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The Paradoxical Effect of Antibodies in Epilepsy

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The Paradoxical Effect of Antibodies in Epilepsy What doesn't kill you makes you stronger: the paradoxical effect of antibodies in epilepsy A dissertation submitted to Kent State University in partial fulfillment of the requirements for the degree of Doctor of Philosophy by Philip H. Iffland II August 2015 © Copyright All rights reserved Except for previously published materials Dissertation written by Philip H. Iffland II B.A., Miami University, Oxford, Ohio, 2009 M.A., Kent State University, Kent, Ohio, 2012 Ph.D., Kent State University, Kent, Ohio, 2015 Approved by Derek S. Damron, Ph.D , Chair, Doctoral Dissertation Committee Trine N. JØrgensen, Ph.D , Members, Doctoral Dissertation Committee Gary K. Koski, Ph.D , Ernest J. Freeman, Ph.D , Accepted by Ernest J. Freeman, Ph.D , Director, School of Biomedical Sciences James L. Blank, Ph.D , Dean, College of Arts and Sciences Table of Contents List of Figures .......................................................................................................iv List of Tables ........................................................................................................vi List of Abbreviations ............................................................................................ vii Dedication .......................................................................................................... xiii Acknowledgements ............................................................................................ xiii Abstract .............................................................................................................. xix CHAPTER 1: BACKGROUND AND AIMS ......................................................... 21 1.1 Epilepsy: an ancient disease ..................................................................... 21 1.2 Current epidemiological perspective of epilepsy ....................................... 23 1.3 Clinical definitions of epilepsy and classifications of seizures ................... 25 Partial seizures: ........................................................................................ 26 Generalized seizures: ............................................................................... 30 1.4 Pathophysiology of epilepsy as it relates to seizure threshold .................. 37 1.5 A brief introduction to the blood-brain barrier ............................................ 39 1.6 The blood-brain barrier and epilepsy ......................................................... 45 1.7 Autoimmunity in epilepsy ........................................................................... 48 Anti-NMDA receptor encephalitis ................................................................. 49 Limbic encephalitis ....................................................................................... 53 Emerging evidence for an "anti-GAD encephalitis ....................................... 55 The rare exception: Rasmussen's encephalitis ............................................ 55 Other antibodies in epilepsy ......................................................................... 58 1.8 The use of IVIg in epilepsy ........................................................................ 58 ii 1.9 The overarching goals of this research ..................................................... 63 CHAPTER 2: AIM 1: DISCOVERY OF INTRACELLULAR AND CIRCULATING ANTINUCLEAR ANTIBODIES IN EPILEPSY ..................................................... 64 2.1 Introduction ............................................................................................... 64 2.2 Materials and methods .............................................................................. 68 2.3 Results ...................................................................................................... 78 2.5 Conclusions ............................................................................................. 104 2.6 Acknowledgements ................................................................................. 105 CHAPTER 3: AIM 2: THE PROTECTIVE EFFECT OF IgGs IN AN ANIMAL MODEL OF STATUS EPILEPTICUS ............................................................... 106 3.1 Introduction ............................................................................................. 106 3.2 Materials and methods ............................................................................ 109 3.3 Results .................................................................................................... 114 3.4 Discussion ............................................................................................... 130 3.5 Conclusions ............................................................................................. 135 3.6 Acknowledgements ................................................................................. 135 CHAPTER 4: OVERALL SIGNIFICANCE AND FUTURE DIRECTIONS ......... 136 4.1 Summary of findings ................................................................................ 136 4.2 Significance and clinical application of intracellular accumulation of IgGs ...................................................................................................................... 137 4.3 Significance and clinical application of antinuclear antibodies in epilepsy ...................................................................................................................... 142 4.4 Significance and clinical applications of the seizure mitigating effects of IgGs ............................................................................................................... 146 4.5 Significance and clinical applications of decreased BBB permeability after IVIg administration......................................................................................... 148 4.7 Conclusion .............................................................................................. 150 BIBLIOGRAPHY ............................................................................................... 154 Appendix ......................................................................................................... 205 iii List of Figures Figure 1.1 Classical etiologies of epilepsy as percent of total cases 16 Figure 1.2 Graphical depiction of the concept of seizure threshold 30 Figure 1.3 2D depiction of the basic cell types and layout of the 34 blood-brain barrier Figure 1.4 Gradients across a normal and disrupted blood-brain 37 barrier Figure 1.5 Proposed hypothesis for the action of IVIg in the CNS 53 Figure 2.1 Schematic representation of the experimental design used 61 for different aspects of research herein Figure 2.2 Extravasation of IgGs in brain of patients with epilepsy 75 coincides with regions of albumin extravasation Figure 2.3 Nuclear IgGs are exclusive to neurons in brain of 77 patients with epilepsy Figure 2.4 Subcellular fractionation and comparison of AVM brain 79 tissue from patients with epilepsy reveals that BBBD alone is sufficient to cause antibodies to bind to chromatin Figure 2.5 Mass spec. analysis reveals histones are a likely target of 81 autoantibodies in brain from patients with epilepsy iv Figure 2.6 A multimodal analysis of serum from patients with 85 epilepsy reveals the presence of specific anti-histone and anti-chromatin antibodies Figure 3.1 Schematic representation of animal experiments 99 performed Figure 3.2 High endogenous and prophylactic administration of 109 exogenous non-specific antibodies reduces mortality and mitigates seizures in NSBWF1/J mice Figure 3.3 Only intact IgGs mitigate seizures when injected IV at 112 time of pilocarpine SE Figure 3.4 In IgG treated mice that did not develop SE, no injected 113 rat IgGs or endogenous mouse IgGs were found in the brain parenchyma but were abundant in the vasculature Figure 3.5 Injected IgGs do not have a seizure mitigating effect 116 in the kainic acid (KA) model of SE Figure 3.6 Endogenous and exogenous IgGs are observed in 117 brain tissue sections of KA treated mice after SE Figure 3.7 BBB leakage and cellular uptake of IgGs in a control 118 pilocarpine mouse after SE Figure 4.1 IgGs taken up by neurons in the brain of CTE patients 134 are targeted towards the same epitopes as those observed in patients with epilepsy v List of Tables Table 1.1 Summary of antibody mediated epilepsies and 43 paraneoplastic neurological syndromes Table 1.2 Summary of literature demonstrating the efficacy of IVIg 52 in non-autoimmune epilepsies Table 2.1a Patient information 70 Table 2.1b Patient information (continued) 71 Table 2.1c Patient information (continued) 72 Table 2.2 Candidate autoantigens 82 Table 2.3 Additional putative autoantigens identified by mass spec. 83 analysis Table 3.1 Mouse data and experimental use 105 Table 3.2 Correlations and statistical significance between measured 107 seizure parameters and antibody levels in serum Table 3.3 Statistical data of measured seizure parameters versus 111 treatments vi List of Abbreviations ABTS 2,2’-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) ALS Amyotrophic lateral sclerosis AMPA α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ANA Antinuclear antibody ANNA-1 Anti-neuronal autoantibody 1, anti-Hu ANRE Anti-NMDA receptor encephalitis ATP Adenosine triphosphate AVM Arteriovenous malformation BBB Blood-brain barrier BBBD Blood-brain barrier disruption Black 6 C57B6/J mice Ca++ Calcium CA1 Cornu ammonis 1 CA2 Cornu ammonis 2 CA3 Cornu ammonis 3 CASPR2 Contactin-associated protein-like 2 CB Chromatin bound CD4 Cluster of differentiation 4 vii CNS
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