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Beendigung Der Entzündungsreaktion Durch Interleukin-9 Sezernierende

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Beendigung Der Entzündungsreaktion Durch Interleukin-9 Sezernierende Beendigung der Entz¨undungsreaktion durch Interleukin-9 sezernierende angeborene Lymphozyten Der Naturwissenschaftlichen Fakult¨at der Friedrich-Alexander-Universit¨at Erlangen-Nurnberg¨ zur Erlangung des Doktorgrades Dr. rer. nat. vorgelegt von Simon Rauber Als Dissertation genehmigt von der Naturwissenschaftlichen Fakult¨at der Friedrich-Alexander-Universit¨at Erlangen-Nurnberg¨ Tag der mundlichen¨ Prufung:¨ 02. 05. 2919 Vorsitzender des Promotionsorgans: Prof. Dr. Georg Kreimer Gutachter: Prof. Dr. Steffen Backert Prof. Dr. Georg Schett Resolution of inflammation by interleukin-9 producing innate lymphoid cells To the Faculty of Natural Sciences of the Friedrich-Alexander-University Erlangen-Nuremberg for the obtainment of the academic degree doctor rerum naturalium (Dr. rer. nat.) submitted by Simon Rauber Approved by the Faculty of Natural Sciences of the Friedrich-Alexander-University Erlangen-Nuremberg Date of oral examination: 02. 05. 2019 Chairman of examination board: Prof. Dr. Georg Kreimer Referees: Prof. Dr. Steffen Backert Prof. Dr. Georg Schett Table of contents 1 Deutsche Kurzfassung1 2 English abstract3 3 Introduction 5 3.1 Innate lymphoid cells and the bridge between primary and adaptive immune response6 3.1.1 The discovery . .7 3.1.2 The classification of innate lymphoid cells and their integration into the im- mune system . 11 3.1.3 Are innate lymphoid cells only innate mirrors or fully-fledged immune cells . 12 3.2 The interleukin-9 . 15 3.2.1 The cellular source of interleukin-9 . 15 3.2.2 The immune-modulatory capacities of interleukin-9 . 17 3.2.2.1 Interleukin-9 in infection, tumour and allergy . 18 3.2.2.2 Interleukin-9 in autoimmune diseases . 18 3.3 Rheumatoid arthritis . 19 3.3.1 Molecular and cellular pathways in rheumatoid arthritis . 20 3.3.1.1 Auto-antibodies . 20 3.3.1.2 Alterations of the synovial joint micro-architecture in early and in clinically manifested rheumatoid arthritis . 21 3.3.1.3 T cells in rheumatoid arthritis . 23 3.3.1.4 The pro-inflammatory cyotkine cascades in rheumatoid arthritis . 23 I Table of contents 3.3.2 Current therapies . 24 3.3.2.1 Biological disease modifying anti-rheumatic drugs that block cy- tokine pathways . 25 3.3.2.2 Other pathways targeted by disease modifying anti-rheumatic drugs 26 3.3.2.3 Antibody dependant cell mediated cytotoxicity induced by disease modifying anti-rheumatic drugs . 26 3.3.2.4 Are disease modifying anti-rheumatic drugs pro-resolving? . 27 3.4 Aim and rationale of the study . 27 4 Material and methods 29 4.1 Instruments, equipment, reagents, kits, buffers and media . 29 4.1.1 Auxiliary equipments . 30 4.1.2 Inorganic and organic chemicals . 31 4.1.3 Kits and other reagents . 33 4.1.4 Buffers and media for cell culture and lymphocyte isolations . 33 4.2 Software . 34 4.3 Patients . 34 4.3.1 Ethical statement . 35 4.3.2 Blood donors . 35 4.3.3 Donors of synovial biopsies . 35 4.4 Animals . 36 4.4.1 Genotypting . 36 4.4.2 Ethical statement . 38 4.4.3 Animal models . 38 4.4.3.1 Antigen induced arthritis . 38 4.4.3.2 Serum transfer induced arthritis . 39 4.4.3.3 Gouty arthritis . 40 4.4.3.4 Hydrodynamic gene transfer . 40 II Table of contents 4.5 Flow cytometry and cell sorting . 41 4.5.1 Sample preparation . 42 4.5.1.1 Secondary lymphoid organs . 42 4.5.1.2 Joints . 43 4.5.1.3 Blood . 44 4.5.2 Antibody staining . 44 4.6 T cell polarisation . 46 4.7 Restimulation of sorted ILC2s and T cells . 47 4.7.1 Culture of type 2 innate lymphoid cells . 47 4.7.2 Restimulation of sorted regulatory T cells . 47 4.7.3 Suppression assay . 49 4.8 Enzyme-linked immunosorbent assays . 50 4.9 Histology and microscopy . 50 4.9.1 Sample preparation . 50 4.9.2 Thin section cutting . 50 4.9.3 Deparaffinization and rehydration . 51 4.9.4 Conventional histological stainings . 51 4.9.4.1 Haematoxylin and eosin staining . 51 4.9.4.2 Safranin O staining . 51 4.9.4.3 Detection of tartrate-resistant acetic phosphatase . 52 4.9.5 Immunofluorescence staining . 52 4.9.5.1 Epitope retrieval . 52 4.9.5.2 Antibody staining . 52 4.10 X-ray microtomography . 53 4.11 Semi-quantitative real-time expression analysis . 54 4.11.1 Primers . 54 4.12 Statistical analysis . 54 5 Results 56 5.1 Interleukin-9 deficiency leads to chronic inflammation in antigen induced arthritis . 56 III Table of contents 5.2 Interleukin-9 limits chronic inflammation in the serum transfer induced arthritis . 61 5.3 Alterations of the cytokine signature in chronic arthritis . 62 5.4 Regulatory T cells are impaired in interleukin-9 deficient mice . 66 5.5 Type 2 innate lymphoid cells are the main producers of interleukin-9 in the arthritic joint . 69 5.6 Type 2 innate lymphoid cells significantly rely on interleukin-9 . 71 5.7 Type 2 innate lymphoid cells reinforce regulatory T cells . 74 5.8 Innate lymphoid cells as a potential diagnostic biomarker in human rheumatoid arthritis 77 6 Discussion 82 6.1 Skewing the innate compartment by interleukin-9 to a pro-resolving milieu in arthritis 82 6.2 Mast cell - regulatory T cell cooperation during inflammation control . 85 6.3 The balance of type 2 and type 3 innate lymphoid cells in arthritis . 87 6.4 Regulatory T cells in rheumatoid arthritis . 88 6.5 Co-stimulation of regulatory T cells and the interaction with type 2 innate lymphoid cells . 89 7 Conclusion and outlook 92 8 References 93 9 Appendix 122 9.1 List of acronyms . .I 9.2 List of figures . .V 9.3 List of tables . VII 9.4 Acknowledgments . VIII IV 1 Deutsche Kurzfassung Die Aktivierung der k¨orpereigenen Selbstverteidigungsmechanismen, auch Entzundung¨ genannt, ist ein streng kontrollierter physiologischer Prozess. Eine aus der Balance geratene Entzundungsreaktion¨ kann zu einer unkontrollierten Attacke gegen den eigenen K¨orper fuhren.¨ Man spricht dann von einer sogenannten Autoimmunerkrankung. Autoimmunerkrankungen verlaufen zumeist chronisch und durch die persistierende Entzundungsreaktion¨ wird mit der Zeit das betroffene Gewebe zerst¨ort. Dadurch wird dessen physiologische Funktionsf¨ahigkeit beeintr¨achtigt und geht letztlich verloren. Rheumatoide Arthritis ist eine prototypische chronische Autoimmunerkrankung des Menschen, die etwa 1 % der weltweiten Bev¨olkerung betrifft. Es ist daher nicht nur von gr¨oßter klinischer Bedeutung, sondern auch im sozio-¨okonomischem Interesse, die Mechanismen, die dieser Erkrankung zugrunde liegen, zu verstehen. Ziel ist es daher, das Wissen um die Krankheitsmechanismen zu vertiefen und ein besseres Verst¨andnis dafur¨ zu entwickeln, warum die Entzundung¨ persistiert und wie sie beendet werden kann. Dies erlaubte einerseits die Entwicklung neuer diagnostischer Biomarker, andererseits w¨are auch die Entwicklung komplett neuer Therapieans¨atze m¨oglich. In dieser Studie wurde dargelegt, wie das Zytokin Interleukin-9 (IL-9) durch die Aktivierung von Typ 2 angeborenen Lymphozyten (engl. type 2 innate lymphoid cells, ILC2s) die Beendigung ei- ner chronischen Entzundungsreaktion¨ einleiten kann. IL-9 agierte dabei als ein autokriner Faktor, der sowohl von ILC2s produziert wurde, als auch proliferativ und aktivierend auf diese wirkte. Aktivierte ILC2s exprimierten Rezeptorliganden, die wiederum regulatorische T Zellen aktivieren konnten. Diese Liganden (-L) waren ICOS-L und GITR-L (engl. fur¨ inducible T cell co-stimulator und glucocorticoid-induced tumour necrosis factor-related). Regulatorische T Zellen wurden also durch die ILC2-vermittelte Aktivierung in die Lage versetzt, die Beendigung der persistierenden Entzundungsreaktion¨ einzuleiten. IL-9 konnte somit als zentraler Schalter in der Entzundungskontrolle¨ etabliert werden. Im Maus- 1 modell konnte gezeigt werden, dass das Fehlen dieses Zytokins zu einer chronisch persistierenden Arthritis fuhrte.¨ Umgekehrt konnte der Gentransfer von Il9, als therapeutischer Ansatz, die Been- digung der Entzundungsreaktion¨ einleiten. Im Menschen reicherten sich IL-9 sezernierende ILC2s besonders in den Gelenken derjenigen Patienten an, die sich in einer Phase klinisch unauff¨alliger rheumatoiden Arthritis befanden, also in sogenannter Remission waren. Da die Anzahl der ILC2s im Blut mit der Aktivit¨at der Erkrankung korrelierte, k¨onnte die Anzahl der zirkulierenden ILC2s zukunftig¨ als diagnostischer Biomarker genutzt werden. Schlussendlich ist es nicht nur fur¨ Autoimmunerkrankungen, sondern auch bei chronischen Infek- tionserkrankungen von zentraler Bedeutung die Mechanismen der chronischen Entzundungsreaktion¨ zu entschlusseln¨ und Wege zu finden, diese zu beenden. Aktuell zielen anti-rheumatische Therapien lediglich darauf ab, die entzundungsf¨ ¨ordernden Signalwege zu blockieren. Die Aktivierung von ILC2s durch IL-9 f¨ordert im Gegensatz dazu pro-aktiv die Entzundungskontrolle¨ und stellt somit ein neues Therapiekonzept dar. 2 2 English abstract Inflammation is the tightly controlled physiological process of activation of the body’s self-defence mechanisms. Dysbalanced inflammation leads to a misdirected self-defence and manifests as autoim- mune disease, marked by a chronic inflammation and the destruction of the normal tissue physiology. This ultimately leads to the loss of the tissue’s functionality. Rheumatoid arthritis is one of the most chronic forms of inflammatory disease in humans. It affects roughly 1 % of the population world wide. Understanding the underlying mechanisms of chronic inflammation in rheumatoid arthritis is of pivotal clinical and socio-economic interest. Novel therapies and diagnostic biomarkers therefore are desirable. In this study, it was shown that interleukin-9 (IL-9) induced the resolution of inflammation by the activation and expansion of type 2 innate lymphoid cells (ILC2s). IL-9 was found to be an autocrine factor produced by ILC2s. The induction and activation of ILC2s by IL-9 positively affected the capacity of regulatory T cells. IL-9 up-regulated the expression of inducible T cell co-stimulator ligand (ICOS-L) and glucocorticoid-induced tumour necrosis factor-related ligand (GITR-L) on ILC2s.
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