Human herpesvirus-6, varicella-zoster virus and oligoclonal bands in demyelinating diseases of the central nervous system Jenna Nicklén Doctoral Programme in Clinical Research Department of Virology, Haartman Institute, Medicum Department of Neurology, Clinicum Faculty of Medicine University of Helsinki Finland ACADEMIC DISSERTATION To be presented for public examination, with permission of the Faculty of Medicine of the University of Helsinki on 18th March 2016, at noon Supervisor Professor Markus Färkkilä Department of Neurology, Clinicum Faculty of Medicine University of Helsinki Reviewers Docent Merja Soilu-Hänninen Department of Neurology Faculty of Medicine University of Turku Docent Veijo Hukkanen Department of Virology Faculty of Medicine University of Turku Official Opponent Professor Irina Elovaara Department of Neurology Faculty of Medicine University of Tampere ISBN 978-951-51-1910-0 (paperback) ISBN 978-951-51-1911-7 (PDF) http://ethesis.helsinki.fi Unigrafia Oy, Helsinki 2016 TABLE OF CONTENTS LIST OF ORIGINAL PUBLICATIONS .................................................................................................... 5 ABBREVIATIONS ................................................................................................................................ 6 ABSTRACT ......................................................................................................................................... 8 TIIVISTELMÄ .................................................................................................................................... 10 INTRODUCTION .............................................................................................................................. 12 1 LITERATURE REVIEW ............................................................................................................... 14 1.1 HUMAN HERPESVIRUS-6 (HHV-6) .................................................................................... 14 1.1.1 Introduction of the virus .......................................................................................... 14 1.1.2 Characteristic features ............................................................................................. 15 1.1.3 Clinical significance in adults .................................................................................... 16 1.1.4 Diagnostic tools for diagnosing HHV-6 infection in the CNS .................................... 17 1.1.5 HHV-6 and demyelinating diseases .......................................................................... 18 1.1.6 HHV-6 in other neurological diseases ...................................................................... 19 1.1.7 Antiviral treatment of HHV-6 ................................................................................... 20 1.1.8 Radiological features in HHV-6 encephalopathy...................................................... 21 1.2 VARICELLA-ZOSTER VIRUS ............................................................................................... 22 1.2.1 Introduction and characteristic features of the virus .............................................. 22 1.2.2 Clinical significance in adults .................................................................................... 25 1.2.3 Diagnostic tools for diagnosing VZV infection in CNS .............................................. 25 1.2.4 VZV and demyelinating diseases .............................................................................. 26 1.2.5 Antiviral treatment and prevention of VZV ............................................................. 26 1.3 MULTIPLE SCLEROSIS ....................................................................................................... 27 1.3.1 Introduction and clinical characteristics of MS ........................................................ 27 1.3.2 Pathogenesis of MS .................................................................................................. 29 1.3.2.1 Cell-mediated autoimmunity theory of MS ......................................................... 30 1.3.2.2 Humoral autoimmunity theory of MS .................................................................. 30 1.3.2.3 Viral theories of MS pathogenesis ........................................................................ 31 1.3.3 Treatment of MS ...................................................................................................... 31 1.4 OLIGOCLONAL BANDS ..................................................................................................... 33 1.4.1 Introduction of OCBs ................................................................................................ 33 1.4.2 OCBs in clinical use ................................................................................................... 34 1.4.3 OCBs in neurological diseases .................................................................................. 34 1.4.4 OCBs reactivity against different pathogens ............................................................ 35 2 AIMS OF THE STUDY ................................................................................................................ 36 3 PATIENTS AND METHODS ....................................................................................................... 37 3.1 PATIENTS .......................................................................................................................... 37 3.1.1 Patients (I-V) ............................................................................................................. 37 3.1.2 Samples (I-V) ............................................................................................................. 37 3.1.3 Ethical approval ........................................................................................................ 38 3.2 METHODS ......................................................................................................................... 38 3.2.1 Antibody tests of HHV-6A and HHV-6B (I-IV) ........................................................... 38 3.2.2 Avidity test (I-IV) ....................................................................................................... 38 3.2.3 OCB detection (II-V) .................................................................................................. 38 3.2.4 HHV-6 and VZV-reactivity in OCBs (II-V) ................................................................... 39 3.2.5 Clinical data (I-V) ...................................................................................................... 39 3.2.6 Neurological diagnoses (I-V)..................................................................................... 40 3.2.7 Statistical analysis (III, V, thesis) ............................................................................... 40 4 RESULTS ................................................................................................................................... 41 4.1 HHV-6 SEROLOGICAL PRIMARY INFECTION AND MS (I, III, IV) ...................................... 41 4.2 VIRUS-REACTIVE OCBS (II-V) .......................................................................................... 44 5 DISCUSSION ............................................................................................................................. 49 5.1 SEROLOGICALLY CONFIRMED HHV-6 IN MS .................................................................... 49 5.2 VIRUS-REACTIVE OCBS IN MS .......................................................................................... 51 5.2.1 Total number of OCB ................................................................................................ 52 5.2.2 How can the small number of virus-reactive OCBs be explained, when compared to the total number of OCBs? ..................................................................................................... 54 5.2.3 Virus-reactive OCBs; polyclonal activation or antibody production against relevant antigens? ................................................................................................................................. 54 5.3 MECHANISMS FOR HOW HHV-6 AND VZV COULD BE INVOLVED IN DEMYELINATION AND MS PATHOGENESIS ............................................................................................................. 55 5.3.1 Cell-mediated and humoral autoimmunity theories of MS ..................................... 55 5.3.1.1 Molecular mimicry ................................................................................................ 55 5.3.1.2 Interaction with leukocytes .................................................................................. 55 5.3.2 Direct virus infection of the CNS .............................................................................. 56 5.3.3 Gives access to other pathogens to infect the host CNS? ....................................... 57 6 CONCLUSIONS AND FUTURE ASPECTS .................................................................................... 58 ACKNOWLEDGEMENTS .................................................................................................................. 59 REFERENCES ................................................................................................................................... 61 SUPPLEMENT “Potilaskaavake” LIST OF ORIGINAL PUBLICATIONS I Pietiläinen J, Virtanen JO, Uotila L, Salonen O, Koskiniemi M and Färkkilä M. HHV-6 infection in multiple sclerosis.