic, environmental, and physiological factors act together in the multifactorial pathogenesis of atopic eczema by activating well-known immunological and inflammatory pathways. In addition, IgE- mediated reactivity against human proteins, so called autoreactivity, has been postulated as a further pathogenic mechanism. Already in 1941 it was described that human skin dander is able to trigger immediate type skin reactions in patients with severe atopic eczema, suggesting that endogenous proteins may serve as targets for IgE autoantibodies. However, only the application of modern molecular biology methods led to the elucidation of the biochemical nature of these self-antigens. Although several IgE- binding self-antigens associated with atopic eczema are described in deep detail, the whole repertoire of these proteins and their role in the pathogenesis of the disease are still largely unknown. Therefore, the aim of this thesis was the identification of new IgE- binding self-antigens associated with atopic eczema and the characterization of their immunological properties and their expression in the skin. To identify new IgE-binding self-antigens, a human cDNA library displayed on phage surface was screened with solid-phase immobilized serum IgE of patients suffering from atopic eczema. 140 complete and partial sequences encoding putative IgE-binding self- antigens were identified. The presence of nine out of twelve already described self- antigens among the enriched clones indicated a high specificity of the screening system used. Five putative self-antigens namely actin-alpha, tubulin-alpha, eukaryotic initiation factor for translation 6, HLA-DR-alpha, and RP1 were randomly selected for cloning, 2+ expression as His6-tagged fusion proteins in Escherichia coli, and purification by Ni - chelate affinity chromatography. Western blot as well as ELISA experiments confirmed that the recombinant self-antigens bind IgE of sera of atopic eczema patients while healthy controls had no detectable levels of self-antigen-specific IgE. Moreover, the recombinant self-antigens cross-linked receptor bound IgE on the surface of basophils as demonstrated by the upregulation of CD63 and CD203c and induced the proliferation of peripheral blood mononuclear cells of sensitized patients. Interestingly, immunohistochemistry staining of skin biopsies demonstrated that tubulin-α and HLA-DR- α are upregulated in acute and chronic atopic eczema lesions compared to unaffected skin from the same patient or healthy controls. 2 Summary In summary it can be ascertained that the spectrum of IgE-binding self-antigens involved in the pathogenesis of AE is much broader than initially expected. Many human proteins might serve as IgE-binding self-antigens in atopic eczema and most atopic eczema patients have autoreactive IgE-antibodies in serum. Self-antigens are supposed to exacerbate the chronic inflammation in the skin by activating the humoral and cellular
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