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Endothelial Injury and Repair in Vasculitis of the Young

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Endothelial Injury and Repair in Vasculitis of the Young University College London Endothelial injury and repair in vasculitis of the young Lindsey Anne Clarke Submitted for the degree of Doctor of Philosophy Department of Infectious Diseases/Department of Rheumatology Institute of Child Health, University College London 1 I, Lindsey Anne Clarke confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. 2 Acknowledgements I would like to express my thanks to the many people too numerous to mention individually who contributed in some way to this study by their guidance, support, understanding and willingness to donate blood. Without the help of the patients, their families and the clinical staff at Great Ormond Street Hospital this project could not have been carried out – so a big thankyou to you all. Special thanks must go to my supervisors at ICH Paul Brogan and Nigel Klein, who have kept me focused on the task in hand throughout this project. To Francesca Arrigoni for her excellent guidance in the lab and all round support throughout the project – a true mentor. To Despina Eleftheriou and Ying Hong who have had the reins of the project passed to them – best of luck for the continuation of the work! To Markella Ponticos for her help proofreading this manuscript. The Oliver Bird Rheumatism Programme, which has generously funded me throughout and the head of the programme at UCL, David Isenberg have been a continual source of support and I thank them greatly for the opportunities they have provided. In particular I thank them for introducing me to my fellow birdies, who I hope will remain good friends for a long time to come. Finally, I would like to thank my family for understanding my need to be a perpetual student and most importantly Andrew, who knew I would get to the end of this project one day. Lindsey Anne Clarke, August 2009 3 Thesis Abstract The vasculitides are a wide spectrum of disorders which are characterised by vascular inflammation. Endothelial injury can occur as a consequence of inappropriate inflammation and is central to the pathogenesis of these varied diseases. This thesis documents the development of assays for detection of novel biomarkers of endothelial injury and/or activation and subsequent reparative responses in children with primary systemic vasculitis. It focuses in particular on circulating endothelial cells, cellular microparticles, growth factors involved in angiogenesis/vasculogenesis and endothelial progenitor cells. Circulating endothelial cells are mature endothelial cells which have become detached from the vessel wall and represent a highly damaged vasculature and were found to be significantly higher in children with active primary systemic vasculitis compared to healthy child controls and patients in remission. Microparticles are released from activated cells, including the endothelium and leukocytes. In this study endothelial and monocyte derived microparticles were found to be elevated during active vasculitis. Growth factors released in response to endothelial injury regulate reparative responses, of which endothelial progenitor cells may play a key role. In this study, patients at disease onset prior to treatment were found to have significantly higher levels of growth factors and endothelial progenitor cells, which decreased with remission inducing therapy. Overall this thesis has investigated the changes in these interlinked biomarkers of injury and repair during active disease, remission and disease flare. 4 Table of Contents ACKNOWLEDGEMENTS ......................................................................................................................... 3 THESIS ABSTRACT .................................................................................................................................. 4 TABLE OF CONTENTS ............................................................................................................................. 5 FIGURES ...............................................................................................................................................11 TABLES .................................................................................................................................................13 ABBREVIATIONS ...................................................................................................................................14 1 INTRODUCTION .................................................................................................................................16 1.1 THE ENDOTHELIUM AND ITS FUNCTIONS .................................................................................................... 17 1.1.1 Control of vessel tone .............................................................................................................. 17 1.1.2 Fluid and solute exchange ....................................................................................................... 18 1.1.3 Haemostasis ............................................................................................................................. 19 1.1.4 Angiogenesis and Vasculogenesis ............................................................................................ 20 1.1.5 Inflammatory responses and the endothelium ........................................................................ 22 1.1.6 Conclusions .............................................................................................................................. 24 1.2 VASCULITIS – A CLINICAL PERSPECTIVE ....................................................................................................... 24 1.2.1 Primary systemic vasculitis ...................................................................................................... 24 1.2.2 Polyarteritis Nodosa and associated diseases ......................................................................... 26 1.2.3 Wegener’s Granulomatosis ..................................................................................................... 27 1.2.4 Takayasu disease ..................................................................................................................... 28 1.2.5 Kawasaki disease ..................................................................................................................... 28 1.2.6 Henoch-Schönlein purpura ....................................................................................................... 29 1.2.7 Churg-Strauss syndrome .......................................................................................................... 29 1.2.8 Other vasculitic disorders ......................................................................................................... 30 1.2.9 Treating vasculitis .................................................................................................................... 34 1.2.10 Prognosis ............................................................................................................................... 35 5 1.2.11 Conclusions relating to clinical perspectives on vasculitis ..................................................... 36 1.3 THE PATHOGENESIS OF VASCULITIS ........................................................................................................... 36 1.3.1 Environmental triggers ............................................................................................................ 37 1.3.2 Genetics of vasculitis ................................................................................................................ 38 1.3.3 Immunological pathways in vasculitis ..................................................................................... 40 1.3.4 Conclusions regarding the pathogenesis of vasculitis ............................................................. 52 1.4 ASSESSMENT OF DISEASE ACTIVITY IN VASCULITIS – THE NEED FOR RELIABLE BIOMARKERS .................................... 52 1.4.1 Routine clinical tests for diagnosis and assessment of disease activity ............................................ 53 1.4.2 Novel Biomarkers in vasculitis ................................................................................................. 57 1.5 AIMS OF THIS THESIS ............................................................................................................................. 65 2 METHODS AND MATERIALS ...............................................................................................................66 2.1 INTRODUCTION .................................................................................................................................... 67 2.2 PATIENTS, VASCULITIS CLASSIFICATION AND ASSESSMENT OF DISEASE ACTIVITY .................................................. 67 2.2.1 Classification of the vasculitic syndromes ................................................................................ 67 2.2.2 Assessment of disease activity ................................................................................................. 68 2.3 MATERIALS.......................................................................................................................................... 69 2.3.1 Reagents for blood collection .................................................................................................. 69 2.3.2 Fluorochrome conjugated antibodies for flow cytometry.......................................................
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