B and T Cell-Mediated Central Nervous System Demyelinating Disease: Underlying Mechanisms and Clinical Perspectives

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B and T Cell-Mediated Central Nervous System Demyelinating Disease: Underlying Mechanisms and Clinical Perspectives B and T cell-mediated central nervous system demyelinating disease: underlying mechanisms and clinical perspectives Jamie van Langelaar No parts of this thesis may be reproduced or transmitted in any form by any means, electronic or mechanical, including photocopying, recording or any information storage and retrieval system, without permission in writing from the author. The research for this thesis was performed within the framework of the Erasmus MC Postgraduate School Molecular Medicine. The studies described in this thesis were performed at the Department of Immunology and the Department of Neurology, Erasmus MC, Rotterdam, the Netherlands. The studies were financially supported by the Dutch MS Research Foundation and Zabawas. The printing of this thesis was supported by Erasmus MC. ISBN: 978-94-91811-28-9 Cover design: Karien van Langelaar Lay-out: Bibi van Bodegom & Daniëlle Korpershoek Printing: Ridderprint | www.ridderprint.nl Copyright © 2021 by Jamie van Langelaar. All rights reserved. B and T Cell-mediated Central Nervous System Demyelinating Disease: Underlying mechanisms and clinical perspectives B en T cel-gemedieerde demyeliniserende ziekte van het centrale zenuwstelsel: Onderliggende mechanismen en klinische perspectieven Thesis to obtain the degree of Doctor from the Erasmus University Rotterdam by command of the rector magnicus Prof.dr. F.A. van der Duijn Schouten and in accordance with the decision of the Doctoral Board The Public defense will be held on Tuesday 16 March 2021 at 10:30 hrs by Jamie van Langelaar born in East London, South Africa DOCTORAL COMMITTEE Promotors Prof.dr. P. Katsikis Prof.dr. P.A.E. Sillevis Smitt Other members Prof.dr. B.C. Jacobs Prof.dr. J.D. Laman Prof.dr. R.W. Hendriks Copromotor Dr. M.M. van Luijn CONTENTS CHAPTER 1 9 General introduction CHAPTER 2 39 T helper 17.1 cells associate with multiple sclerosis disease activity: perspectives for early intervention Brain 2018;141;1334-1349 CHAPTER 3 69 Brain-homing CD4+ T cells display glucocorticoid-resistant features in multiple sclerosis Neurology, Neuroimmunology and Neuroinflammation 2020;7 CHAPTER 4 89 Induction of brain-infiltrating T-bet-expressing B cells in multiple sclerosis Annals of Neurology 2019;86:264-278 CHAPTER 5 115 The association of Epstein-Barr virus infection with CXCR3+ B-cell development in multiple sclerosis: impact of immunotherapies European Journal of Immunology 2020; Epub ahead of print CHAPTER 6 133 Naive B cells in neuromyelitis optica spectrum disorders: impact of steroid use and relapses Brain Communications 2020; Epub ahead of print CHAPTER 7 155 General discussion ADDENDUM 181 List of abbreviations 182 Summary 184 Samenvatting 187 Acknowledgements 191 Curriculum vitae 198 PhD portfolio 199 List of publications 201 Chapter 1 General introduction 1_ 1- General introduction GENERAL INTRODUCTION 1 Every day the human body encounters various pathogens such as bacteria and viruses. If these pathogens break through the initial physical and chemical barriers of the body, the immune system is recruited to eliminate them. To achieve this, the immune system uses tightly regulated innate and adaptive defense mechanisms. Rapid recognition and elimination of the pathogen is mediated by the innate immune response, while the adap- tive immune response is slower but more specic and generates immunological memory for a quicker response if re-exposure occurs. The intricate balance between eector and regulatory immune cells ensures an optimal immune response. This balance also prevents immune responses against self-antigens through a phenomenon called immune toler- ance. However, the interplay between intrinsic (genetic) and extrinsic (environmental) fac- tors likely causes breakdown of self-tolerance, eventually resulting in autoimmune disease. Adaptive immunity (B and T cells) plays a fundamental, but yet incompletely understood role in patients with multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). MS and NMOSD are inammatory and demyelinating diseases of the central nervous system (CNS) that are mediated by autoimmune-related processes. In this chapter, we introduce how B and T cells develop and interact in healthy individuals and what could trigger particular subsets to become pathogenic instead of protective in such patients. This sets the stage for the current thesis, which addresses the underlying mechanisms and clinical impact of human B and T cells on inammatory CNS demyelinating disease. ADAPTIVE IMMUNITY B and T cells initially develop in the bone marrow and originate from hematopoietic stem cells (HSCs) committed to the lymphoid lineage [1]. Depending on the cytokine milieu and distinct transcription factors [1-3], lymphoid progenitor cells will either remain in the bone marrow to mature into B cells or migrate to the thymus to mature into T cells. During these processes, highly specic and unique B- and T-cell receptors are generated, making it possible to recognize a large variety of antigens. Both central and peripheral tol- erance checkpoints are exploited to prevent recognition of self-antigens and to promote the development of functional subsets with non-self-reactive receptors [4]. Such B and T cells recirculate in the blood until an antigen is encountered within lymphoid organs. Upon encounter with antigens, B and T cells are activated and dierentiate into eector and memory cells in order to remove the pathogen through antibody-mediated humoral and cytotoxic cellular immunity [5, 6]. To reach these eector and memory stages, B and T 11 Chapter 1 cells undergo a series of well-regulated developmental steps, which are further explained below. B-cell development and eector functions In the bone marrow, HSC-derived precursors develop into immature B cells with a B cell receptor (BCR) that is generated by random gene recombination of their immunoglobulin (Ig) heavy and light chain loci, known as V(D)J rearrangements [7, 8]. Two main central tolerance mechanisms ensure that immature B cells expressing high anity BCRs for self-antigens are removed. Receptor editing occurs when a self-reactive BCR is expressed during the early stages of B-cell development and certies that this specicity is lost through a second round of V(D)J rearrangements [9]. This mechanism involves the removal of an autoreactive BCR by deleting the self-reactive light-chain gene and replacing it with another sequence. If receptor editing fails, clonal deletion in the bone marrow removes self-reactive B cells [9]. The cells that survive these checkpoints exit the bone marrow and enter the circulation as transitional B cells (CD38high CD24highIgM+IgD+), which then further dierentiate into naive mature B cells (CD38-/dimIgM+CD27- IgD+; Fig. 1) with a functional BCR [7, 8]. At this particular stage, peripheral tolerance mechanisms including apoptosis, anergy and T regulatory cell (Treg)-mediated suppression are important to control autore- active B cells that have escaped negative selection in the bone marrow [10]. Within secondary lymphoid organs such as the lymph nodes, mature naive B cells encounter antigens via the BCR, internalize, process and present these antigens on human leukocyte antigen (HLA) class II molecules to CD4+ T cells [11]. This can initiate either germi- nal center (GC)-dependent or –independent dierentiation of naive B cells into memory B cells and antibody-secreting cells (ASCs; Fig. 1) [12, 13]. In GC-dependent responses B cells receive signals from CD4+ T follicular helper (Tfh) cells via CD40 ligand (CD40L[CD40]), CD28 (CD80/CD86) and interleukin (IL)-21 to undergo clonal expansion, class switch recombina- tion and somatic hypermutations of the VH genes [6]. During class switch recombination, the constant region of the BCR Ig heavy chain is replaced by other isotypes that have vary- ing properties and functions. Somatic hypermutations take place at the variable regions of both the Ig heavy and light chains and comprises of single-nucleotide exchanges, deletions and point mutations [14]. Both these processes increase the anity of B cells for antigens. Somatic hypermutations in the GC can lead to formation of self-reactive B cells as well, however the tolerance mechanisms involved here to regulate their removal remains poorly understood [15]. Strong HLA-II antigen presentation and co-stimulation via CD40L/CD40 are key processes for maintaining peripheral tolerance [9, 16]. B cells that survive peripheral tolerance checkpoints and enter GCs develop into class switched IgG+, IgA+ or IgE+ memory B cells and long-lived plasma cells (CD38highCD27highCD138+) [17, 18]. There is also generation of non-class switched IgM+ memory B cells [19, 20]. This can occur 12 General introduction in a GC-independent manner via the marginal zone in the spleen giving rise to natural eector B cells (CD27+IgM+IgD+) or in a GC-dependent manner that results in the devel- 1 opment of ‘IgM-only’ (CD27+IgM+IgD-) B cells (Fig. 1) [20]. Furthermore, GC-independent responses can lead to the generation of short-lived plasmablasts (CD38highCD27high) when B cells interact with CD4+ T cells in extra-follicular regions [12, 13]. Memory B cells function to act as antigen-presenting cells (APCs) and secrete pro- or anti-inammatory cytokines [21, 22]. Whereas, ASCs consist of both short-lived plasmablasts and long-lived plasma cells + /dim + + + Central Peripheral tolerance tolerance Short-lived PB dim + + high high /dim high high - - + + + Short-/long-lived PC + dim high high + + /dim
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