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The Role of CD73 in the Pathogenesis of Juvenile Idiopathic Arthritis

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The Role of CD73 in the Pathogenesis of Juvenile Idiopathic Arthritis The role of CD73 in the pathogenesis of Juvenile Idiopathic Arthritis Sophie Botta Gordon-Smith A thesis submitted for the degree of Doctor of Philosophy to University College London February 2015 Infection, Immunity, Inflammation and Physiological Medicine Programme UCL, Institute of Child Health, London, United Kingdom 1 Declaration I, Sophie Botta Gordon-Smith, confirm that the work presented in this thesis is my own. Where information or data has been derived from other sources or produced by others, I confirm that this has been indicated. 2 Abstract Juvenile idiopathic arthritis (JIA) manifests as a persistent arthropathy, thought to be immune-driven, that when untreated leads to progressive joint destruction. This group of diseases represents an excellent model to investigate immunoregulation because of the possibility to sample cells aspirated from the site of inflammation. This PhD investigated the contribution of defects in purinergic pathways to the pathogenesis of JIA by examining the distribution and enzymatic activity of the ecto-nucleotidase CD73, together with some investigation of expression of CD39 and CD26. The data presented here demonstrate the significantly decreased proportion of CD73+ T and B synovial lymphocytes from JIA patients compared to peripheral blood lymphocytes of both patients and healthy subjects. This reduction increased with higher disease severity (worse in extended compared to persistent oligoarticular JIA patients) and correlated with patient’s cumulative joint count, but not with disease duration. No genetic association for NT5E (encoding CD73) was found that could explain the different levels of CD73 observed within different subtypes of JIA. Treatment with methotrexate, the first line DMARD to control arthritis, did not affect the proportion of CD73+ peripheral blood lymphocytes, nor did this proportion predict response to methotrexate. The reduction of CD73+ synovial lymphocytes and of CD73 protein expression per CD73+ cell was associated with a reduced ability to generate immunoregulatory adenosine in vitro, suggesting low levels of adenosine in the synovium. An incapacity of CD39+ and CD73+ cells to act cooperatively to metabolize ATP to adenosine, further contributes to the impression of low adenosine generation in the JIA joint, and of defective attenuation of inflammation. In vitro, downregulation of CD73+ PBMC and purified CD8+CD73+ T cells was demonstrated upon cell activation. The loss of CD73+ PBMC was associated with a diminished potential to generate adenosine. The loss of CD73+ PBMC appeared to be restricted to proliferating cells. I propose that the CD73 downregulation is associated with defective adenosine levels within the joint, which could contribute to the locally destructive inflammation seen in JIA. 3 Acknowledgements I would like to express my gratitude to a number of individuals without whom this thesis would not have been possible. First, to my principal supervisor Prof Lucy Wedderburn, for her great insights and direction throughout my PhD and her guidance which made this research possible. I am also greatly indebted to my secondary supervisor Prof Robin Callard who generously read a draft of my thesis (as did Lucy) and steered me away from error, while also contributing valuable ideas to this project. Together with Robin, I would like to thank Dr Siobhan Burns for their advice during my MPhil viva. I am very grateful to all present and past members of our research group for their support and enthusiasm. In particular, I would like to thank Halima Moncrieffe, David Bending, Anne Pesenacker, and Simona Ursu for their support in the lab and for the scientific discussions and input. Many thanks also go to Dr Joanna Cobb and Prof Wendy Thompson from University of Manchester for their extensive support for the genetic association study. Without Dr Simon Eaton, no HPLC experiments would have been feasible, so I would like to express my warmest thanks to him too for his helpful comments and the time he spent teaching me this area. I would also like to thank my fellow students and staff from the infection and immunity department for their guidance, discussions, and company. Especially for reminding me to keep my PhD into perspective. Special thanks go to Mario Songane, Enea Milioris, and Katja Brunner for helping me come to terms with Western and for brightening the lab and the office. I wish you all good luck with your PhDs. I also appreciate the help of Dr Ayad Eddaoudi and his colleagues with flow cytometry sorting. Special thanks go to all healthy volunteers, patients and their families for donation of samples to the study, all hospital staff, and my funders: Child Health Research Appeal Trust. I would like to thank all my friends for their support, especially Grant who was always there to help me out and make me laugh and who will make an amazing professor. I owe a great deal of loving thanks to my mother, who always believed in me and spurred me to make me who I am today. I would therefore like to dedicate this thesis to her and thank her for all her support, encouragement, and love. 4 Abbreviations Ab Antibody ACR American college of rheumatology ACR-Ped70 70% improvement in joint count ACPA Anti-citrullinated protein/peptide antibody ADA Adenosine deaminase ADP Adenosine diphosphate ADK Adenylate kinase AICAR 5-aminoimidazole-4-carboxamide ribonucleotide AK Adenosine kinase AMP Adenosine monophosphate ANA Antinuclear antibody AP Alkaline phosphatase APC Antigen presenting cell APS Ammonium persulfate APC (dye) Allophycocyanin ATIC AICAR transformylase ATP Adenosine triphosphate BCR B cell receptor BSA Bovine serum albumin cAMP Cyclic AMP CD Cluster of differentiation CFSE Carboxyfluorescein diacetate succinimidyl ester CHO Chinese hamster ovary CIA Collagen induced arthritis CNT Concentrative nucleoside transporter CRE cAMP responsive element CREB cAMP-dependent co-activator CRE-binding protein CRP C reactive protein CTL Cytotoxic lymphocyte CTLA-4 Cytotoxic T lymphocyte antigen -4 5 DC Dendritic cells DCK Deoxycytidine kinase DMARD Disease-modifying anti-rheumatic drugs DMSO Dimethyl sulphoxide DP Double positive DPP4 Dipeptidyl-peptidase 4 ENT Equilibrative nucleoside transporter ESR Erythrocyte sedimentation rate ERK Extracellular signal-related kinase FACS Fluorescent activated cell sorting FCS Fetal calf serum FITC Fluorescein isothiocyanate fMLP N-formyl-methionyl-leucyl-phenylalanine Foxp3 Forkhead box protein P3 FPGS Folylpolyglutamate synthase g Gravity GITR Glucocorticoid-induced TNF-receptor-related protein GPI Glycosyl phosphatidlyinositol HLA Human leukocyte antigen HPLC High performance liquid chromatography IFN Interferon IFN-γ Interferon-gamma Ig Immunoglobulin IL Interleukin ILAR International league of associations for rheumatology JIA Juvenile idiopathic arthritis LPS Lipopolysaccharide(s) MAPK Mitogen-activated protein kinase MFI Median fluorescence intensity MHC Major histocompatibility locus mRNA Messenger ribonucleic acid MTX Methotrexate 6 NK Natural killer NSAID Non-steroidal anti-inflammatory drugs P Probability PBS Phosphate buffered saline PCR Polymerase chain reaction PE R-phycoerythrin PeCy5 R-phycoerythrin-cyanine 5 PerCP Peridinin chlorophyll protein PBMC Peripheral blood mononuclear cells PKA Protein kinase A PRRs Pattern recognition receptors SAH S-adenosyl homocysteine SCID Severe combined immunodeficiency SF Synovial fluid SFMC Synovial fluid mononuclear cells SNP Single nucleotide polymorphism spMHC Self-peptide presented by MHC RA Rheumatoid arthritis RAG Recombination-activating gene RF Rheumatoid factor RT Room temperature TCR T cell receptor TdT Terminal deoxynucleotidyl transferase TEMED N, N, N', N'-tetramethylethylenediamine TGF-β Transforming growth factor-Beta TNF Tumour necrosis factor Treg regulatory T cell TSDR T-reg specific demethylated region TYMS Thymylidate synthase VEGF Vascular endothelial growth factor WTCCC2 Wellcome Trust case control consortium -2 7 Contents Declaration ....................................................................................................... 2 Abstract ............................................................................................................ 3 Acknowledgements .......................................................................................... 4 Abbreviations ................................................................................................... 5 Contents ............................................................................................................ 8 List of Figures ................................................................................................ 14 List of Tables .................................................................................................. 17 Chapter 1 Introduction .................................................................................. 18 1.1 From an effective adaptive immune response to autoimmunity: break of self-tolerance . 19 1.1.1 T cell development, generation of T cell receptor (TCR) diversity and recognition of antigen ..................................................................................................................... 19 1.1.2 B cell development and immunoglobulin gene rearrangement ............................. 22 1.1.3 Immune regulation and tolerance ......................................................................... 23 1.2 Juvenile Idiopathic Arthritis (JIA): definition, epidemiology and classification ............. 25 1.2.1 Aetiology
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