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Mechanisms of Inflammation in Mevalonate Kinase Deficiency – Loes M Mechanisms of inflammation in mevalonate kinase deficiency – Loes M. Kuijk Mechanisms of inflammation in mevalonate kinase deficiency Loes M. Kuijk Mechanisms of inflammation in mevalonate kinase deficiency – Loes M. Kuijk ISBN: 978-90-393-4780-5 Loesje Marjan Kuijk, Universiteit Utrecht, faculteit Geneeskunde Mechanisms of inflammation in mevalonate kinase deficiency Proefschrift Universiteit Utrecht, met samenvatting in het Nederlands Cover design: Marieke van der Vaart Printed by: Ponsen & Looijen BV, Wageningen Mechanisms of inflammation in mevalonate kinase deficiency – Loes M. Kuijk Mechanisms of inflammation in mevalonate kinase deficiency Mechanismen van inflammatie in mevalonaat kinase deficiëntie (met een samenvatting in het Nederlands) Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de rector magnificus, prof. dr. J.C. Stoof, ingevolge het besluit van het college voor promoties in het openbaar te verdedigen op donderdag 29 mei 2008 des middags te 12.45 uur door Loesje Marjan Kuijk geboren op 28 juni 1977, te Roermond Mechanisms of inflammation in mevalonate kinase deficiency – Loes M. Kuijk Promotor: Prof. dr. P.J. Coffer Co-promotoren: Dr. J. Frenkel Dr. ir. G.T. Rijkers Mechanisms of inflammation in mevalonate kinase deficiency – Loes M. Kuijk “Times are bad. Children no longer obey their parents, and everyone is writing a book.” Marcus Tullius Cicero, statesman, orator and writer (106-43 BC) Voor mijn ouders Mechanisms of inflammation in mevalonate kinase deficiency – Loes M. Kuijk Commissie: Prof. dr. W. Kuis Prof. dr. A. Kummer Prof. dr. F. Miedema Prof. dr. B. Burgering De uitgave van dit proefschrift werd mede mogelijk gemaakt door financiële steun van: Amgen BV, BD Biosciences, Bristol-Meyers Squibb BV, Corning Life Sciences BV, Divisie Kinderen UMC Utrecht, Eijkman Graduate School for Immunology and Infectious Diseases, Greiner Bio-One, J.E. Jurriaanse stichting en het Reumafonds Mechanisms of inflammation in mevalonate kinase deficiency – Loes M. Kuijk Contents Chapter 1: General Introduction I 9 Episodic Autoinflammatory Disorders in Children Pediatrics in Systemic Autoimmune diseases; Handbook in Systemic Autoimmune Diseases 2008 vol. 6, p 119 General Introduction II 35 Mevalonate kinase deficiency Chapter 2: A role for geranylgeranylation in interleukin-1β secretion 45 Arthritis Rheum. 2006 vol. 54, p3690 Chapter 3: Statin synergizes with LPS to induce IL-1β release by 57 THP-1 cells through activation of caspase-1 Mol. Immunol. 2008, doi:10.1016/j.molimm.2007.12.008 Chapter 4: HMG-CoA reductase inhibition induces IL-1β release through 73 Rac1/PI3K/PKB-dependent caspase-1 activation - Rac1 as a potential target for the treatment of MKD Submitted Chapter 5: Effects of IL-1 receptor antagonism in MKD patients 95 Chapter 6: Effective treatment of a colchicine-resistant FMF patient with anakinra 121 Ann. Rheum. Dis. 2007 vol. 66, p1545 Chapter 7: General Discussion 127 Nederlandse samenvatting 141 Dankwoord 151 Curriculum Vitae 157 List of publications 159 Mechanisms of inflammation in mevalonate kinase deficiency – Loes M. Kuijk Mechanisms of inflammation in mevalonate kinase deficiency – Loes M. Kuijk Chapter 1 General Introduction I Episodic autoinflammatory disorders in children Loes M Kuijk1, Hal M Hoffman2, Bénédicte Neven3, Joost Frenkel4 1 Department of Paediatric Immunology, University Medical Centre Utrecht, Utrecht 2 Division of Rheumatology, Allergy, and Immunology, University of California, San Diego 3 Department of Paediatric hemato-immunology and rheumatology, Hôpital Necker-Enfants Malades, Paris 4 Department of Paediatrics, University Medical Centre Utrecht, Utrecht Pediatrics in Systemic Autoimmune diseases; Handbook in Systemic Autoimmune Diseases 2008 vol. 6, p 119 Mechanisms of inflammation in mevalonate kinase deficiency – Loes M. Kuijk Mechanisms of inflammation in mevalonate kinase deficiency – Loes M. Kuijk Episodic autoinflammatory disorders in children INtrODUctiON The autoinflammatory diseases are a newly recognized and expanding class of inflammatory disorders that share many features with autoimmune diseases (1). They differ significantly, however, in that autoinflammatory syndromes are characterized by an absence, not only of pathogens, but also of high titre autoantibodies and pathogenic autoreactive T cells (2). Chronic autoinflammatory diseases in childhood include systemic onset juvenile idiopathic arthritis, sarcoidosis and Blau syndrome, which fall beyond the scope of this chapter. The intermittent autoinflammatory disorders, known as periodic fever syndromes, lead to recurrent episodes of fever alternating with more or less prolonged periods of disease remission. The fever episodes are usually accompanied by additional systemic and localized inflammatory symptoms involving joints, skin, eyes or abdomen (3). Each of these disorders has unique symptoms, as well as a unique pathophysiology and treatment. Many are inherited, which has allowed for determination of the responsible genes. In the last decade, an increasing number of patients has been appropriately recognized, diagnosed and treated due to advances in the understanding of the clinical characteristics and molecular basis of these diseases. In this chapter the clinical presentation and recent progress in elucidating the underlying pathophysiology will be described for each of these disorders (4). The chapter will be concluded by a paragraph on diagnosis. Familial Mediterranean Fever (FMF) Prevalence/epidemiology Familial Mediterranean Fever (FMF; MIM#249100) is the most prevalent of the hereditary autoinflammatory diseases, probably affecting more than 100,000 patients worldwide. It is an autosomal recessive disease, affecting mostly people from the Mediterranean area, including Armenians, Arabs, Turks and Sephardic Jews. By migration it has now also spread to Northern and Western Europe, Australia and the Americas. Etiology/pathogenesis The gene affected in FMF,MEFV , encodes the protein pyrin or marenostrin (5;6). Since its discovery in 1997, more than 100 exon mutations have been described for the MEFV gene (http://fmf.igh. cnrs.fr/infevers/). The most common mutations: M680I, M694V, M694I and V726A (7) are situated within exon 10, which encodes the C-terminal B30.2 domain of the protein. The functional role of this domain is unknown. The protein further consists of a B-Box-type zinc finger, a coiled-coil domain and an N-terminal PYRIN domain. Pyrin is mainly expressed as a cytoplasmic protein in mature neutrophils and monocytes (8), and it associates with actin (9). The exact role of pyrin in the clinical manifestations of FMF has not been elucidated thus far, but the N-terminal PYRIN domain was shown to interact with a protein called apoptosis-associated specklike protein containing a CARD (ASC), whereas the carboxyterminal B30.2 can bind to caspase-1. This interaction places 11 Mechanisms of inflammation in mevalonate kinase deficiency – Loes M. Kuijk Chapter 1 pyrin upstream in a pathway regulating caspase-1 and IL-1β processing, linking it to inflammation (10-12). Clinical manifestations Most patients suffer from recurrent fever attacks, with acute monoarthritis and/or serositis, affecting the peritoneum, pleura, pericardium or scrotum. Some patients display an erysipelas- like rash (Figure 1) and a few develop chronic erosive arthritis (13-17). However, in the rare case, recurrent abdominal pain during childhood can be the only manifestation of FMF (18). Disease onset is usually in childhood, with 75-89% of patients having their first attack before the age of 20 years (14;19). Frequency of attacks can vary from several times per week to once every few months or even years. The attacks usually last 1-3 days. Figure 1: Characteristic erysipelas-like erythema in FMF. Diagnostic investigations During fever episodes serum markers of acute phase response: serum amyloid A (SAA) protein, C- reactive protein (CRP), complement and plasma fibrinogen are elevated and there is granulocytosis (20-22). Often, erythrocyte sedimentation rate (ESR) is increased. Between attacks patients are well, even though they may continue to have increased acute phase reactants. However, the prolonged elevation of SAA protein predisposes to AA systemic amyloidosis in which SAA deposition occurs in several organs leading to organ failure (16;23;24). The diagnosis can be made on clinical grounds (Table I), provided that the patient is from a population with a high prevalence of FMF (25). The response to colchicine therapy is so characteristic that it is considered a major diagnostic criterion. Genetic testing may support the diagnosis, but in up to one-third of patients one or both MEFV alleles are normal (13;17). There are no clinical diagnostic criteria validated for populations with intermediate prevalence (Greeks, Italians, Spanish) and in these, genetic testing might offer an advantage. The value ofMEFV -testing in populations with a low prevalence of FMF is limited at best (26). 12 Mechanisms of inflammation in mevalonate kinase deficiency – Loes M. Kuijk Episodic autoinflammatory disorders in children Table I: Diagnostic criteria for FMF in a population with high prevalence of the disease (25) Tel Hashomer criteria for diagnosis of Familial Mediterranean Fever Major criteria Minor criteria Recurrent fever with arthritis and/or serositis Recurrent fever attacks AA-amyloidosis in the absence of a predisposing illness Erysipelas-like erythema Favourable effect of colchicine FMF in
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