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Sex and Puberty Influence the Innate Immune System Type 1 IFN Response

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Sex and Puberty Influence the Innate Immune System Type 1 IFN Response Sex and puberty influence the innate immune system type 1 interferon response PhD, Division of Medicine, University College London Student: Kate Webb Supervisors: Dr John Ioannou, Prof Lucy R. Wedderburn, Dr Coziana Ciurtin, Prof Gary Butler Declaration: I, Kate Webb 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. Signed………………Date……………………. Table of Contents Impact statement .......................................................................................................................... 9 Abstract ....................................................................................................................................... 12 Dedication.................................................................................................................................... 13 Acknowledgements ..................................................................................................................... 14 Glossary of abbreviations ............................................................................................................ 15 List of Tables ................................................................................................................................ 19 List of Figures ............................................................................................................................... 21 Chapter 1: Introduction ............................................................................................................... 24 1.1.1. The immune system ............................................................................................ 24 1.1.1.1. The adaptive immune system-brief overview ............................................. 25 1.1.1.2. The innate immune system-brief overview ................................................. 26 1.1.1.2.3. Toll like receptors ........................................................................................ 28 1.1.1.3. The innate antiviral immune system ........................................................... 30 1.1.1.3.1. Type 1 IFN .................................................................................................... 30 1.1.1.3.2. Type 1 IFN signalling .................................................................................... 30 1.1.1.3.3. Type 1 IFN function and IFN inducible genes .............................................. 32 1.1.1.3.4. Nucleic acid sensing and type 1 IFN production.......................................... 33 1.1.1.3.5. Interferon regulatory factors ....................................................................... 36 1.1.1.3.6. Plasmacytoid dendritic cells-brief overview ................................................ 36 1.1.1.4. Summary ...................................................................................................... 37 1.1.2. Sex ........................................................................................................................ 37 1.1.2.1. Sex and the immune system............................................................................... 37 1.1.2.1.1. Sex and disease......................................................................................... 38 1.1.2.1.2. Sex and the adaptive immune system ..................................................... 40 1.1.2.1.3. Sex and the innate immune system ......................................................... 42 1.1.2.2. Summary ...................................................................................................... 43 1.1.3. Sex Chromosomes ............................................................................................... 43 1.1.3.1. X chromosome related immune disease ..................................................... 43 1.1.3.2. X chromosome related immune genes........................................................ 45 1.1.3.3. Turner’s syndrome ....................................................................................... 47 1.1.3.4. Summary ...................................................................................................... 47 1.1.4. Hormones ............................................................................................................ 48 1.1.4.1. Hormones and the immune system ............................................................ 51 1.1.4.1.1. Oestradiol ................................................................................................. 51 1.1.4.1.2. Testosterone ................................................................................................ 51 2 1.1.4.2. Summary ..................................................................................................... 51 1.1.5. Puberty ................................................................................................................ 51 1.1.5.1. Hormonal changes in puberty ............................................................................ 53 1.1.5.2. Mini puberty of infancy ...................................................................................... 56 1.1.5.3. Puberty and the immune system ....................................................................... 57 1.1.5.4. Gender dysphoria ............................................................................................... 58 1.1.5.5. Summary ............................................................................................................ 60 1.1.6. Sex, puberty, hormone, X chromosome and the TLR7 mediated production of type 1 IFN. ........................................................................................................................... 60 1.1.6.1. TLR7 mediated IFNα production is higher in females ................................. 60 1.1.6.2. Oestradiol and TLR7 induced IFNα production ........................................... 62 1.1.6.3. Testosterone and TLR7 induced IFNα production ...................................... 63 1.1.6.4. TLR7 is coded on the X chromosome. ......................................................... 64 1.1.6.5. Summary ..................................................................................................... 64 1.3. Juvenile systemic lupus erythematosus. .......................................................................... 65 1.3.1. Epidemiology of jSLE ................................................................................................. 65 1.3.1.1. Sex ...................................................................................................................... 65 1.3.1.2. Ethnicity ............................................................................................................. 66 1.3.1.3. Age ..................................................................................................................... 67 1.3.2. The clinical manifestations of jSLE ............................................................................ 68 1.3.2.2. Measures of disease activity in jSLE ................................................................... 70 1.3.3. Treatment of jSLE ...................................................................................................... 70 1.3.3.1. General ............................................................................................................... 70 1.3.3.1.1. Anti-malarials .............................................................................................. 71 1.3.3.1.2. Glucocorticoids ........................................................................................... 71 1.3.3.1.3. Immunomodulatory drugs in SLE ................................................................ 72 1.3.3.1.4. Biologic agents in SLE .................................................................................. 72 1.3.4. Summary ................................................................................................................... 75 1.4. Type 1 IFN in the pathogenesis of jSLE ............................................................................ 75 1.4.2. The genetics of SLE .................................................................................................... 75 1.4.2.1. Rare monogenic lupus ....................................................................................... 76 1.4.3. The epigenetics of SLE. .............................................................................................. 79 1.4.3. The transcriptomics of SLE ........................................................................................ 79 1.4.3. The adaptive immune system in SLE. ........................................................................ 81 1.4.4. Type 1 IFN in SLE ....................................................................................................... 82 1.4.5. The source of nucleic acids in SLE ............................................................................. 83 3 1.4.5.1. Apoptosis in SLE .................................................................................................. 83 1.4.5.2. Endogenous nucleic acids ................................................................................... 83 1.4.5.3. Neutrophils ......................................................................................................... 84 1.4.6. Sensing nucleic acids in SLE ......................................................................................
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