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Gender Differences in T Cell Regulation and Responses to Sex Hormones

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Gender Differences in T Cell Regulation and Responses to Sex Hormones Gender differences in T cell regulation and responses to sex hormones By FARRAH Z. ALI A thesis submitted to The University of Birmingham for the degree of DOCTOR OF PHILOSOPHY School of Immunity and Infection College of Medical and Dental Sciences The University of Birmingham September 2013 University of Birmingham Research Archive e-theses repository This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. ABSTRACT Conflicting effects of sex hormones on the immune system could potentially explain the increased susceptibility of females to autoimmune diseases. In this study, I wanted to explore the regulation of the response to sex hormones in T cells from male and female donors. We initially investigated the levels of gene expression for sex hormone receptors and sex hormone metabolising enzymes in CD45RA+ /CD4+ T cells from male and female donors at baseline and after in vitro stimulation. I found that expression of 5α-reductase 1, an enzyme which converts testosterone into the more active dihydrotestosterone (DHT), is upregulated both on the mRNA and protein level in T cells from female but not male donors after stimulation. Since androgens are generally thought to have an anti-inflammatory role, this may be a mechanism that regulates the exposure of stimulated T cells to the inhibitory influence of DHT. SLE is a systemic autoimmune disease which mainly affects women. I investigated the regulation of 5α-reductase in peripheral blood mononuclear cells from patients with active or inactive SLE in comparison to normal controls. I did not observe any significant differences in 5α-reductase 1 expression in T cells at the baseline or after stimulation between SLE patients and healthy controls. However, I did find a significantly higher expression of 5α-reductase in B cells from SLE patients compared to healthy controls, suggesting that SLE B cells are increasing their exposure to DHT. In a third section of my experimental work I investigated the effects of a range of physiological concentrations of testosterone and DHT on T cell stimulation and cytokine production. In vitro treatment of T cells from female donors with low doses of testosterone resulted in a significant increase of the proportion of IL-2-producing CD4+ T cells. Intriguingly, this effect was neither seen at higher testosterone concentrations nor with DHT, suggesting that it may not be mediated through the androgen receptor. As testosterone, but not DHT can be converted to 17β- oestradiol by aromatase, we tested whether tamoxifen, a competitive antagonist of the oestrogen receptor could block the increase in IL-2 production induced by low doses of testosterone in T cells. These experiments confirmed that low doses of testosterone could lead to oestrogen dependent upregulation of IL-2 production in T cells. In conclusion, we have observed both long-term effects of the hormone environment the T cells have been generated in as well as immediate effects of sex hormones on T cell responses. Attempts have been made to therapeutically target the sex hormone system in patients with autoimmune diseases. For the efficient development of these therapies we need to improve our understanding of the regulatory effects of androgens and oestrogens on the human immune system. ACKNOWLEDGEMENTS Firstly, I would like to thank my supervisor Dr Dagmar Scheel-Toellner for her endless support and guidance throughout my project, and for always making time for me whenever I needed advice. I have also received a vast amount of support from my 2nd supervisors Prof Wiebke Arlt and Prof Janet Lord, who have always taken a key interest in the developments of my project. I would also like to thank Dr Caroline Gordon for all the clinical samples and her invaluable knowledge. I have been extremely lucky to be surrounded by so many kind and helpful people, who have always given up their time for training and technical support. For this I would like to thank Mr Steve Kissane, Dr Angela Taylor, Miss Kath Bignal, Miss Holly Adams, Dr Ewan Ross and everyone else in the labs for all your help. I have thoroughly enjoyed my PhD experience and that is mostly down to my lovely colleagues and now friends from the Rheumatology Research Group, and everyone else in the IBR and the QE, both past and present. I would like to thank Dr Lorraine Yeo, Mr Božo Lugonja, Mrs Kath Bignal, Mr Mark Watson, Miss Fern Barrington, Mrs Beth Clay, Miss Rachel Bayley, Miss Holly Adams, Dr Jon Hazeldine, Miss Julia Spengler, Miss Nichola Adlard, Dr Jawaher Alsalem, Mrs Hema Chalal, Mrs Niharika Arora-Duggal, Miss Saba Nayar, Miss Hannah Greenwood, Mr David Bartlett, Dr Pete Hampson, Mr Martin Fitzpatrick, Dr Matt Edmunds, Miss Sian Lax, Miss Siobhan Restorick, Miss Vikki Harrison among many, many others, who have made this experience truly unforgettable. I would also like to thank all the blood donors and BBSRC for funding this project. Finally, my family have given me endless support and encouragement over the years, which I am eternally grateful for. CONTENTS 1 INTRODUCTION ........................................................................................................................... 2 1.1 The immune system .................................................................................................................... 2 1.1.1 Introduction .......................................................................................................................... 2 1.1.2 T cells in adaptive immunity ................................................................................................ 4 1.1.3 Autoimmunity ...................................................................................................................... 6 1.1.4 The role of T cells in autoimmunity ..................................................................................... 9 1.2 Systemic Lupus Erythematosus (SLE) ..................................................................................... 13 1.2.1 Introduction ........................................................................................................................ 13 1.2.2 Pathogenesis of SLE .......................................................................................................... 13 1.2.3 Treatment of SLE ................................................................................................................ 15 1.2.4 Genetic basis of SLE ........................................................................................................... 16 1.2.5 Defects of innate immunity in SLE ..................................................................................... 18 1.2.6 The role of B cells in SLE ................................................................................................... 20 1.2.7 T cell defects in SLE ........................................................................................................... 21 1.3 Gender differences in autoimmunity ......................................................................................... 23 1.3.1 Introduction ........................................................................................................................ 23 1.3.2 Genetic factors responsible for sex differences in autoimmunity ....................................... 28 1.4 Steroid sex hormones ................................................................................................................ 32 1.4.1 Hypothalamic-pituitary-gonadal axis ................................................................................. 32 1.4.2 Hypothalamus-Pituitary-Adrenal axis ................................................................................ 33 1.4.3 Steroidogenesis ................................................................................................................... 35 1.4.4 5α-reductase ....................................................................................................................... 38 1.4.5 Steroid nuclear receptors ..................................................................................................... 40 1.4.6 Steroid hormones and the immune system.......................................................................... 42 1.4.7 Sex hormones and autoimmunity ......................................................................................... 44 1.4.8 Effect of sex hormones on the immune system: mice studies............................................. 45 1.4.9 Effect of sex hormones on the immune system in humans ................................................. 48 1.5 PPAR ....................................................................................................................................... 52 1.5.1 Introduction ........................................................................................................................ 52 1.5.2 PPAR ligand mediated activation ....................................................................................... 52 1.5.3 PPARs and the immune system .........................................................................................
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