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Investigating the Role of Igg and Fcγ Receptors in Intestinal Inflammation

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Investigating the Role of Igg and Fcγ Receptors in Intestinal Inflammation Investigating the role of IgG and Fcγ receptors in intestinal inflammation Tomas Castro Dopico Christ’s College, University of Cambridge Supervisor: Dr. Menna R. Clatworthy Submitted September 2017 This dissertation is submitted for the degree of Doctor of Philosophy Preface This dissertation is the result of my own work and includes nothing which is the outcome of work done in collaboration, except as declared in the Preface or specified in the text. This dissertation is not substantially the same as any that I have submitted, or, is being concurrently submitted for a degree or diploma or other qualification at the University of Cambridge or any other University or similar institution except as declared in the Preface and specified in the text. I further state that no substantial part of my dissertation has already been submitted, or, is being concurrently submitted for any such degree, diploma or other qualification at the University of Cambridge or any other University or similar institution except as declared in the Preface and specified in the text. This dissertation does not exceed the prescribed word limit and is approximately 52,000 words in length. Tomas Castro Dopico September 2017 Contents 1. Introduction ..................................................................................................................... 1 1.1. The immune system .................................................................................................... 1 1.2. Antibodies ................................................................................................................... 4 1.3. Fcγ receptors ............................................................................................................ 11 1.4. Fcγ receptors and disease ........................................................................................ 22 1.5. The gastrointestinal tract and inflammatory bowel disease ........................................ 28 1.6. Immunopathology in inflammatory bowel disease ...................................................... 35 1.7. Intestinal B cells ........................................................................................................ 44 1.8. The intestinal macrophage system ............................................................................ 51 1.9. Innate lymphoid cells ................................................................................................. 59 1.10. Hypotheses and aims of PhD ................................................................................. 68 2. Methods ........................................................................................................................ 70 2.1. Mice .......................................................................................................................... 70 2.2. In vivo procedures ..................................................................................................... 71 2.3. Tissue sample preparation ........................................................................................ 73 2.4. Flow cytometry .......................................................................................................... 75 2.5. In vitro stimulation assays ......................................................................................... 78 2.6. Immunofluorescence ................................................................................................. 79 2.7. RNA analysis ............................................................................................................. 80 2.8. Soluble protein assays .............................................................................................. 81 2.9. RNAseq and microarray analyses (with John Ferdinand) .......................................... 82 2.10. Statistics ................................................................................................................ 86 3. IgG and FcγR signalling in intestinal inflammation ........................................................ 87 3.1. Introduction and hypotheses ..................................................................................... 87 3.2. IgG within the gastrointestinal tract ............................................................................ 87 3.3. Profiling intestinal B cell populations in intestinal inflammation .................................. 92 3.4. Fcγ receptor signalling in intestinal inflammation ....................................................... 94 3.5. Tissue-resident immune cell FcγR expression ........................................................... 97 3.6. FcγR-associated inflammatory networks in intestinal inflammation .......................... 101 3.7. Immune complex stimulation of intestinal leukocytes ............................................... 107 3.8. Discussion ............................................................................................................... 111 4. Fcγ receptor signalling drives IL-1β-dependent intestinal inflammation ....................... 119 4.1. Introduction and hypotheses ................................................................................... 119 4.2. Transcriptomic analysis of FcγR signalling in intestinal macrophages ..................... 120 4.3. Manipulation of the A/I ratio using FcγRIIB-transgenic mouse models ..................... 126 4.4. Chronic DSS-induced colitis in Fcgr2b-deficient mice .............................................. 127 4.5. Chronic DSS-induced colitis in macrophage transgenic mice .................................. 145 4.6. Discussion ............................................................................................................... 151 5. Expression and function of Fcγ receptors on group 3 innate lymphoid cells ................ 160 5.1. Introduction and hypotheses ................................................................................... 160 5.2. Profiling FcγR expression on innate lymphoid cells ................................................. 161 5.3. Immune complex stimulation of ILC3s in vitro.......................................................... 164 5.4. Analysis of canonical FcγR signalling in ILC3s ........................................................ 166 5.5. The role of FcγR signalling on ILC3 antigen presentation ........................................ 167 5.6. Modulation of ILC3 FcγR expression during inflammation ....................................... 169 5.7. ILC3 activation in Fcgr2b-deficient mice .................................................................. 170 5.8. Global transcriptional profiling of IgG-stimulated ILC3s ........................................... 173 5.9. Discussion ............................................................................................................... 180 6. ILC-macrophage crosstalk mediates intestinal immune defence ................................. 187 6.1. Introduction and hypotheses ................................................................................... 187 6.2. ILC depletion in Citrobacter rodentium infection ...................................................... 188 6.3. ILC depletion in DSS-induced colitis ........................................................................ 193 6.4. Potential mechanisms for macrophage regulation by ILCs ...................................... 196 6.5. Chemokine expression by intestinal ILCs ................................................................ 197 6.6. Cytokine analysis in ILC-depleted colons ................................................................ 198 6.7. In vitro macrophage GM-CSF stimulation ................................................................ 200 6.8. GM-CSF neutralisation in DSS-induced colitis ......................................................... 202 6.9. Potential mechanisms for GM-CSF-mediated macrophage activation ..................... 204 6.10. IL-1β-mediated cross-talk between macrophages and ILCs ................................. 207 6.11. Discussion ........................................................................................................... 209 7. Conclusion and future directions ................................................................................. 216 7.1. IgG and FcγR signalling in intestinal inflammation ................................................... 216 7.2. The function of FcγRs on ILC3s .............................................................................. 218 7.3. ILC-macrophage crosstalk mediates intestinal immune defence ............................. 220 8. Acknowledgements ..................................................................................................... 222 9. Appendix..................................................................................................................... 223 10. References .............................................................................................................. 224 Abbreviations ABMR Antibody-mediated rejection AHR Aryl hydrocarbon receptor A/I Activating-to-inhibitory ratio AID Activation-induced cytidine deaminase AMP Anti-microbial peptide AOM Azoxymethane APC Antigen presenting cell APRIL A proliferation-inducing ligand ARNT Aryl hydrocarbon receptor nuclear translocator BAFF B cell activating factor BCR B cell receptor BMDC Bone marrow-derived dendritic cell BMDM Bone marrow-derived macrophage BMP2 Bone morphogenic protein 2 Breg Regulatory B cell BSA Bovine serum albumin
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