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Functional Effects of Anti-Neuronal Antibodies in Patients with Encephalitis Lethargica and Related Disorders Associated with Streptococcal Infection

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Functional Effects of Anti-Neuronal Antibodies in Patients with Encephalitis Lethargica and Related Disorders Associated with Streptococcal Infection Functional effects of anti-neuronal antibodies in patients with encephalitis lethargica and related disorders associated with streptococcal infection PRIYAMVADA DUA Queen Mary University of London Submitted for the Degree of Doctor of Philosophy (PhD) 1 DEDICATION I would like to dedicate this thesis to my MOTHER 2 ACKNOWLEDGEMENTS It would not have been possible to write this doctoral thesis without the help and support of people around me, to only some of whom it is possible to give particular mention here. This thesis would not have been possible without the advice, support and clinical knowledge of my principal supervisor and mentor, Prof. Gavin Giovannoni. The help, support and research expertise of my second supervisor, Prof. David Baker. I would especially like to thank Dr. Ute Meier for her trust, constant encouragement and both professional and personal advice at all times. Their input has been invaluable and instrumental on both an academic and a personal level, for which I am extremely grateful. I would like to thanks members of the Blizard Institute for the use of their facilities, equipment and the warm welcome, especially Dr. Gary Warnes for his help with Flow Cytometry and Dr. Ann Wheeler for her help with Microscopy. Special mention goes to Dr. Veronika Souslova whose expertise in molecular biology made a large part of this project possible. Additionally I would like to acknowledge: Dr. Kathryn Harris (Great Ormond Street Hospital, London) for her guidance, help and use of facilities for all the streptococcal work and Prof. Angela Vincent and her team (WIMM, University of Oxford) for providing the facilities to carry out the NMDAR and VGKC assays. Among the members of the Neuroimmunology group I would like to acknowledge the special effort made by Ute Meir, Monica Marta, David Holden, Sofia Sisay, Fabiola Puentes, Katie Lidster, Sarah Al-Izki and Paul Creeke in promoting a stimulating and welcoming academic and social environment which will stand as an example to those that succeed them. 3 My family has offered me enormous support though the span of my studies without them this thesis would not have been possible. I would like to thank my parents for their constant love and understanding. I would particularly like to thank my brother Kaustubh for his support and encouragement to pursue my goals. My heartfelt thanks goes to my very dear friends Sofia, Priya, Artur, Ketan, Alicia, Rohit, Anto and Shikha who were a constant source of strength and encouragement. They stood by me through the toughest of times. Last but not the least I would like to thank The Sophie Cameron Trust for funding this study. 4 CONTENTS DEDICATION .................................................................................................................. 2 ACKNOWLEDGEMENTS ................................................................................................... 3 LIST OF FIGURES ............................................................................................................. 9 LIST OF SUPPLEMENTARY FIGURES ............................................................................... 12 LIST OF TABLES ............................................................................................................. 14 ABSTRACT .................................................................................................................... 15 ABBREVIATIONS ........................................................................................................... 17 CHAPTER 1: INTRODUCTION ......................................................................................... 19 1.1 THE BASAL GANGLIA ............................................................................................... 19 1.1.1 Background ................................................................................................................... 19 1.1.2 Basal Ganglia Disorders ................................................................................................. 20 1.2 AUTOIMMUNITY .................................................................................................... 24 1.2.1 What is Autoimmunity? ................................................................................................ 24 1.2.2 Bacteria and Autoimmunity .......................................................................................... 26 1.3 GROUP A BETA-HAEMOLYTIC STREPTOCOCCUS (GABHS) ......................................... 28 1.3.1 Background ................................................................................................................... 28 1.3.2 Virulence factors ........................................................................................................... 29 1.3.3 Anti-streptococcal antibodies as surrogate markers of infection ................................ 40 1.3.4 Molecular Mimicry Model ............................................................................................ 42 1.4 POSTULATED POST-STREPTOCOCCAL DISORDERS .................................................... 44 1.4.1 Acute Rheumatic Fever (ARF) ....................................................................................... 44 1.4.2 Sydenhams chorea (SC) ................................................................................................. 47 1.4.3 Paediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) ............................................................................................................... 50 1.4.4 Tourettes syndrome (TS)............................................................................................... 53 1.4.5 Dystonia ........................................................................................................................ 57 1.4.6 Encephalitis Lethargica (EL) .......................................................................................... 60 1.4.7 NMDAR Encephalitis ..................................................................................................... 62 1.5 CANDIDATE AUTOANTIGENS ................................................................................... 65 1.5.1 Aldolase C (Ald C) .......................................................................................................... 65 5 1.5.2 Enolase (Eno) ................................................................................................................ 67 1.5.3 Pyruvate kinase (PK) ..................................................................................................... 70 1.6 CONCLUSION .......................................................................................................... 71 1.7 HYPOTHESIS ........................................................................................................... 72 1.8 AIMS ...................................................................................................................... 73 CHAPTER 2: GROUP A BETA-HAEMOLYTIC STREPTOCOCCUS (GABHS) ............................ 74 2.1 INTRODUCTION ...................................................................................................... 74 2.1.1 GABHS Background ....................................................................................................... 74 2.2 HYPOTHESIS AND AIMS .......................................................................................... 75 2.3 MATERIALS AND METHODS .................................................................................... 75 2.3.1 GABHS Samples ............................................................................................................. 76 2.3.3 Latex Agglutination Test ............................................................................................... 76 2.3.4 Emm Typing ................................................................................................................... 77 2.3.5 Superantigen Screening ................................................................................................ 80 2.4 RESULTS ................................................................................................................. 83 2.4.1 Emm typing ................................................................................................................... 83 2.4.2 Superantigens ............................................................................................................... 85 2.4.3 Correlation: emm type and superantigens ................................................................... 87 2.5 DISCUSSION ........................................................................................................... 89 CHAPTER 3: ANIMAL MODELS ....................................................................................... 94 3.1 INTRODUCTION ...................................................................................................... 95 3.1.1 Putative Antigen: GABHS Proteins ............................................................................... 95 3.1.2 Putative Antigen: Glycolytic Enzymes ........................................................................... 97 3.1.3 Animal Models .............................................................................................................. 98 3.3 MATERIALS AND METHODS .................................................................................. 102 3.3.1 GABHS Protein Fractions ............................................................................................
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