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The Function and Regulation of Lfa-3 in Oral Mucosal Inflammation

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The Function and Regulation of Lfa-3 in Oral Mucosal Inflammation THE FUNCTION AND REGULATION OF LFA-3 IN ORAL MUCOSAL INFLAMMATION Thesis submitted by Alun C. Kirby, BSc (Hons) for the degree of DOCTOR OF PHILOSOPHY in the Faculty of Medicine University of London Department of Oral Medicine Eastman Dental Institute for Oral Health Care Sciences 256 Grays Inn Road London, WC1X 8LD - 1999 - ProQuest Number: 10631525 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a com plete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest ProQuest 10631525 Published by ProQuest LLC(2017). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States C ode Microform Edition © ProQuest LLC. ProQuest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106- 1346 Abstract The adhesion molecule lymphocyte function-associated antigen 3 (LFA-3), the major ligand of the T lymphocyte receptor CD2, is involved in cellular adhesion, activation and functional modulation. However, the role of LFA-3 and regulation of LFA-3 expression in oral mucosal and other diseases is poorly understood. The role of LFA-3 was investigated in the inflammatory disease oral lichen planus (OLP). Expression <of LFA-3 was found to be up-regulated in OLP lesions compared with heallthy oral tissues. Two distinct expression patterns were identified in OLP lesiions - intracellular LFA-3 was localised within a population of infiltrating cells, andl a ‘soluble’ form of LFA-3 (sLFA-3) was apparent within affected tissues. In 'contrast with the increased lesional expression of LFA-3, systemic sLFA-3 levels were not significantly altered in the sera of OLP patients compared with control subjects. RT-PCR of mRNA from OLP, other oral mucosal diseases and healthy oral mucosa revealed LFA-3 mRNA isoform expression to be neither tissue- nor disease-specific. However, a novel in vivo isoform of LFA-3 mRNA was detected. This mRNA isoform was cloned, sequenced and identified as LFA-3 AD2. Possible mechanisms for LFA-3 regulation and sLFA-3 generation in vivo were investigated in vitro. An intracellular pool of LFA-3 was demonstrated to be present within a range of cell lines. Although both surface and intracellular LFA-3 expression were relatively unaffected by inflammatory cytokines, the release of sLFA-3 from these cells was susceptible to cytokine-mediated modulation. 2 Differential susceptibility to cleavage of surface LFA-3 by a phospholipase C (PLC) was demonstrated. PLC-mediated LFA-3 cleavage, a possible mechanism of sLFA-3 generation, was found to be associated with an increase in intracellular LFA-3 followed by replacement of LFA-3 at the cell surface. Finally, the in vivo role of LFA-3 in OLP was examined by adaptation of the Stamper-Woodruff adhesion assay. The results of these antibody blockade studies suggest that LFA-3 may be of equivalent importance to intercellular adhesion molecule 1 (ICAM-1) for lymphocyte adhesion within the OLP inflammatory infiltrate, and may be a potential therapeutic target for the control of OLP. 3 Declaration I hereby certify that the work embodied in this thesis is the result of my own investigations, except where otherwise stated. Alun Kirby January 1999 London 4 Acknowledgements I would like to express great thanks to my supervisors, Dr. Irwin Olsen and Professor Stephen Porter, for guidance and support during these studies. I am extremely grateful to Dr Vanessa Hill, GeneSys Ltd., who supervised in the cloning of the LFA-3 AD2 mRNA isoform. Thanks to Dr. Paula Hochman, Biogen Corp., for supplying antibodies, LFA-3TIP and the basic ELISA protocol. Thanks also to Dr. Paula Farthing for aiding with the initial immunohistochemistry samples, and to the clinicians of the Department Oral Medicine of for their continuing help. Many thanks to all my colleagues at the Eastman Dental Institute, whose continued friendship has been invaluable. I would especially like to thank Gio (carino!), Vanessa (strange times, indeed), Nicci, Lois, Jon, Mike, Brian, Simon, Sean and Pierre. ‘It’s not where you are, it’s who you’re with.’ Much love and thanks to my parents (Yes, Dad, it’s finished) and to my sister, Geraldine. I am very proud of them. 5 For Sarah, forever. 6 Index of contents Title page 1 Abstract 2 Declaration 4 Acknowledgements 5 Dedication 6 Index of contents 7 Index of figures 12 Index of tables 14 Abbreviations 15 Publications resulting from this thesis 17 Chapter I Background 20 I.A LFA-3 - an overview (i) Introduction 21 (ii) Molecular biology of LFA-3 21 (iii) Constitutive expression of LFA-3 23 (iv) Functional interactions with CD2: T cell adhesion 24 (v) Functional interactions with CD2: Co-stimulation 28 (vi) LFA-3 and T lymphocyte cytokine regulation 29 (vii) LFA-3 as target cell effector molecule 30 (viii) Regulation of LFA-3 expression 31 (ix) Soluble LFA-3 as an immunomodulatory molecule 33 (x) LFA-3 in vivo 35 I.B Oral lichen planus: an overview (i) Introduction 38 7 (ii) Aetiology 41 (iii) Immunopathogenesis 44 (iv) Summary 51 I.C Aims 53 Chapter II Materials and methods 54 II. A Immunohistochemistry of cryostat sections 54 (i) Origin of tissue samples 54 (ii) Sample preparation and cryosectioning 55 (iii) Horse-radish peroxidase technique 55 II.B ELISA for soluble LFA-3 58 (i) General procedure 59 (ii) Adaptation for lower detection limit 60 II.C Reverse-transcription polymerase chain reaction and associated techniques 61 (i) RNA extraction and quantification 61 (ii) Reverse-transcription polymerase chain reaction 63 (iii) Agarose gel electrophoresis 67 (iv) Polyacrylamide gel electrophoresis 68 (v) Image analysis 69 II.D. Cloning of PCR products 69 (i) Ligation and electroporation 70 (ii) Screening of putative clones 71 (iii) Amplification and purification of plasmid DNA 72 (iv) Characterization of insert 73 II.E. Tissue culture techniques 74 (i) General procedures 75 (ii) Assay for cytokine effects 7 8 8 (iii) Assay for enzyme and enzyme inhibitor effects 80 (iv) Preparation of cells for fluorescence activated cell scanning (FACS) analysis 82 II.F FACS techniques 83 (i) Cell preparation and labelling 83 (ii) Data acquisition and analysis 84 II.G Stamper-Woodruff lymphocyte adherence assay 87 (i) Lymphocyte isolation and activation 87 (ii) Tissue section preparation 88 (iii) Adherence assay 89 (iv) Periodic acid-Schiff/methyl green-thionin staining 89 (v) Adaptation: Blocking studies 90 (vi) Result acquisition and analysis 91 Chapter III Immunohistochemical analyses 92 ID. A Comparison of idiopathic OLP and normal buccal mucosa 93 (i) Phenotypic distributions in idiopathic OLP 95 (ii) Expression of 61 integrins in idiopathic OLP 100 (iii) Expression of ICAM-1 in idiopathic OLP 104 (iv) Expression of LFA-3 in idiopathic OLP 106 III.B Immunohistochemical analyses: Discussion 110 (i) LFA-3 expression in idiopathic OLP 112 Chapter IV Soluble LFA-3 in vivo 115 IV. A Soluble adhesion molecules in OLP 117 (i) Serum sLFA-3 levels 118 (ii) Serum sICAM-1 levels 121 IV.B Soluble LFA-3 in vivo: Discussion 121 9 Chapter V Expression of LFA-3 mRNA in vivo and in vitro 124 Y.A LFA-3 mRNA expression in vivo 125 V.B LFA-3 mRNA expression in vitro 130 V.C Semi-quantitative RT-PCR of LFA-3 mRNA expression 132 V.D LFA-3 mRNA expression in vivo and in vitro: Discussion 134 Chapter VI Identification and cloning of human LFA-3 AD2 138 VI. A RT-PCR for LFA-3 AD2 mRNA expression 139 VLB Cloning and sequencing of LFA-3 AD2 142 VLC Identification and cloning of human LFA-3 AD2: Discussion 143 Chapter VII Regulation of cell-associated and soluble forms of LFA-3 146 VILA Basal levels of surface and intracellular LFA-3 expression 148 VII.B Basal levels of sLFA-3 production 149 (i) Effect of GPI-PLC on sLFA-3 production 152 VII. C Effect of cytokines on cell-associated LFA-3 expression 157 VD.D Effect of cytokines on sLFA-3 production 159 VILE Regulation of cell-associated and soluble LFA-3: Discussion 162 Chapter VIII LFA-3-mediated adhesion in vivo: Stamper-Woodruff adhesion assays 169 VID.A Assay adaptations for lymphocyte-infiltrate binding 170 VIII.B Lymphocyte adhesion assays 171 VIII.C LFA-3-mediated adhesion in vivo: Discussion 175 10 Chapter IX Summary 179 References 186 Appendix 217 Reprints of published papers Phenotypic distributions in normal and OLP mucosa Regulation of LFA-3: Raw data Stamper-Woodruff adhesion assay: Raw data i i Index of figures I.A.l Schematic representation of LFA-3 structure at the gene, mRNA and protein level for each isoform 26 I.A.2 The ‘zone of close contact’ model of T cell triggering 27 I.A.3 Putative mechanisms of sLFA-3 generation 36 I.B.l Schematic representation of the putative mechanism of OLP pathogenesis 39 I.B.2 Histological features of reticular oral lichen planus lesion. 40 II. A. 1 Tissue orientation and mounting for cryosectioning 56 II.F.l Representative FACS analysis plots 85 III.A.l Expression of CD la in (a) normal buccal mucosa and (b) OLP lesional mucosa 97 HI.A.2 Expression of CD3 in (a) normal buccal mucosa and (b) OLP lesional mucosa 98 III.A.3 Expression of CD68 in (a) normal buccal mucosa and (b) OLP lesional mucosa 99 III.A.4 Expression of VLA-2 in (a) normal buccal mucosa and (b) (b) OLP lesional mucosa 101 III.A.5 Expression of VLA-4 in (a) normal buccal mucosa and (b) OLP lesional mucosa 102 III.
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