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The Role of Mannose Binding Lectin (MBL) in Susceptibility to Infection in Preterm Neonates

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The Role of Mannose Binding Lectin (MBL) in Susceptibility to Infection in Preterm Neonates always THE ROLE of MANNOSE BINDING LECTIN (MBL) in PAEDIATRIC INFECTION The thesis presented for the degree of Master of Philosophy in the Faculty of Medicine, UNIVERSITY COLLEGE LONDON Agnieszka Balbina Dzwonek M.D. Department of Infectious Diseases and Microbiology Institute o f Child Health University College London 30 Guilford Street London WCl 2EH 2008 UMI Number: U591456 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 complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. Disscrrlation Publishing UMI U591456 Published by ProQuest LLC 2013. Copyright in the Dissertation held by the Author. Microform Edition © ProQuest LLC. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 ABSTRACT Mannose-binding lectin (MBL) is a circulating pattem-recognition molecule that recognizes microbial carbohydrate motifs leading to complement activation and cell lysis. Mutations in MBL promoter and exon-1 result in reduced protein levels and in a number of studies appear to increase susceptibility to infection. This thesis explores the role of MBL in paediatric infection in two clinical settings. The effect of MBL deficiency on susceptibility and progression of HIV-1 infection was investigated in one hundred and twenty eight children, aged 2-16 years. MBL deficiency appeared to be less frequent in this population than in published series of Caucasian or African children. This may be due to selective survival of children with wild type MBL genotypes as patients with severe disease, as assessed by low CD4+T cell counts, were more likely to have MBL variant alleles. In support of this hypothesis, MBL deficiency was less frequent in children classified as long term non- progressors (LTNP-s). A second study explored the impact of MBL on susceptibility and severity of infection in preterm neonates. One hundred sixty six preterm neonates were genotyped for MBL mutations by polymerase chain reaction (PCR) and heteroduplex analyses. Serum MBL levels were measured by ELISA. Comparison of genotypes (A= wild type, 0=variant alleles) and protein levels between groups was performed using Chi-square, Mann-Whitney or Kruskal-Wallis test. Low MBL levels were observed in premature neonates, particularly in the first week of life (p=0.001). MBL deficiency was associated with an increased risk of sepsis in VLBW neonates (<1500g), (p=0.01). The studies described in this thesis provide support for MBL having a role in susceptibility to and severity of infection in children. ACKNOWLEDGEMENTS Firstly, I would like to thank European Commission Brussels, Belgium, British Council and Ministry of Scientific Research and Information Technology, Warsaw, Poland, University College London for their vision and financial support for my research time. Secondly, I would like to thank Professor Nigel Klein, my principal supervisor. Also thank you to Dr. Mona Bajaj-Elliott and Dr. Vas Novelli for their invaluable guidance, encouragement, and support through out the course of the study. Thirdly, a special thanks to all collaborators, especially to Professors Henryk Tchorzewski, Dr Ewa Gulczynska and colleagues at the Polish Mother Memorial Hospital-Research Institute, Lodz, Poland. Also I would like to thank collaborators at University College London Hospitals NHS Trust and Great Ormond Street Hospital for Sick Children NHS Trust. I would also like to thank members of the Department Infectious Diseases and Microbiology at the Institute of Child Health: Clare Booth, Marina Johnson, Olaf Neth and Rodolphe Thiebaut for their help and advice. Also thank you to Professor Malcolm Turner for discussing my research results. A very special thanks to the “tiny babies” without whom this study would not be possible. Finally, I am sincerely grateful for the support of mother Sabina, and all my fiiends in London who supported me while I performed the work and completed my written thesis. It is a great pleasure to have a profession where not a day passes that I don’t learn something new. Undertaking an M PhiL has opened my eyes to the fact that I didn’t really understand many of occurrences I observed and attempted to manipulate. It has also made me aware as a doctor, that many of things we credit ourselves with achieving when managing patients are probably being achieved by the homeostatic mechanisms that exist within our bodies. Despite the glimpse into the extraordinary amount of new information that is being discovered every day in science, the art of medicine is fundamental to its successful practice and being a truly great doctor. Agnieszka B. Dzwonek January 2007. II DECLARATION The work presented in this thesis was performed by myself. I would like to acknowledge the importance of specific contribution of the following Departments and Institutions. The work presented in chapter 3 was carried out at Great Ormond Street Hospital, HIV Family Clinic. I have set up the HTV study described in Chapter 3 .1 recruited all the children, collected blood samples, performed the laboratory and statistical analysis and collected the clinical data. The work presented in chapter 4 was carried out as a part of collaborative study with the departments of Immunology and Neonatal Intensive Care Units at the Polish Mother Memorial Hospital-Research Institute and University College London Hospitals, NHS Trust. Blood samples and clinical data were collected jointly. All laboratory analysis, statistical analysis, and discussion are solely the work of the author. I personally conducted all the laboratory experiments described in this thesis. In addition I have analysed and interpreted results of all studies described in this thesis. Statistical support was received by Dr Angie Wade from Department of Statistics and Rodolphe Thiebaunt at the ICH/ UCL. Thank you last but not least, my principal supervisor. Professor Nigel Klein, who has a significant intellectual contribution to this work, helped me with interpretation of the data and supervised the writing of this thesis. The research projects described in this thesis was conducted during Marie Curie European Union Individual Fellowship which was awarded to me in May 2004 by European Commission, Belgium. All reagents and consumables were funded by European Commission. Also this study was financially supported by British Council and Ministry of Scientific Research and Information Technology, Warsaw, Poland. Ill TABLE OF CONTENTS ABSTRACT........................................................................................................................ I ACKNOWLEDGENTS......................................................................................................II DECLARATION................................................................................................................ Ill TABLE OF CONTENTS............................................................................................... IV FIGURES......................................................................................................................... VII TABLES......................................................................................................................... VII ABREVATIONS............................................................................................................. IX CHAPTER 1: INTRODUCTION AND THESIS AIMS.....................................................1 1.1 Mannose Binding Lectin and Innate Immunity .............................................................2 1.2 The complement system .................................................................................................5 1.2.1 The lectin pathway of complement activation ..............................................10 1.3 MBL synthesis, structure and function ....................................................................... 13 1.4 MBL gene structure ...................................................................................................... 18 1.5 MBL and Host Defence ...............................................................................................22 1.5.1 The role of MBL in opsonisation and phagocytosis .................................... 22 1.5.2 MBL and inflammation ............................................................................. 23 1.5.3 The common opsonic defect and MBL deficiency .................................. 23 1.6 The role of MBL in infectious disease ........................................................................ 25 1.6.1 Disease model of MBL deficiency-MBL mouse knock-out ...................25 1.6.2 The human studies-the role of MBL in health and disease ..................... 27 1.7 MBL and susceptibility to infection .......................................................................... 30 1.7.1 Changes in serum MBL levels with ag e ......................................................32 1.7.2 Changes in serum MBL levels in early life .................................................32 1.7.3 MBL and infection in early childhood ........................................................34 1.8 AIMS OF THIS THESIS ..........................................................................................36 IV CHAPTER 2: METHODOLOGY ...............................................................................
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