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FINAL THESIS No Signature REGULATION AND FUNCTION OF THE LEUKOCYTE IMMUNOGLOBULIN-LIKE RECEPTORS (LILRS) IN RHEUMATOID ARTHRITIS. A thesis submitted to the University of New South Wales by OWEN ANTHONY HUYNH For the degree of Doctor of Philosophy (Ph.D) Inflammatory Diseases Research Unit, School of Medical Sciences University of New South Wales 2008 ORIGINALITY / COPYRIGHT / AUTHENTICITY STATEMENTS ‘I hereby declare that this submission is my own work and to the best of my knowledge it contains no materials previously published or written by another person, or substantial proportions of material which have been accepted for the award of any other degree or diploma at UNSW or any other educational institution, except where due acknowledgement is made in the thesis. Any contribution made to the research by others, with whom I have worked at UNSW or elsewhere, is explicitly acknowledged in the thesis. I also declare that the intellectual content of this thesis is the product of my own work, except to the extent that assistance from others in the project's design and conception or in style, presentation and linguistic expression is acknowledged.’ ‘I hereby grant the University of New South Wales or its agents the right to archive and to make available my thesis or dissertation in whole or part in the University libraries in all forms of media, now or here after known, subject to the provisions of the Copyright Act 1968. I retain all proprietary rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation. I also authorise University Microfilms to use the 350 word abstract of my thesis in Dissertation Abstract International (this is applicable to doctoral theses only). I have either used no substantial portions of copyright material in my thesis or I have obtained permission to use copyright material; where permission has not been granted I have applied/will apply for a partial restriction of the digital copy of my thesis or dissertation.' ‘I certify that the Library deposit digital copy is a direct equivalent of the final officially approved version of my thesis. No emendation of content has occurred and if there are any minor variations in formatting, they are the result of the conversion to digital format.’ th Owen Anthony HUYNH 24 November, 2008 B.MedSci (Hons) Date TABLE OF CONTENTS ORIGINALITY / COPYRIGHT / AUTHENTICITY STATEMENTS ...................................................... i TABLE OF CONTENTS ................................................................................................................................ ii ABSTRACT .................................................................................................................................................... vi ACKNOWLEDGEMENTS .........................................................................................................................viii PERSONAL THANKS .................................................................................................................................. ix PUBLICATIONS ARISING FROM CANDIDATURE.............................................................................. xi CONFERENCES ATTENDED DURING CANDIDATURE..................................................................... xi LIST OF IMPORTANT ABBREVIATIONS ............................................................................................. xii LIST OF TABLES........................................................................................................................................ xvi LIST OF FIGURES..................................................................................................................................... xvii CHAPTER 1. LITERATURE REVIEW....................................................................................................... 1 1.1 THE IMMUNE SYSTEM AND ITS REGULATION........................................................................................... 1 1.2 PATHWAYS FOR NEGATIVE AND POSITIVE SIGNALLING BY IMMUNE CELLS............................................ 3 1.2.1 Immunoreceptor Tyrosine-based Activation Motifs (ITAMs)........................................................ 3 1.2.2 Immunoreceptor Tyrosine-based Inhibitory Motifs (ITIMs) .......................................................... 4 1.3 THE LEUKOCYTE IMMUNOGLOBULIN-LIKE RECEPTORS (LILRS)............................................................. 8 1.3.1 Nomenclature of LILRs ................................................................................................................ 11 1.3.2 Structure of LILRs ........................................................................................................................ 13 1.3.3 Expression of LILRs ..................................................................................................................... 16 1.3.4 Ligands of LILRs.......................................................................................................................... 20 1.3.5 Function of LILRs......................................................................................................................... 25 1.3.6 Pathological Role of LILRs .......................................................................................................... 34 1.4 LILR-RELATED RECEPTORS .................................................................................................................. 41 1.4.1 Killer Cell Immunoglobulin-like Receptors (KIRs)...................................................................... 41 1.4.2 LAIR-1 (CD305)........................................................................................................................... 44 1.4.3 Murine Paired Immunoglobulin-like Receptor-B (PIR-B)............................................................ 45 1.4.4 Murine LILRB4 (mLILRB4 or gp49B) ........................................................................................ 45 1.5 TOLL-LIKE RECEPTORS (TLRS) ............................................................................................................. 48 1.6 RHEUMATOID ARTHRITIS ...................................................................................................................... 52 1.6.1 Background................................................................................................................................... 52 ii 1.6.2 Etiology......................................................................................................................................... 52 1.6.3 Pathology ...................................................................................................................................... 54 1.6.4 Treatments..................................................................................................................................... 61 1.6.5 LILRs in Rheumatoid Arthritis ..................................................................................................... 70 1.7 HYPOTHESIS AND AIMS ......................................................................................................................... 71 CHAPTER 2. REGULATION OF LILRA2 AND LILRB4 BY CYTOKINES AND LPS ..................... 72 2.1 INTRODUCTION ...................................................................................................................................... 72 2.2 MATERIALS AND METHODS................................................................................................................... 75 2.2.1 Antibodies and Reagents............................................................................................................... 75 2.2.2 Cell Culture................................................................................................................................... 76 2.2.3 Peripheral Blood Mononuclear Cells (PBMCs) Extraction .......................................................... 76 2.2.4 Differentiation of THP-1 Cells using Vitamin D3......................................................................... 77 2.2.5 Cell Stimulation ............................................................................................................................ 77 2.2.6 Flow Cytometry ............................................................................................................................ 77 2.2.7 RNA Extraction ............................................................................................................................ 78 2.2.8 DNase-Treatment and Reverse Trascription (RT) ........................................................................ 78 2.2.9 Quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) ................................................ 79 2.2.10 Statistical Analyses ..................................................................................................................... 81 2.3 RESULTS ................................................................................................................................................ 82 2.3.1 Regulation of LILRA2 and LILRB4 Expression upon Differentiation of Monocytes to Macrophages.......................................................................................................................................... 82 2.3.2 Regulation of LILRA2 and LILRB4 Expression by Cytokines and LPS on Monocytes and Macrophages.........................................................................................................................................
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