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Iris Louise Agaath Bodewes Interferon in Sjögren’s syndrome and other systemic autoimmune diseases: A driver of disease pathogenesis and potential treatment target Iris Louise Agaath Bodewes 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 Laboratory for Medical Immunology, Department of Immunology, Erasmus MC, Rotterdam, the Netherlands. The studiesprinting were of this financially thesis was supported supported by by ReumaNederland. Erasmus MC. ISBN: 978-94-91811-21-0 Illustrations: Iris Bodewes Cover and invitation design: Sharon Maasland (Haveka) Thesis lay-out: Bibi van Bodegom & Daniëlle Korpershoek Printing: Haveka BV, Hendrik-Ido-Ambacht Copyright © 2019 by Iris Bodewes. All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means, without prior permission of the author. Interferon in Sjögren’s syndrome and other systemic autoimmune diseases: A driver of disease pathogenesis and potential treatment target Interferon bij het Syndroom van Sjögren en andere systemische auto-immuunziekten: Een sleutelrol in de pathogenese en potentieel doelwit voor behandeling Proefschrift ter verkrijging van de graad van doctor aan de Erasmus Universiteit Rotterdam op gezagProf.dr. van R.C.M.E.de rector Engels magnificus en volgens besluit van het College voor Promoties. De openbare verdediging zal plaatsvinden op woensdag 17 april 2019 om 13.30 uur Iris Louise Agaath Bodewes geboren te Breda PROMOTIECOMMISSIE Promotoren Dr. M.A. Versnel Prof.dr. P.D. Katsikis Overige leden Prof.dr. P.M. van Hagen Prof.dr. M. Wahren-Herlenius Dr. J.A.G. van Roon CONTENTS CHAPTER 1 9 General introduction Rheumatology 2019; epub ahead of print CHAPTER 2 41 Systemic interferon type I and type II signatures in primary Sjögren’s syndrome reveal differences in biological disease activity Rheumatology 2018; 57(5): 921-930 CHAPTER 3 65 Type I IFN signature in childhood-onset Systemic Lupus Erythematosus: a conspiracy of DNA- and RNA-sensing receptors? Arthritis Research & Therapy 2018; 20(4) CHAPTER 4 83 TBK1: a key regulator and potential treatment target for interferon positive Sjögren’s syndrome, systemic lupus erythematosus and systemic sclerosis Journal of Autoimmunity 2018; 91: 97-102 CHAPTER 5 97 Hydroxychloroquine treatment downregulates systemic interferon activation in primary Sjögren’s syndrome in the JOQUER randomized clinical trial Rheumatology; under review CHAPTER 6 111 Interferon activation in primary Sjögren’s syndrome: recent insights and future perspective as novel treatment target Expert Review of Clinical Immunology 2018; 14(10): 817-829 CHAPTER 7 143 Fatigue in Sjögren’s syndrome: a search for biomarkers and treatment targets. Frontiers in Immunology 2019; 10(312) CHAPTER 8 175 General discussion ADDENDUM 205 Abbreviations 206 Summary 208 Samenvatting 211 Samenvatting voor een breed publiek 214 Dankwoord/Acknowledgements 218 Curriculum Vitae 223 PhD Portfolio 224 Publications 226 Chapter 1 General Introduction Parts of this chapter were published in Rheumatology 2019 General Introduction GENERAL INTRODUCTION 1 In this thesis we study the role of interferon (IFN) and its downstream signaling pathways on the pathogenesis of several systemic autoimmune diseases, with primary Sjögren’s syndrome (pSS) being the main focus. In this chapter we introduce the immune system and describe in short how the loss of tolerance to self-proteins can lead to autoimmunity. Type I IFN activity is present in a subgroup of patients with systemic autoimmune diseases and here we describe how these IFNs are thought to contribute to the pathogenesis of systemic autoimmunity focusing on pSS. Finally, we summarize existing and new IFN targeting therapies and the latest literature on their effectivity. THE IMMUNE SYSTEM During life we are exposed to a wide variety of pathogens like viruses, bacteria and parasites. The immune system is a complex mechanism of biological structures and processes that helps to protect and eliminate these invaders. Furthermore, the immune system recognizes abnormal cells, thereby protecting us from cancer. Traditionally, the immune system is divided in an innate and adaptive arm. pathogens from entering. Examples are the skin, the enzymes in the oral cavity and the The bodies first line of defense consist of physical and chemical barriers that prevent low pH of the stomach [1]. If pathogens are able to breach these barriers, the next line of defense is activated. The innate arm of the immune system consists of a variety of different cells (such as monocytes, neutrophils, macrophages and natural killer cells) and mechanisms (complement system) which can kill the invading organism. A hallmark formation. of this type of immune response is that it is very rapid, but it lacks specificity and memory The adaptive immune response, mainly consisting of T and B cells, can recognize an almost unlimited amount of antigens and are able to form memory cells. T cells are divided in 2 major types: CD4+ T helper and CD8+ T cytotoxic cells (Tc). The CD4+ T helper (Th) subgroup can further be divided in a number of subsets including Th1, Th2, While the Tc cells are specialized in the clearing or controlling of viruses and tumors, Th17, Th9, regulatory Th cells (Treg) and some recently identified novel subsets [2]. Th cells are important for the activation and function of B cells. The primary function of B cells is to produce antibodies (immunoglobulins) [3]. These antibodies are important for the neutralization of pathogens, activation of the complement system and mediate antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis. 11 Chapter 1 Innate immune responses are necessary for the activation of adaptive immunity. One of the important cells bridging innate and adaptive immunity is the dendritic cell (DC). This cell type is an antigen-presenting cell (APC) consisting of two major subtypes, conventional DC and plasmacytoid DC (pDC). DCs are innate cells and express pattern recognition receptors (PRRs), which recognize molecular patterns foreign to the host. These patterns are evolutionary highly conserved, and are called pattern-associated molecular patterns (PAMPs) [4]. An example of a PRR family are the toll-like receptors (TLRs). This family of transmembrane receptors are located both on the cell surface and in endosomal compartments. TLRs on the surface of the host cell recognize mainly components of the cell wall of pathogens, while intracellular TLRs mainly recognize (microbial) nucleic acids. Other PRRs present in the cytoplasm are the RIG-I like (RLR) and DNA sensing receptors (DSR) sensing respectively cytosolic RNA or DNA. Triggering of PRRs by PAMPs leads to a cascade of host defense responses including the production of cytokines [5]. Additionally, PRR stimulation induces maturation of DCs and facilitates the antigen presenting function by the induction of costimulatory molecules leading to activation of adaptive immunity. AUTOIMMUNITY The immune system is a powerful mechanism to protect us from unwanted invaders, however in order to do so it is critical to distinguish self from non-self. In patients with autoimmune diseases the immune system mistakenly reacts to self-antigens, resulting in an immune response directed against the body’s own nucleic acids, proteins, cells or tissues [6]. The development of autoimmunity is multifactorial which involves amongst others a contribution of genetics and the environment. Autoimmune diseases can be one organ is affected, examples of these type of autoimmune diseases are Hashimoto’s classified in organ-specific or systemic. In organ-specific autoimmune diseases only thyroiditis, type I diabetes or Addison’s disease. Systemic autoimmune diseases affect multiple sites of the body like rheumatoid arthritis (RA), primary Sjögren’s syndrome (pSS), Systemic Lupus Erythematosus (SLE) and Systemic Sclerosis (SSc). In systemic autoimmune diseases autoreactive B and T cells directed against molecules found throughout the body like RNA and DNA are present [7]. During the development of B and T cells the body negatively selects cells that are targeting the for self-antigen. This process is called central tolerance. When autoreactive T and B body’s own tissue by deleting cells that express antigen receptors with a high affinity cells escape this selection process there are several mechanisms in the periphery to prevent reaction to self, called peripheral tolerance. Despite these selection processes 12 General Introduction autoreactive cells are increased in patients with autoimmune diseases resulting in loss of tolerance. In systemic autoimmunity often antinuclear autoantibodies (ANAs) can be 1 found. These ANAs are produced by autoreactive B cells and are directed against nuclear macromolecules and their complexes like dsDNA, small nuclear ribonucleoproteins are described. Some are strongly associated with a particular disease, while others are (snRNPs), histones or centromeres [8]. A large variety of different ANA specificities expressed more heterogeneous amongst patients. ANAs can form immune complexes (ICs), which can be deposited in multiple organs triggering vascular
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