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Assessment of the Humoral Immune System in Adults with Respiratory Tract Disease

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Assessment of the Humoral Immune System in Adults with Respiratory Tract Disease Assessment of the humoral immune system in adults with respiratory tract disease Diana van Kessel Assesment of the humoral immune system in adults with respiratory tract disease D.A. van Kessel Thesis University Utrecht, the Netherlands ISBN: 978-94-90329-35-8 NUR: 870 Cover illustration: Henk ten Have, Zoelen, the Netherlands Cover design and lay-out: emjee | grafische vormgeving, Varik, the Netherlands Print: Veldhuis Media BV, Raalte, the Netherlands © 2017, D.A. van Kessel All rights are reserved. No part of this publication may be reproduced without written permission of the author. The copyright of articles that already have been published has been transferred to the respective journals. Assessment of the humoral immune system in adults with respiratory tract disease Evaluatie van het humorale afweersysteem bij volwassenen met een aandoening van de ademhalingswegen (met een samenvatting in het Nederlands) Proefschrift ter verdediging van de graad van 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 7 november 2017 des middags te 12.45 uur door Dirkje Anna van Kessel geboren op 13 december 1955 te Culemborg Promotoren: Prof.dr. J.C. Grutters Prof.dr. G.T. Rijkers Copromotor: Dr. P. Zanen Paranimfen: Thijs Hoffman Joost Jacobs Dedicated to Frans Jozef†, Isabelle en Joost Jacobs Table of contents Chapter 1: General introduction, aims and outline of the thesis 3 Part I: Immunological screening of patients with 21 recurrent respiratory tract infections Chapter 2: Response to pneumococcal vaccination in mannose- 23 binding lectin-deficient adults with recurrent respiratory tract infections Chapter 3: Clinical and immunological evaluation of patients 39 with mild IgG1 deficiency Chapter 4: Impaired pneumococcal antibody response in patients 53 with bronchiectasis of unknown aetiology Part II: Immune status in patients before and after lung 71 transplantation Chapter 5: Immune status assessment in adult lung transplants 73 candidates Chapter 6: Long-term follow up of humoral immune status in 85 adult lung transplant recipients Part III: Antibody replacement therapy in patients with 101 humoral immunodeficiency Chapter 7: Antibody replacement therapy in primary antibody 103 deficiencies and iatrogenic hypogammaglobulinemia Chapter 8: Long-term clinical outcome of antibody replacement 131 therapy in humoral immunodeficient adults with respiratory tract infections Part IV: Remarkable clinical cases 153 Chapter 9: Defective antibody response against pneumococcal 155 polysaccharide serotype 9V in a patient with a single episode of pneumonia Chapter 10: An unusual presentation of severe 163 hypogammaglobulinemia Chapter 11: Summary and general discussion 181 Chapter 12: Nederlandse samenvatting 195 Dankwoord 209 Curriculum vitae 213 CHAPTER 1 General introduction, aims and outline of the thesis General introduction, aims and outline of the thesis 5 1. Introduction The lung is a vital organ that is in constant contact with the outside world. This causes life-long continuous exposure to potential pathogenic microorganisms. Recurrent respiratory tract infections are a common complaint in the daily clini cal practice at the outpatient pulmonology department. This can have var- ious causes but importantly it is also the most common presentation of a pri- mary immunodeficiency.1-4 Long-term complications of primary immunodeficiency include bronchiecta- sis, immune-mediated diseases such as granulomatous-lymphocytic intersti- tial lung disease and lymphoma5-7 It is therefore important for the clinician to recognize this possible cause of recurrent respiratory tract infections, so that treatment can be started early and complications can be prevented. Normally, there are several defence mechanisms that protect the respiratory system against infections.8, 9 The first line of defence is formed by the mucosa itself. This compromises the internal body surfaces that are lined by a mu- cus-secreting epithelium, including the upper and lower respiratory tract. The mucociliary system of the respiratory tract forms a mechanical, biochemical and biological barrier for microorganisms. The epithelial cells lining the airways can secrete host-defence proteins that increase the efficacy of the immune sys- tem in clearing pathogens from the respiratory tract.10 1.1 Immunological defences of the lung 1.1.1 Innate immunity The immune system can be divided into innate and adaptive immunity (Figure 1). The innate immune system is a fast reacting system, recognizing molecular patterns on microorganisms with limited or no immunologic memory.8 It has a cellular and humoral component. The cellular component consists of phago- cytes like monocytes, macrophages and granulocytes. These cells recognize pathogens through pattern recognition receptors on the membrane. The hu- moral component consists of several circulating proteins like lactoferrin, de- fensins, collectins and an elaborate system of different cytokines, as well as the complement system. 6 Chapter 1 Figure 1. The immune system can be divided into innate and adaptive immunity. On encountering a pathogen, both an innate and an adaptive immune response will be mounted in the host. The main function of the complement system is to neutralize and/or kill micro- organisms.8 The complement system can be activated through 3 pathways: the classical pathway, the lectin pathway and the alternative pathway (Figure 2). The classical pathway is activated by antibodies. Complement factor 1 (C1) binds to antibodies on pathogen surfaces. C1 then activates complement factors further downstream in the complement cascade. The lectin pathway is activated by mannose binding lectin (MBL) and ficolins, both soluble pattern recognition molecules. MBL and ficolins bind to mannose-containing or other carbohydrates on the surface of yeast and encapsulated bacteria, such as pneumococci. The al- ternative pathway works through low-level spontaneous activation. Spontane- ously activated complement factor C3 can also bind to pathogen surfaces. Activation of the complement system is mostly through the classical pathway. But, against microorganisms with repetitive carbohydrate structures on their surface, the lectin pathway can also be used for complement activation. The al- ternative pathway functions mainly as an amplifying loop for the classical and lectin pathways.8 Interestingly, in the MBL2 gene, the gene that encodes the MBL protein, a number of genetic polymorphisms can be found. Some of these variants have functional consequences. Patients carrying these polymorphisms have decreased serum levels of MBL. Polymorphisms leading to very low or ab- sent circulating MBL can be found in 10-25% of the population.11 The reason for General introduction, aims and outline of the thesis 7 the high prevalence of these polymorphisms is not yet known. The association between decreased MBL levels and the risk of infections with encapsulated bac- teria is still unclear.12 Figure 2. The complement system can be divided in three pathways. Activation of the complement system can be initiated via the classical, MBL, and alternative pathway. For the classical pathway, when IgG or IgM is bound to surface antigens on microorganisms, a C1q molecule can be recruited to the Fc region of the antibody. C1s and C1r bind to C1q becoming an enzymatic active com- plex that causes cleavage of C4 and C2 into C4a and C4b and C2a and C2b, respectively. C4b associates with C2a on the pathogen surface, and this complex functions as a C3 convertase. C3 is cleaved into C3a and C3b. C3a is released from the site and act as a soluble factor, whereas C3b, when bound to complement factor B (which is activated by complement factor D), remains bound to the pathogen surface. C3b then activates complement proteins that are further downstream in the complement cascade, causing the for- mation of the so-called membrane-attack complex (MAC). The MAC creates holes in the pathogen mem- brane, causing death of the pathogen by lysis. The MBL pathway (representing the lectin pathway in this Figure) can be initiated by binding of MBL to mannose containing carbohydrates on bacteria or viruses. Bound MBL then complexes with the MBL-associated serine protease (MASP), which has similar functiona- lity as the C1q-C1r-C1s complex. The MASP-complex can activate C2 and C4, further initiating the same cascade as described above for the classical pathway. The alternative pathway is initiated when a sponta- neously activated C3 molecule binds to the surface of a pathogen. The C3b molecule itself can function as a C3 convertase as well, causing low level activity when spontaneously activated and amplifying the res- ponse when the classical or lectin pathways are activated. Figure and legend based on Leerboek immuno- logie8 (page 33 and 35). 8 Chapter 1 1.1.2 Adaptive immunity The cellular component of the adaptive immune system consists of lympho- cytes and antigen presenting cells.8 (Figure 3) There are two major groups: T- and B-lymphocytes. These cells are characterized by the presence of T- or B-cell receptors on their surface. These receptors are highly polymorphic, and each T- or B-cell that is produced in the thymus or bone marrow, respectively, has a different receptor. These receptors form the binding sites for antigens, either autoantigens or alloantigens. In the normal selection process within the thy- mus and bone marrow, most T- and B-cells
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