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The Role of the Prion Protein in the Immune System

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The Role of the Prion Protein in the Immune System Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2013 The role of the prion protein in the immune system Kana, V Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-79331 Dissertation Published Version Originally published at: Kana, V. The role of the prion protein in the immune system. 2013, University of Zurich, Faculty of Science. The Role of the Prion Protein in the Immune System Dissertation zur Erlangung der naturwissenschaftlichen Doktorwürde (Dr. sc. nat.) vorgelegt der Mathematisch-naturwissenschaftlichen Fakultät der Universität Zürich von Veronika Kana von Chur GR Promotionskomitee Prof. Dr. Adriano Aguzzi (Vorsitz) Prof. Dr. Cornelia Halin Winter Prof. Dr. Christian Grimm Prof. Dr. Christian Münz Zürich, 2013 TABLE OF CONTENTS 1 SUMMARY ........................................................................................................................................ 3 2 ZUSAMMENFASSUNG .................................................................................................................... 6 3 ABBREVIATIONS ............................................................................................................................. 9 4 THE ROLE OF THE PRION PROTEIN IN THE IMMUNE SYSTEM .............................................. 11 4.1 INTRODUCTION ...................................................................................................................... 12 4.1.1 Prion diseases – the inglorious reason for the prion protein’s fame .................................. 12 4.1.2 A function for PrPC in the immune system ......................................................................... 16 4.1.3 The Prnp knockout mouse and the flanking gene problem ............................................... 22 4.1.4 Scientific aims .................................................................................................................... 25 4.2 RESULTS ................................................................................................................................. 26 4.2.1 Higher phagocytic activity in congenic – but not in coisogenic – Prnp knockout mice ...... 26 4.2.2 RNA sequencing identifies candidate confounder genes linked to Prnp on mouse Chr2 33 4.2.3 Analysis of candidate confounder genes Sirpa, Mertk, Tyro3 and Thbs1 ......................... 41 4.2.4 Sirpa129 is linked to Prnp-/- allele in all analysed Prnp knockout strains ............................. 44 4.2.5 Sirpa129 enhances phagocytosis in the absence of Prnp ................................................... 46 4.2.6 Sirpa regulates phagocytosis irrespective of Prnp status .................................................. 49 4.2.7 Sirpa129 exacerbates mouse EAE in the absence of Prnp ................................................. 59 4.2.8 EAE development in congenic B6.129 mice with different combinations of Prnp (wt and ZrchI) and Sirpa (B6 and 129) alleles ..................................................................................... 67 4.3 DISCUSSION ........................................................................................................................... 71 4.3.1 Mouse genetics excludes PrPC as inhibitor of phagocytosis ............................................. 71 4.3.2 Modulation of EAE development by Prnp and its polymorphic flanking genes – a blurry picture ................................................................................................................................... 73 4.3.3 Concluding remarks ........................................................................................................... 75 4.4 MICE, MATERIAL AND METHODS ......................................................................................... 78 4.4.1 Mice .................................................................................................................................... 78 4.4.2 RNA-Seq ............................................................................................................................ 79 4.4.3 RFLP and sequencing analysis of candidate genes .......................................................... 80 4.4.4 Genome-wide and Chr2 STR analysis .............................................................................. 82 4.4.5 High-resolution microsatellite genotyping on Chr2 ............................................................ 82 4.4.6 Phagocytosis assay with pMΦ ........................................................................................... 83 4.4.7 Phagocytosis assay with BMDM ........................................................................................ 84 4.4.8 Flow cytometric analysis .................................................................................................... 84 4.4.9 Immunofluorescence .......................................................................................................... 85 4.4.10 Induction of EAE and clinical evaluation ............................................................................ 85 4.4.11 Histology and immunohistochemistry ................................................................................ 85 4.4.12 Statistical analysis .............................................................................................................. 86 4.5 SUPPLEMENTARY TABLES ................................................................................................... 87 1 | 4.5.1 Supplementary Table 1. List of differentially expressed genes in pMΦ of B6.129- PrnpZrchI/ZrchI vs. B6.129-Prnpwt/wt identified by RNA-Seq. ............................................................... 87 4.5.2 Supplementary Table 2. Genes containing non-synonymous SNPs between B6.129- PrnpZrchI/ZrchI vs. B6.129-Prnpwt/wt ..................................................................................................... 96 5 TRANSPLANTED STROMAL-VASCULAR PDGFRβ+ CELLS DEVELOP INTO FUNCTIONAL FOLLICULAR DENDRITIC CELLS ...................................................................................................... 101 5.1 INTRODUCTION ..................................................................................................................... 102 5.1.1 The stromal compartment of lymphoid tissues ................................................................. 102 5.1.2 FDC in physiological and pathological conditions ............................................................ 107 5.1.3 Scientific aims ................................................................................................................... 109 5.2 RESULTS ................................................................................................................................ 111 5.2.1 FDC are derived from PDGFRβ+ precursors .................................................................... 111 5.2.2 Characterization of isolated stromal-vascular PDGFRβ+ cells ......................................... 115 5.2.3 Transplanted PDGFRβ+ stromal-vascular cells develop into mature FDC ...................... 121 5.2.4 FDC derived from transplanted PDGFRβ+ stromal-vascular cells trap IC ....................... 126 5.2.5 Factors influencing outcome of stromal-derived PDGFRβ+ cells transplantations ........... 130 5.3 DISCUSSION .......................................................................................................................... 132 5.3.1 PDGFRβ as a marker for FDC precursors ....................................................................... 132 5.3.2 Recapitulation of FDC development in a collagen sponge .............................................. 134 5.3.3 A role for FDC precursors in prion diseases? .................................................................. 136 5.4 MICE, MATERIAL AND METHODS ....................................................................................... 139 5.4.1 Mice .................................................................................................................................. 139 5.4.2 Isolation of perigonadal white adipose stromal-vascular cell fraction .............................. 139 5.4.3 Quantitative RT PCR ........................................................................................................ 140 5.4.4 Subcapsular renal transplantation of PDGFRβ++ stromal-vascular cells .......................... 141 5.4.5 In vitro IC trapping ............................................................................................................ 141 5.4.6 In vivo IC trapping ............................................................................................................. 142 5.4.7 Immunohistochemistry and immunofluorescence ............................................................ 142 5.4.8 Quantification of Mfge8 staining on Pdgfrb-Cre+ x CAG-tdTomato (Ai14) spleen sections ......................................................................................................................................... 143 6 ACKNOWLEDGMENTS ................................................................................................................ 144 7 CURRICULUM VITAE AND PUBLICATIONS ............................................................................... 147 8 BIBLIOGRAPHY ............................................................................................................................ 149 2 |
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