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Paraneoplastic Neurological Syndromes Associated with Anti-Hu Antibodies: Are T Lymphocytes Involved Or Not?

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Paraneoplastic Neurological Syndromes Associated with Anti-Hu Antibodies: Are T Lymphocytes Involved Or Not? PARANEOPLASTIC NEUROLOGICAL SYNDROMES ASSOCIATED WITH ANTI-HU ANTIBODIES: ARE T LYMPHOCYTES INVOLVED OR NOT? Marieke T. de Graaf Paraneoplastic Neurological Syndromes associated with anti-Hu antibodies: are T lymphocytes involved or not? Paraneoplastische Neurologische Syndromen geassocieerd met anti-Hu antistoffen: betrokkenheid van T lymfocyten of niet? PROEFSCHRIFT Colofon ter verkrijging van de graad van doctor The studies described in this thesis were performed at the Departments of Neurology aan de Erasmus Universiteit Rotterdam and Medical Oncology from the Erasmus University Medical Center in Rotterdam, op gezag van de rector magnificus The Netherlands. Prof.dr. H.G. Schmidt en volgens besluit van het College voor Promoties. This research project was supported by the Gratama Foundation (Teteringen, De openbare verdediging zal plaatsvinden op The Netherlands), Erasmus MC Grant (Rotterdam, The Netherlands) and ZonMW woensdag 5 oktober 2011 om 15:30 uur AGIKO Stipendium (Den Haag, The Netherlands). Printing of this thesis was sponsored by Sysmex, Duke Scientific Corporation, Beckman Coulter, BD Biosciences and Zebra Bioscience. door ISBN: 978-90-8891-305-1 Copyright © 2011 Marieke T. de Graaf, Rotterdam, The Netherlands Marieke Theodora de Graaf All rights reserved. No part of this thesis may be reproduced, stored in a retrieval system, geboren te Alkmaar or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise without the prior written permission of the copyright owner. Lay out and cover design: Jan Heijnen, Hieke Denijs Printed by: Proefschriftmaken.nl || Printyourthesis.com Published by: Uitgeverij BOXPress, Oisterwijk PROMOTIECOMMISSIE Contents Chapter 1 General Introduction 9 Promotor: Prof.dr. P.A.E. Sillevis Smitt Chapter 2 Neurological Paraneoplasias 17 Overige leden: Prof.dr. M.J. van den Bent In: Wick MR: Metastatic carcinomas of unknown origin; Chapter 2: Prof.dr. H. Hooijkaas Paraneoplastic syndromes associated with MCUOs. New York, Demos, Prof.dr. F. Claas 2008: pp 27-41 Copromotor: Dr. J.W. Gratama Chapter 3 Flow cytometric characterization of cerebrospinal 39 fluid cells Cytometry Part B: Clinical Cytometry, 2011 May 12 (Epub) Chapter 4 Addition of serum-containing medium to 59 cerebrospinal fluid prevents cellular loss over time Journal of Neurology, 2011 March 12 (Epub) Chapter 5 Central memory CD4+ T cells dominate the normal 71 cerebrospinal fluid Cytometry Part B: Clinical Cytometry 2011;80:43-50 Chapter 6 B and T cell imbalances in CSF of patients with 87 Hu-antibody associated PNS Journal of Neuroimmunology 2008;195:164-170 Chapter 7 No evidence for the presence of HuD-specificT cells in the 101 cerebrospinal fluid of patients with Hu-associated paraneoplastic neurological syndromes Journal of Neurology 2009;256:279-282 Chapter 8 HLA-DQ2+ individuals are susceptible to Hu-Ab associated 107 paraneoplastic neurological syndromes Journal of Neuroimmunology 2010;226:147-9 Chapter 9 Contamination of synthetic HuD protein spanning peptide 117 pools with a CMV-encoded peptide Cytometry Part A 2008;73:1079-1085 Chapter 10 Human chorionic gonadotropin treatment of anti-Hu 133 associated paraneoplastic neurological syndromes Journal of Neurology, Neurosurgery & Psychiatry 2010;81:1341-4 Chapter 11 General Discussion 143 Chapter 12 Summary/Samenvatting 151 References 160 List of abbreviations 190 Dankwoord 197 PhD Portfolio 200 Curriculum Vitae 203 List of publications 204 Chapter 1 General Introduction 10 Chapter 1 General Introduction 11 PARANEOPLASTIC NEUROLOGICAL SYNDROMES tissue distress, e.g., cytokine production by the tumor25, in SCLC patients developing Hu- PNS which is absent in SCLC patients without Hu-PNS. Apparently, this tissue distress is Clinical aspects present in a minority of SCLC patients, given that only a small population of SCLC patients Paraneoplastic neurological syndromes (PNS) are remote effects of cancer that are not succumbs to neuronal degeneration. caused by invasion of the tumor or its metastases, nor by infection, ischemia, metabolic The immune response that is triggered in Hu-PNS, not only reacts with the tumor but and nutritional deficits, surgery or other forms of tumor treatment1. PNS may effect any is also directed against HuD expressed in the nervous system. Ninety-five percent of level of the nervous system (central or peripheral nervous system, including neuromuscular SCLC patients with Hu-PNS have limited disease26, 27, which could partly be explained junction and muscle), and are devastating neurological syndromes leaving most of the by lead time bias as a search is performed towards an asymptomatic SCLC in 60%-80% patients severely disabled within a few months. In Chapter 2 the diagnosis and clinical of patients26. Alternatively, the anti-tumor immune response might be responsible for management of PNS are reviewed. One of the most frequently involved tumors in PNS is the indolent course and extended survival in many Hu-PNS patients20, 26, 27. However, small cell lung cancer (SCLC), and approximately 50% of patients with PNS and SCLC have the price of tumor control is high, because PNS also cause neuronal damage resulting in high-titer antibodies against the onconeural HuD antigen (anti-Hu)2. Detection of anti-Hu severe neurological symptoms. While all patients with high anti-Hu titers suffer from PNS, antibodies in serum or cerebrospinal fluid (CSF) definitively diagnoses the neurological an additional 16% of SCLC patients have low-titer anti-Hu antibodies without PNS19, 20, syndrome as paraneoplastic3, 4. The first goal of treatment for PNS is antitumor therapy, 27. In these patients, the presence of low-titered anti-Hu antibodies was correlated with which halts neurological deterioration and improves functional outcome5-9. Additional limited stage disease, complete response to chemotherapy, and improved survival9, 15, 19, immunotherapy with steroids, cyclophosphamide, rituximab, intravenous immunoglobulin 27. Although, in another study, no association between the presence of anti-Hu antibodies (IVIg) or plasma exchange has disappointing results6, 9-16. This thesis will focus on PNS and the extent of disease or survival was found28. The lack of neurological symptoms in associated with anti-Hu antibodies (Hu-PNS). patients with low titers of anti-Hu antibodies suggests that antitumor immunity can be dissected from neurological autoimmunity. Pathogenesis of Hu-PNS The general model for Hu-PNS is that the normally neuron-specific expression of the HuD Cellular immunity antigen, combined with immune privilege in the brain, accounts for the immunogenicity Previous studies have clearly demonstrated that anti-Hu antibodies do not play a of the HuD antigen when it is expressed in SCLC17. However, the observation that all SCLC pathogenic role in Hu-PNS and tumor control29-36, but rather are a useful diagnostic express the HuD antigen18, while only 1% of patients develop Hu-PNS with high-titer marker4. Pathological examination of affected areas of the nervous system in Hu-PNS anti-Hu antibodies1 and low-titer anti-Hu antibodies are present in an additional 16% of shows loss of neurons with localized inflammatory cell infiltrates, containing B cells, CD4+ SCLC patients19, 20, does not fit into this model. Therefore, an alternative model has been T-helper lymphocytes and cytotoxic CD8+ T lymphocytes34, 37-43. T lymphocyte receptor proposed recently in which a natural immune response to HuD is absent - to keep the analysis supported a direct effector role of cytotoxic CD8+ T lymphocytes, the same nervous system from autoimmune attack - and HuD tolerance has to be broken before clones being likely operative in neuronal damage and immune-mediated tumor growth Hu-PNS develops21. This alternative model is based on the danger theory22, which states control39, 44. The cerebrospinal fluid (CSF) of Hu-PNS patients generally is abnormal, that the default reaction of T lymphocytes to antigens on non-hematopoietic tissues is showing signs of inflammation, including mononuclear pleocytosis, intrathecal synthesis tolerance, and it is the role of blood-derived antigen presenting cells, particularly dendritic of IgG and HuD-specific oligoclonal bands8, 45-49. In blood, Hu-PNS patients had a variety cells, to detect and report to T lymphocytes in situations of dangerous tissue distress23. of imbalances within their lymphocyte subsets as compared with SCLC patients and The finding that there is a strong tolerance to HuD in normal resting mice, while HuD- healthy controls: i. a lymphopenia of B, CD4+ and CD8+ T lymphocytes50; ii. increased deficient mice generate HuD-specific T lymphocytes without peptide stimulation21, proportions of activated CD4+ and CD8+ T lymphocytes41, 50; iii. increased numbers of supports this model. In cancer, only if tissue cells are damaged by tumor cell infiltration, CD4+ memory T lymphocytes41; iv. reduced numbers of terminally differentiated effector or made to die necrotically due to severe ischemia or infection, danger signals will be CD8+ T lymphocytes and lymphocytes with a cytotoxic phenotype (CD56+ and CD57+)50; produced to stimulate antigen presenting cells and subsequently an antitumor response and v. down-regulation of expression levels of FOX-P3, TGF-β and CTLA-4 mRNA in will be generated24. If this model holds true for Hu-PNS, there has to be some kind of regulatory T-lymphocyte subsets suggesting regulatory T-lymphocyte dysfunction51. 12 Chapter 1 General Introduction 13 Additionally, difficulty in
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