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List of Figures Viii Vi Bidirectional IL-31-driven communication between T cells and basophils during atopic skin inflammation Inaugural-Dissertation for the attainment of the title of doctor in the Faculty of Mathematics and Natural Sciences at the Heinrich Heine University Düsseldorf presented by MSc. Angeliki Datsi from Ioannina (GR) Düsseldorf, April 2019 From the University Hospital Düsseldorf – Department of Dermatology, Research Laboratory for Dermato-Immunology and Oncology of the Heinrich-Heine-University Düsseldorf Printed with permission of the Faculty of Mathematics and Natural Sciences at the Heinrich-Heine-University Düsseldorf Supervisor: Univ.-Prof. Dr. med. Bernhard Homey Co-supervisor: Univ.-Prof. Dr. rer. nat. Eckhardt Lammert Date of the oral examination: 16.09.2019 Abstract I. Abstract The novel TH2-derived cytokine interleukin-31 (IL-31) has been implicated in the pathophysiology of atopic skin inflammation. Here for example, IL-31 has been identified to effectively elicit the cardinal AD symptom of pruritus (itch), relying on a synergistic cooperation of dysregulated immune cells and hyper-stimulated sensory neurons. This study aims to systematically characterize the phenotype of IL-31-producing T cells and to elucidate their interaction with basophils in the context of atopic skin inflammation. + Results of the present study could identify the unique characteristics of IL-31 TH2 cells presenting with a CRTH2+ CCR4+ CCR10+ CXCR3- CCR6- phenotype and a distribution among the effector memory (CD62L- CD45RO+) T cell subset. Furthermore, IL-31+ T cells associate with a marked increase of the skin-homing chemokine receptors CCR4, CCR8, and CCR10 in AD patients. Notably, the abundance of IL-31+ T cells but also the overall production of T cell-derived IL-31 was found increased in AD patients while frequencies of circulating basophils were not affected. Instead, AD patients presented with an increased population of cutaneous lymphocyte-associated antigen (CLA)+ activated ST2+ basophils that produce elevated levels of IL-4. Further, these basophils show increased survival upon IL-31 stimulation. Interestingly, in Il-31ra-knockout mice the presence of activated basophils, and also TH2 cells, were decreased suggesting a dependence on the presence of Il-31/Il-31ra signaling. In line with these observations, AD-derived basophils present with an enhanced expression of IL-31RA/OSMRβ. The present study further describes a prominent communication loop from keratinocytes to basophils, supporting the importance of outside-inside signals for the perpetuation of AD. Mimicking an AD-like environment, circulating basophils from AD patients respond to IL-4/IL-13-treated keratinocyte supernatants by initiating antigen-independent TH2 differentiation and production of IL-31. This observation implies an additional role for IL-31 signaling in TH2 differentiation and probably expansion. Taken together, findings of the present study suggest a role of activated skin-homing CLA+ basophils in the progression and/or perpetuation of AD based on their interaction with keratinocytes as well as skin- infiltrating T cells and strengthens the IL-31/IL-31 receptor complex as a therapeutic target in the treatment of mild to severe atopic dermatitis. I Zusammenfassung II. Zusammenfassung Das neue TH2-assoziierte Zytokin Interleukin-31 (IL-31) steht in Zusammenhang mit der Pathophysiologie von atopischen Hautentzündungen. IL-31 wurde als effektiver Auslöser von „Juckreiz“, ein Kardinalsymptom bei atopischer Dermatitis (AD), identifiziert. Dieser Juckreiz ist auf eine synergistische Kooperation zwischen nicht regulierten Immunzellen und überstimulierten sensorischen Nerven zurückzuführen ist. Diese Studie charakterisiert systematisch den Phänotyp der IL-31-produzierenden T-Zelle und durchleuchtet die Rolle der IL-31+ T-Zelle in atopischer Hautentzündung. Im Focus steht die Interkation der IL-31+ T-Zelle mit Basophilen. Die Ergebnisse dieser Studie beschreiben + + + + - einmalige Charakteristika der IL-31 TH2-Zelle, mit einem CRTH2 CCR4 CCR10 CXCR3 CCR6- Phänotypen und der Zugehörigkeit zu den Effektor-Gedächtnis-T-Zellen (CD62L- CD45RO+). Darüber hinaus exprimiert die IL-31+ T-Zelle von Patienten mit AD vermehrt die typischen Haut-migrierenden Chemokin-Rezeptoren CCR4, CCR8 und CCR10. Hierbei ist nicht nur ein erhöhtes Vorkommen von IL-31+ T-Zellen bei Patienten mit AD zu vermerken, sondern auch eine insgesamt höhere Produktion von IL-31, wobei jedoch die zirkulierende Basophilen-Frequenz unverändert bleibt. Stattdessen weisen sie vermehrt aktivierte ST2+ Basophile auf, die kutanes Lymphozyten-assoziiertes Antigen (CLA) exprimieren und vermehrt IL-4 produzieren. Des Weiteren weisen diese Basophilen unter IL-31 Stimulation ein erhöhtes Zellüberleben auf. Interessanterweise konnten in Il-31ra-/-- Mäusen verminderte Frequenzen von aktivierten Basophilen, sowie TH2-Zellen nachgewiesen werden, was die Rolle des Il-31/Il-31ra Signalweges in der Biologie von Basophilen und der Entwicklung von TH2-Immunantworten weiter unterstreicht. Im Einklang mit diesen Ergebnissen, scheinen Basophile von AD Patienten auch eine erhöhte Expression des IL-31RA/OSMRβ Rezeptorkomplex zu zeigen. Darüber hinaus beschreibt die vorliegende Studie eine Kommunikationsschleife von Keratinozyten zu Basophilen. In einem AD-simulierenden Umfeld fördern zirkulierende Basophile nach Stimulation mit IL- 4/IL-13-behandelte Keratinozyten-Überstände die TH2-Differenzierung und die IL-31 Sekretion. Zusammengefasst unterstützten die Ergebnisse der vorliegenden Studie eine Rolle von aktivierten CLA+ Basophilen in atopischen Hautentzündungsprozessen, weist auf das komplexe Zusammenspiel von Keratinozyten, Basophilen und T-Zellen hin und unterstreicht den Stellenwert des IL-31/IL-31 Rezeptor-Komplexes als therapeutisches Ziel in der Behandlung von AD. II Table of Contents III. Table of Contents I. ABSTRACT I II. ZUSAMMENFASSUNG II III. TABLE OF CONTENTS II IV. ABBREVIATIONS IV V. LIST OF FIGURES VIII VI. LIST OF TABLES IX 1. INTRODUCTION 1 1.1 The adaptive immune system 1 1.1.1 Cellular Response ..............................................................................................................................1 1.1.2 CD4+ T lymphocytes ...........................................................................................................................2 1.2 Pro-inflammatory cytokines and gp130 receptors 8 1.2.1 IL-31 and its receptor heterodimer IL-31RA/OSMRβ ........................................................................9 1.2.2 Molecular source and regulation of IL-31 .......................................................................................10 1.3 Atopic dermatitis and its immunopathology 11 1.3.1 Pruritus as a cardinal symptom of AD .............................................................................................12 1.3.2 IL-31 and its role in AD ....................................................................................................................14 1.3.3 Basophils..........................................................................................................................................17 1.4 Aim of the study 21 2. MATERIAL AND METHODS 22 2.1 Patients 22 2.1.1 Blood sampling ................................................................................................................................23 2.1.2 Primary human keratinocytes .......................................................................................................23 2.2 Isolation of leukocytes 24 2.2.1 Isolation of leukocytes from peripheral blood .................................................................................24 2.3 Magnetic cell sorting 25 2.3.1 Enrichment of CD4+ T cells ..............................................................................................................25 2.3.2 Enrichment of CD123+ cells .............................................................................................................27 2.3.3 Enrichment of CD14+ cells ...............................................................................................................29 2.4 Principle of multicolour flow cytometry and cell sorting 29 2.4.1 Titration of antibodies .....................................................................................................................29 2.4.2 Surface staining ...............................................................................................................................30 2.4.3 Intracellular staining for cytokines ..................................................................................................33 2.4.4 Intracellular staining for transcription factors.................................................................................34 2.5 Molecular biology 36 2.5.1 RNA extraction ................................................................................................................................36 2.5.2 cDNA synthesis ................................................................................................................................36 2.5.3 Quantitative real-time PCR analysis ................................................................................................37 III Table of Contents 2.6 Cell culture 38 2.6.1 T cell differentiation ........................................................................................................................38 2.6.2 Co-cultures of naïve T cells and basophils with stimulated NHEK-supernatants
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