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Download Thesis This electronic thesis or dissertation has been downloaded from the King’s Research Portal at https://kclpure.kcl.ac.uk/portal/ Investigating the role of the protein tyrosine phosphatase non-receptor type 22 (PTPN22) in Fc receptor signalling in myeloid cells Clarke, Fiona Awarding institution: King's College London The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without proper acknowledgement. END USER LICENCE AGREEMENT Unless another licence is stated on the immediately following page this work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence. https://creativecommons.org/licenses/by-nc-nd/4.0/ You are free to copy, distribute and transmit the work Under the following conditions: Attribution: You must attribute the work in the manner specified by the author (but not in any way that suggests that they endorse you or your use of the work). 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Sep. 2021 Investigating the role of the protein tyrosine phosphatase non-receptor type 22 (PTPN22) in Fcγ receptor signalling in myeloid cells Fiona Clarke Faculty of Life Science and Medicine School of Immunology and Microbial Sciences King’s College London Thesis submitted for the degree of Doctor of Philosophy 2019 The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without proper acknowledgement. 1 Table of Contents a. Abstract ................................................................................................................. 8 b. Acknowledgements ............................................................................................... 9 c. List of Figures ...................................................................................................... 10 d. List of Tables........................................................................................................ 13 e. List of Abbreviations ........................................................................................... 14 1. Introduction ......................................................................................................................... 18 1.1 PTPN22 .............................................................................................................................. 18 1.1.1 Phosphatases and kinases.......................................................................................... 18 1.1.2 The structure and function of PTPN22....................................................................... 18 1.1.3 PTPN22 and autoimmunity ........................................................................................ 19 1.2 The role of PTPN22 and PTPN22R619W in murine immune cells in the steady state .......... 20 1.2.1 The role of PTPN22 in murine T cells ..................................................................... 21 1.2.2 The role of PTPN22 in murine B cells ..................................................................... 22 1.2.3 The role of PTPN22 in murine neutrophils ............................................................ 23 1.2.4 The role of PTPN22 in murine myeloid cells .......................................................... 23 1.3 Phenotype of Ptpn22-/- and Ptpn22R619W mice using models of autoimmunity ................ 26 1.4 Phenotype of Ptpn22-/- and Ptpn22R619W mice using viral infection models ..................... 27 1.5 The role of PTPN22 and PTPN22R620W in human immune cells ......................................... 29 1.5.1 The role of PTPN22 in human T cells ..................................................................... 29 1.5.2 The role of PTPN22 in human B cells ..................................................................... 30 1.5.3 The role of PTPN22 in human neutrophils ............................................................. 31 1.5.4 The role of PTPN22 in human natural killer cells ................................................... 31 1.6 Is PTPN22R620W a gain- or loss-of function mutant? .......................................................... 31 1.7 DCs .................................................................................................................................... 32 1.7.1 DC development and differentiation in mice ............................................................ 32 1.7.2 General functions of DCs ........................................................................................... 34 1.7.3 Antigen uptake by DCs ............................................................................................... 35 1.7.4 Antigen processing and presentation by DCs ............................................................ 36 1.7.5 The role of Src and Syk family kinases in regulating antigen uptake, processing and presentation ........................................................................................................................ 39 1.8 FcyRs ................................................................................................................................. 39 1.8.1 FcγR expression and function .................................................................................... 39 1.8.2 Regulation of FcyR signalling...................................................................................... 44 1.8.3 Association of SNPs in FCGR genes with autoimmunity ............................................ 46 1.8.4 Phenotypes of mice lacking FcyR expression ............................................................. 46 1.9 Rheumatoid Arthritis ........................................................................................................ 47 1.10 Mouse models of rheumatoid arthritis ........................................................................... 48 1.10.1 Collagen-induced arthritis .................................................................................... 49 2 1.10.2 Collagen antibody-induced arthritis .................................................................... 49 1.10.3 Zymosan-induced arthritis ................................................................................... 50 1.10.4 K/BxN and K/BxN serum transfer model of arthritis ........................................... 50 1.10.5 Methylated bovine serum albumin (mBSA)-induced arthritis ............................. 52 1.10.6 Spontaneous TNFα transgenic mouse model of arthritis .................................... 52 1.10.7 Spontaneous arthritis using SKG mice ................................................................. 52 1.11 Imaging of arthritic mice ................................................................................................. 53 1.12 The human skeleton and osteoclasts .............................................................................. 53 1.12.1 The skeleton and bone remodelling ........................................................................ 53 1.12.2 Osteoclast differentiation and function ................................................................... 55 1.12.2.1 Regulation of osteoclast function ......................................................................... 56 1.12.2.2 The role of kinases and phosphatases in osteoclast function .............................. 58 1.13 Hypothesis....................................................................................................................... 59 1.14 Aims................................................................................................................................. 59 2. Materials and Methods ........................................................................................................ 60 2.1 Materials ........................................................................................................................... 60 2.1.1 Reagents ..................................................................................................................... 60 2.1.2 Antibodies .................................................................................................................. 61 2.1.3 Solutions ..................................................................................................................... 62 2.1.4 Commercial kits .......................................................................................................... 64 2.1.5 Plastics ........................................................................................................................ 64 2.2 Methods ............................................................................................................................ 65 2.2.1 Animals ....................................................................................................................... 65 2.2.1.1 Ethics Statement ................................................................................................. 65 2.2.1.2 Mice ...................................................................................................................
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