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The Impact of Vitamin D on Innate Immune Responsiveness to Pattern Recognition Receptor Stimulation in Humans

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The Impact of Vitamin D on Innate Immune Responsiveness to Pattern Recognition Receptor Stimulation in Humans The Impact of Vitamin D on Innate Immune Responsiveness to Pattern Recognition Receptor Stimulation in Humans by Natascha Fitch A Thesis submitted to the Faculty of Graduate Studies of The University of Manitoba in partial fulfillment of the requirements of the degree of MASTER OF SCIENCE Department of Immunology University of Manitoba Winnipeg Copyright © 2013 by Natascha Fitch Abstract Objective: Study the effects of vitamin D on viral driven innate immune responses, by looking at differences in cytokine production, receptor expression, and endogenous vitamin D levels. Methods: Primary peripheral blood mononuclear cells (PBMC) and epithelial cells (EC) were cultured in the presence of viral ligands and vitamin D. Enzyme-linked immunosorbent assay (ELISA) and real-time polymerase chain reaction (RT-PCR) were used to determine cytokine production and mRNA expression. Results: PBMC stimulated with toll-like receptor 4 ligand (TLR4L), but not viral TLR8L, led to decreased pro- and anti-inflammatory cytokine production in the presence of 1,25(OH)2D3. RIG-like receptor (RLR) activation, on the other hand, in primary EC exhibited decreased pro-inflammatory cytokine production in the presence of vitamin D. Conclusions: Our findings are among the first to show differences between bacterial and viral driven innate immune responses in the presence of vitamin D. As responsiveness in RLR activated primary EC was altered in the presence of vitamin D, our data reveal the importance of studying the immune system as a whole. i Acknowledgments I would like to thank my supervisor Dr. Kent HayGlass for his guidance and support throughout my program. In particular, I have benefitted from his extensive knowledge, and constructive analysis, but also his ability to present science in a logical and meaningful manner. As a result, completing my Master’s Degree under his supervision has been both enjoyable and productive. I would also like to thank all the members of the HayGlass lab for providing a positive training environment and for being wonderful colleagues. A special thanks to Larisa Lotoski for always making the time to answer my questions and for being a great mentor. I am especially grateful to Rishma Chooniedass and the rest of the MICH Allergy Lab/CHILD team for their immense contribution towards the research and data sample collection upon which my thesis has been developed. To my committee members, Dr. Allan Becker, Dr. Neeloffer Mookerjee and Dr. Carla Taylor, thank you for your support and constructive feedback over the last three years and for reviewing my thesis. Lastly, I would like to acknowledge MHRC, NSERC and Mindel and Tom Olenick for providing financial support to me throughout my degree, as well as CIHR for supporting the research conducted in our lab. To all the members of the department, thank you for making this degree both fun and challenging and for always providing great feedback. ii Dedications I would like to dedicate this thesis to my husband, parents and sister. Thank-you all for you continuous support, especially Jaron who listened to countless research presentations and always provided positive feedback. I love you all! You too Rupes! iii Table of Contents List of Tables ...................................................................................................................... viii List of Figures ....................................................................................................................... ix List of Abbreviations ........................................................................................................ xii Section 1: Pattern Recognition Receptors ................................ 1 1.1 Overview of Innate Immunity ................................................................................... 1 1.2 TLRs ................................................................................................................................... 4 1.21 Cell Surface TLRs .............................................................................................................. 5 1.22 Endosomal TLRs ............................................................................................................... 6 1.3 RLRs ................................................................................................................................... 8 Section 2: Vitamin D ....................................................................... 11 2.1 Mechanism of Action ................................................................................................. 11 2.2 Vitamin D is Regulated by Several Vitamin D Associated Proteins .......... 12 2.21 CYP24a1 and CYP27b1 ................................................................................................... 12 2.22 Vitamin D Binding Protein .............................................................................................. 13 2.23 Vitamin D Receptor and Vitamin D Response Elements ................................................ 15 2.24 PTH, Calcium and FGF23 ................................................................................................ 15 2.3 Vitamin D and Its Impact on Innate Immunity ................................................ 16 2.31 Vitamin D and Antimicrobial Peptide Production .......................................................... 16 2.32 Vitamin D and Cytokine Production ............................................................................... 17 2.33 Vitamin D Influences Intracellular Signalling Pathways: From Receptor Expression to Transcription Factor Function ................................................................................................ 19 Section 3: Vitamin D and Disease .............................................. 23 3.1 Vitamin D Deficiency in the Population ............................................................. 23 3.2 Vitamin D Deficiency and Risk of Respiratory Tract Infections ................ 26 3.21 Epidemiological Evidence ............................................................................................... 26 3.22 Vitamin D Lowers Risk of Infection by Respiratory Syncytial Virus ................................ 27 3.3 Vitamin D Deficiency and Increased Risk of Autoimmunity ....................... 29 3.21 Asthma and Allergic Disease .......................................................................................... 29 iv 3.22 Crohn’s Disease and Diabetes ........................................................................................ 31 Thesis Overview ................................................................................................................ 32 Materials and Methods ................................................................. 34 Volunteers ........................................................................................................................... 34 Peripheral Blood Mononuclear Cell (PBMC) Isolation ........................................ 35 Preparation of Tissue Culture Reagents ................................................................... 35 Preparation of 1,25(OH)2D3 .................................................................................................... 35 Preparation of 25(OH)D3 ........................................................................................................ 36 Preparation of Respiratory Syncytial Virus and Reovirus ....................................................... 37 Primary Cell Culture ........................................................................................................ 37 Human Cytokine Enzyme-Linked Immuno Sorbent Assay (ELISA) ................. 39 RNA Isolation and RT-PCR ............................................................................................. 40 Mass Spectrometry ........................................................................................................... 43 Statistical Analysis ............................................................................................................ 43 CHAPTER 1 ........................................................................................ 44 Abstract ................................................................................................................................ 45 Results ................................................................................................................................... 47 Vitamin D Decreases Pro-inflammatory and Anti-inflammatory Cytokine Production in Adult PBMC Stimulated with LPS ..................................................................................................... 47 Vitamin D Fails to Alter Innate Cytokine Responses to TLR8 Stimulation in Primary PBMC .. 49 Vitamin D Fails to Reduce Pro-inflammatory and Anti-inflammatory Production in the Presence of Intact Infectious Virus RSV .................................................................................. 51 Cathelicidin Gene hCAP-18 is Downregulated in the Presence of LPS and 3M 002 ............... 54 Vitamin D Inhibits TLR4 and TLR8 Receptor Expression in PBMC in the Presence or Absence of Stimulation ......................................................................................................................... 56 Vitamin D Activating and Deactivating Enzyme Expression Levels Differ in TLR8L Compared to TLR4L Stimulated PBMC ..................................................................................................... 58 TLR8L Downregulates VDR
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