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Maturation, Reactivity and Therapy Induced Changes of Memory T-Cells Maturation, reactivity and therapy induced changes of memory T cells in rheumatic autoimmune diseases Ruth Fritsch-Stork All rights reserved. No part of this book may be reproduced or transmitted in any form of by any means, without permission from the author. Maturation, reactivity and therapy induced changes of memory T cells in rheumatic autoimmune diseases Ontwikkeling, reactiviteit en therapie geïnduceerde veranderingen van memory T cellen in reumatische auto-immuunziekten. (met een samenvatting in het Nederlands) Proefschrift ter verkrijging van de graad doctor aan de Universiteit Utrecht op gezag van de rector magnificus, prof. dr. G.J. van der Zwaan, ingevolge het besluit van het college voor promoties in het openbaar te verdedigen op dinsdag 29 april 2014 des morgens te 10:30. door Ruth Fritsch-Stork Geboren op 21 Augustus 1968 te Wenen Promotoren: prof. dr. J.W.J. Bijlsma prof. dr. F.P.J.G. Lafeber Contents Chapter 1 General introduction 1 Chapter 2 Stepwise differentiation of CD4 memory T cells defined by 19 expression of CCR7 and CD27 Chapter 3 Abnormal differentiation of memory T cells in systemic lupus 29 erythematosus Chapter 4 Characterisation of cellular and humoral autoimmune responses to 49 histone H1 and core histones in human systemic lupus erythematosus Chapter 5 The spliceosomal autoantigen heterogeneous nuclear 57 ribonucleoprotein A2 (hnRNP-A2) is a major T cell autoantigen in patients with systemic lupus erythematosus Chapter 6 Characterization of autoreactive T cells to the autoantigens 73 heterogeneous nuclear ribonucleoprotein A2 (RA33) and filaggrin in patients with rheumatoid arthritis Chapter 7 Potential predictors of glucocorticoid-response in rheumatoid 83 arthritis. A role for endoplasmic reticulum aminopeptidase 2 (ERAP2) and leucocyte-specific transcript 1 (LST1)? Chapter 8 Glucocorticoid-responsiveness correlates with an interferon 97 signature in rheumatoid arthritis patients Chapter 9 Summary and general discussion 135 Nederlandse samenvatting 157 Dankwoord / Acknowledgements 165 List of publications 171 Curriculum vitae 177 Chapter 1 General introduction 1 Immunological memory and CD4+ or CD8+ cells acquire altered capacity memory T cells: to produce cytokines, different migratory capability, and diminished activation requirements that allow them to generate an In the description of the Athenian plague by effective secondary response on rechallenge Thucydides in his “History of the with their specific Ag; in short: they become Peloponnesian War” the concept of memory cells, and are identified by the immunological memory entered the literary expression of CD45RO. world. (1) “But those that were recovered had much compassion both on them that died As memory cells are crucial in our defense and on them that lay sick, as having both against pathogens, the exact mechanisms of known the misery themselves and now no lymphocyte maturation and differentiation more subject to the danger. For this disease from naïve to terminally differentiated never took any man the second time so as to memory cells need to be fully understood. be mortal. And these men were both by Our perception of this differentiation others counted happy, and they also pathway has been influenced by a model, themselves, through excess of present joy, which distinguishes central memory T cells conceived a kind of light hope never to die of (T ) from effector memory T cells (T ) by any other sickness hereafter.“ Approximately CM EM the phenotypic expression of the cysteine 2500 years later the pathogen is still chemokine receptor (CCR) CCR7. (3; figure unknown. Some scholars suspect typhus to 1) The ligands of CCR7 are CCL19 (also be the reason for the epidemic, killing known as Epstein Barr Virus-induced approximately a third of the Athenians, molecule 1 ligand) and CCL21 (also called including their leader Pericles. (2) Similar to secondary lymphoid tissue chemokine). the characterization of the pathogen, These markers are predominantly expressed scientific comprehension of man’s by high endothelial venules (HEV) of immunological memory has deepened, and secondary lymphoid organs and parenchymal our insight is still expanding. cells of the T cell zones of lymph nodes. Through the interaction of CCR7 on T - Immunological memory is conferred by the CM cells and the respective ligands, the homing adaptive immune system, in which T cells of T cells to secondary lymphoid organs is play a central role. According to the CM achieved. (4-6) Here they can encounter their expression of glycoproteins on their cell- specific antigen, presented by antigen surface, T cells are divided into the CD4+ or presenting cells such as dendritic cells (DC). to the CD8+ lineage. Whereas the main Notably, T only show a low capacity to function of CD8+ cytotoxic T cells is the CM secrete cytokines. In contrast, CCR7- elimination of virally infected or tumorous negative T display effector functions, such cells, CD4+ helper T cells assist several other EM as vigorous cytokine production or immune cells in their tasks, among which cytotoxicity, which they can exert after their antibody (Ab)-production by B cells. T cells migration to inflamed peripheral tissue. (7) In originate in the bone marrow and mature in line with this model, an enrichment of T the thymus, where their antigen (Ag)- CM was demonstrated in tonsils, whereas most T- specificity as well as lineage commitment to cells isolated from nonlymphoid tissue such CD4+ or CD8+ T cells are determined. as the lung, skin, or intestine lacked the Thereafter they re-enter the circulation as expression of CCR7 and thus were thought to recent thymic emigrants (RTE) and be T . (8) eventually mature into naïve CD4+ or CD8+ EM T cells in the periphery. Naïve T cells are This view, however was challenged by a commonly characterized by the cell surface study showing the majority of cytokine- expression of CD45RA. After the encounter secreting human T cells to express CCR7 and of their respective specific antigen, naïve 2 thus being capable of lymphoid organ Although the division into TCM and TEM has homing. (9) Nevertheless, these authors did advanced our knowledge of lymphocyte find a higher frequency of polarized (T maturational steps, each of these subsets still helper) Th1 or Th2 cells in the CCR7- contain a mixture of different T cells. As T- negative TEM subset. Additionally, the cells, in particular CD4+ T-helper cells, are presence of “pre-Th1” and “pre-Th2” cells in able to produce an array of cytokines (i.e. the TCM compartment secreting low amounts bioactive proteins), by which they influence of interferon gamma (IFN-γ) or interleukin different parts of the immune systems, they (IL-)4, with the potential to differentiate into can also be divided according to the “key” Th1 and Th2 effector memory T cells by cytokines they produce. antigenic stimulation or in response to homeostatic cytokines, were described. (10) Figure 1: The maturation of T cells. T cells originate in the thymus, where their lineage- and antigen- specificity are determined. After migration to the blood they circulate as naïve, CCR7+CD45RA+CD45RO- cells until they encounter their antigen and become CD45RA-CD45RO+ memory T cells. These are distinguished by their expression of CCR7, a chemokine receptor. CCR7 expressing central memory cells (TCM) circulate to secondary lymphoid tissue, whereas CEM migrate to inflamed tissue. The exact relationship between them had not been fully elucidated. (see text) 3 Th1 cells, e.g., produce IFN, and hereby (19) The incidence and prevalence of SLE activate macrophages to fight intracellular varies considerably across the countries and bacteria; Th2 cells in contrast produce IL-4, were found to be the lowest in Finland IL-5 and IL-13 and contribute to the host (prevalence: 28/100,000 persons) and the UK defense against parasites. As both, Th1 and (prevalence: all races 26/100,000 persons), Th2, are implicated in pathological processes and highest in Italy (prevalence: 71/100,000 (e.g. Th1 in some autoimmune diseases and persons) and Spain (prevalence: all races Th2 in allergy), a deviation from the 91/100,000 persons). (20) SLE is programmed differentiation of these cells as characterized by a spectrum of organ therapeutic approach in certain diseases manifestations ranging from musculoskeletal seems desirable. For this purpose, a more and muco-cutaneous symptoms to life- precise knowledge of the steps toward threatening involvement of kidney, brain or terminal differentiation is of importance. lung. The 5-year survival of SLE patients has improved in the past few decades from less In the attempt to find surface markers for than 50% in the 1950s to more than 90% in different developmental stages of T cells, the 1990s. (21,22) phenotypic expression of some co- stimulatory molecules has been employed. The diagnosis of SLE is based on the One of these is CD27, a member of the tumor presence of clinical symptoms and laboratory necrosis factor receptor (TNFR) family, parameters, which were defined in American which is expressed by naive CD4+ and College of Rheumatology (ACR) criteria. CD8+ T cells as well as by most memory T- (22,23) Although drafted as classification- cells. (11-13) Initial up-regulation of CD27 criteria, they are widely used as diagnostic expression upon T cell receptor (TCR) tools among rheumatologists and achieve a engagement is followed by irreversible loss sensitivity of 89% and a specificity of around of this surface molecule after repeated 90% for the diagnosis of SLE. (24) antigenic stimulation. (14-15) The loss of CD27 correlates with an increase of IL-4 The etiology of SLE is multifactorial, production and the accumulation of these including genetic, hormonal, immunologic, cells has been reported in patients with and environmental influences. However, the chronic allergic diseases or rheumatoid precise mechanisms remain elusive. A arthritis, and ageing. (13,16) prominent role is ascribed to a dys-regulated apoptosis and clearance of apoptotic Although the combination of CCR7 and material.
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