DOCSLIB.ORG

“The Molecular Mechanisms of Complement Evasion by Asexual Blood Stages and Infective Sporozoites of Plasmodium Falciparum”

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
“The Molecular Mechanisms of Complement Evasion by Asexual Blood Stages and Infective Sporozoites of Plasmodium Falciparum” “The molecular mechanisms of complement evasion by asexual blood stages and infective sporozoites of Plasmodium falciparum” Von der Fakultät für Mathematik, Informatik und Naturwissenschaften der RWTH Aachen University zur Erlangung des akademischen Grades eines Doktors der Naturwissenschaften genehmigte Dissertation vorgelegt von Thiago Ferreira de Araujo Rosa, M.Sc from Campina Grande, Brazil Supervision: Univ.-Prof. Dr. phil. nat. Gabriele Pradel Univ.-Prof. Dr. rer. nat. Lothar Rink Tag der mündlichen Prüfung: 04. Juli 2018 Diese Dissertation ist auf den Internetseiten der Universitätsbibliothek online verfügbar. Statutory declaration Hereby I declare on oath that I have the present dissertation with the title “The molecular mechanisms of complement evasion by asexual blood stages and infective sporozoites of Plasmodium falciparum” is the result of my own work. I did not receive any help and all sources and / or materials applied are listed and specified in the thesis. _______________________ _________________________ City, Date Thiago Ferreira de Araujo Rosa Acknowledgement At first, I would like to thank Prof. Dr. Gabriele Pradel for giving me the opportunity to develop my doctorate studies in her laboratory. The environment provided and her guidance helped to become a different person and a better professional. I am very grateful for the opportunity to work in my own way and the possibility to incorporate my ideas in my studies. I am very thankful for Prof. Dr. Lothar Rink for the acceptance as a second referee in this thesis. My sincere thanks go to collaborators Prof. Dr. Christine Skerka and Prof Dr. Peter Zipfel for all the support and suggestions given during the development of my studies. Similarly, I would like to thank Prof. Dr. Marcelo Jacobs-Lorena and Dr. Joel Vega-Rodriguez for the support, encouragement and suggestions given in order to develop my thesis and to make me a better scientist. I owe my deepest gratitude to my colleague Dr. Che Julius Ngwa who invested his time to guide me through my journey in complement system and malaria researches. His support and honest words were essentials to the development of this thesis. My heartfelt thanks also go to the students who developed their studies and dissertations in the project of complement evasion by malaria parasites. So many thanks Ansgar Flammersfeld, Janine Wenker, Martin Kochem, Frederick Huppertz, Loana Epping, Rebecca Bobbert and Timo Reiss. You all taught me a lot. I also wish to express my sincerest thanks for the help and encouragement to Tim Weissbach (RiTimTim), Dr. Christine Wirth (CC Wirth) and Dr. Andreas von Bohl (Dedé) who supported me during the first years in Germany. I truly respect them as professionals but also as great friends. Furthermore I would like to thank Alexandra Golzmann for constant support, her help and friendship. I highly appreciate Christine Böhme and Elke Wilden for all the bureaucratic work needed for the development of my studies and trips. I also thank all members of Pradel’s group, in special Emilie Njila, Meike Kiesow, Sandra Bennink and Dr. Martin Singheiser. My studies and stay in Germany would not be possible without the support of my German family, so many thanks Markus Breuer, Mohammed Sharaf, Michael Buenten, Dirk Meyle, Frau Inge Meyle and Frank Buettner for being by my side these four years. Similarly, many thanks to my family back in Brazil, in special to my big brother Wagner, who is so proud of me without knowing exactly what I do. LOL Finally, my biggest thanks go to my parents, heroes and best friends, Nerildo Rosa and Gilene F. de A. Rosa who support in everything I proposed myself to do. I am lucky. Table of contents List of figures………………………………………………………………………………………………………….i List of tables…………………………………………………………………………………………………………..iii Summary……………………………………………………………………………………………………………....iv Kurzdarstellung……………………………………………………………………………………………………......vi 1. Introduction…………………………………………………………………………………………………...1 1.1. Malaria…………………………………………………………………………………………………...1 1.2. Plasmodium falciparum………………………………………………………………………………….4 1.3. Immune response to Malaria…………………………………………………………………………….7 1.4. The human complement system………………………………………………………………………..10 1.4.1. Complement system activation……………………………………………………………….10 1.4.2. Regulation of the complement system………………………………………………………..13 1.5. Factor H family proteins………………………………………………………………………………..15 1.6. Strategies of complement regulation by pathogens…………………………………………………….21 1.6.1. Acquisition of host inhibitors by pathogens promotes complement evasion…………………21 1.6.2. Microbial proteins involved in complement evasion………………………………………...24 1.6.3. Fibrinolytic protease Plasmin as an inhibitor of the complement system…………………….25 1.7. The complement system and malaria…………………………………………………………………..27 1.8. Aim of the study……………………………………………………………………………………….30 2. Materials and Methods……………………………………………………………………………………..32 2.1. Materials……………………………………………………………………………………………….32 2.1.1. Instruments……………………………………………………………………………………...32 2.1.2. Consumables…………………………………………………………………………………….33 2.1.3. Chemicals..............................................................................................................................…...34 2.1.4. Antibodies and antisera………………………………………………………………………….34 2.1.5. Purified and recombinant proteins and peptides………………………………………………...36 2.1.6. Protein ladder……………………………………………………………………………………37 2.1.7. Miscellaneous materials…………………………………………………………………………37 2.1.8. Kits………………………………………………………………………………………………38 2.1.9. Bioinformatic Sources and Computer Programs…………………………………………….….38 2.1.10. Parasite lines and mosquitos…………………………………………………………………...38 2.1.11. Buffers, media and solutions…………………………………………………………………..39 2.2. Methods………………………………………………………………………………………………...42 2.2.1. Cell biology……………………………………………………………………………………...42 2.2.1.1. Culture of Plasmodium falciparum…………………………………………………….42 2.2.1.2. Freezing and thawing of P. falciparum cultures………………………………………..43 2.2.1.3. Determination of parasitemia and gametocytemia……………......................................44 2.2.1.4. Synchronization and percoll purification of P. falciparum asexual stage…………...…46 2.2.1.5. Purification of P. falciparum infective stage sporozoites………………………………48 2.2.1.6. Pig erythrocyte lysis assay……………………………………………………………...48 2.2.1.7. P. falciparum replication assay…………………………………………………………49 2.2.1.8. Gametocytogenesis assay………………………………………………………………49 2.2.1.9. Gelatin flotation purification…………………………………………………………...50 2.2.1.10. Microwell adhesion assay……………………………………………………………..50 2.2.1.11. Merozoite invasion assay……………………………………………………………...51 2.2.1.12. Indirect immunofluorescence assay…………………………………………………...51 2.2.2. Protein biochemical methods……………………………………………………………………52 2.2.2.1. SDS polyacrylamide gel electrophoresis..................................................................…...52 2.2.2.2. Western blot analysis…………………………………………………………………...53 2.2.2.3. Cofactor activity assay………………………………………………………………….54 2.2.2.4. ELISA for terminal complement complex detection…………………………………...54 2.2.2.5. Competition assay………………………………………………………………………55 2.2.2.6. Deposition assay………………………………………………………………………..55 2.2.2.7. Complement cleavage assay……………………………………………………………56 2.2.2.8. FH deletion mutants binding assay……………………………………………………..56 3. Results……………………………………………………………………………………………………….57 3.1. Effect of human complement system on the survival of Plasmodium falciparum…………………….57 3.2. Effect of human complement system components on the viability of Plasmodium falciparum………62 3.2.1. The deposition of complement components on Plasmodium falciparum surface……………62 3.2.2. Recruitment of complement regulators by asexual blood stage of Plasmodium falciparum…67 3.2.3. Factor H interaction to P. falciparum membrane is knob-independent………………………73 3.3. The role of plasmin(ogen) during complement evasion by Plasmodium falciparum……………….....76 3.3.1. The binding of plasmin(ogen) to asexual blood stages……………………………………….76 3.3.2. Plasmin-mediated complement C3b degradation on the parasite surface…………………….79 3.4. Factor H-related proteins and their role in complement evasion by malaria parasites………………...81 3.4.1. Factor H-related proteins 1 and 3 binding to asexual stages of P. falciparum…………………..81 3.4.2. The effect of FHR-1 binding during complement evasion by Plasmodium falciparum sexual stages…………………………………………………………………………………………………...85 3.5. Effect of complement system and its components on Plasmodium falciparum infective stage ……....90 3.5.1. Complement C3b deposition and MAC on sporozoite surface……………………………….90 3.5.2. The recruitment of FH and its effect on sporozoite surface…………………………………..92 3.5.3. The role of plasminogen on the surface of Plasmodium falciparum sporozoites…………….94 4. Discussion…………………………………………………………………………………………………...96 4.1. The effect of human complement on the viabily of P. falciparum asexual blood stages………………97 4.2. Recruitment of complement factor H by Plasmodium falciparum asexual blood stages……………..100 4.3. The role of plasmin(ogen) during complement evasion by P. falciparum……………………………103 4.4. The role of factor H-related protein 1 during complement evasion by malaria parasites…………….105 4.5. Complement evasion mechanisms of Plasmodium falciparum sporozoites…………………………..107 5. Conclusion…………………………………………………………………………………………………109 6. Future perspectives………………………………………………………………………………………...110 7. References………………………………………………………………………………………………….112 8. Abbreviations………………………………………………………………………………………………129 9. List of Publication………………………………………………………………………………………….130
Load more

Recommended publications
  • WO 2016/147053 Al 22 September 2016 (22.09.2016) P O P C T
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2016/147053 Al 22 September 2016 (22.09.2016) P O P C T (51) International Patent Classification: (71) Applicant: RESVERLOGIX CORP. [CA/CA]; 300, A61K 31/551 (2006.01) A61P 37/02 (2006.01) 4820 Richard Road Sw, Calgary, AB, T3E 6L1 (CA). A61K 31/517 (2006.01) C07D 239/91 (2006.01) (72) Inventors: WASIAK, Sylwia; 431 Whispering Water (21) International Application Number: Trail, Calgary, AB, T3Z 3V1 (CA). KULIKOWSKI, PCT/IB20 16/000443 Ewelina, B.; 31100 Swift Creek Terrace, Calgary, AB, T3Z 0B7 (CA). HALLIDAY, Christopher, R.A.; 403 (22) International Filing Date: 138-18th Avenue SE, Calgary, AB, T2G 5P9 (CA). GIL- 10 March 2016 (10.03.2016) HAM, Dean; 249 Scenic View Close NW, Calgary, AB, (25) Filing Language: English T3L 1Y5 (CA). (26) Publication Language: English (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (30) Priority Data: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, 62/132,572 13 March 2015 (13.03.2015) US BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, 62/264,768 8 December 2015 (08. 12.2015) US DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, [Continued on nextpage] (54) Title: COMPOSITIONS AND THERAPEUTIC METHODS FOR THE TREATMENT OF COMPLEMENT-ASSOCIATED DISEASES (57) Abstract: The invention comprises methods of modulating the complement cascade in a mammal and for treating and/or preventing diseases and disorders as sociated with the complement pathway by administering a compound of Formula I or Formula II, such as, for example, 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)- 5,7-dimethoxyquinazolin-4(3H)-one or a pharmaceutically acceptable salt thereof.
    [Show full text]
  • Molecular Characterization of Gcc8 Alpha, the Functional Homologue Of
    Florida International University FIU Digital Commons FIU Electronic Theses and Dissertations University Graduate School 6-17-2010 Molecular characterization of GcC8 alpha, the functional homologue of human C8 alpha in the shark, Ginglymostoma cirratum Lydia Tatiana Aybar Florida International University DOI: 10.25148/etd.FI14032381 Follow this and additional works at: https://digitalcommons.fiu.edu/etd Part of the Biology Commons Recommended Citation Aybar, Lydia Tatiana, "Molecular characterization of GcC8 alpha, the functional homologue of human C8 alpha in the shark, Ginglymostoma cirratum" (2010). FIU Electronic Theses and Dissertations. 1350. https://digitalcommons.fiu.edu/etd/1350 This work is brought to you for free and open access by the University Graduate School at FIU Digital Commons. It has been accepted for inclusion in FIU Electronic Theses and Dissertations by an authorized administrator of FIU Digital Commons. For more information, please contact [email protected]. FLORIDA INTERNATIONAL UNIVERSITY Miami, Florida MOLECULAR CHARACTERIZATION OF GcC8 ALPHA, THE FUNCTIONAL HOMOLOGUE OF HUMAN C8 ALPHA IN THE SHARK, GINGLYMOSTOMA CIRRATUM A thesis submitted in partial fulfillment of the requirements for the degree of MASTER OF SCIENCE in BIOLOGY by Lydia Tatiana Aybar 2010 To: Dean Kenneth Furton College of Arts and Sciences This thesis, written by Lydia Tatiana Aybar, and entitled Molecular Characterization of GcC8 alpha, the Functional Homologue of Human C8 alpha in the Shark, Ginglymostoma cirratum, having been approved in respect to style and intellectual content, is referred to you for judgment. We have read this thesis and recommend that it be approved. Sylvia L. Smith Dong-Ho Shin Charles H\ Nigger, Major Professor Date of Defense: June 17, 2010 The thesis of Lydia Tatiana Aybar is approved.
    [Show full text]
  • Longitudinal Assessment of Complement Components C3, C4
    University of Connecticut OpenCommons@UConn SoDM Masters Theses School of Dental Medicine June 1983 Longitudinal Assessment of Complement Components C3, C4, and B and Their leC avage Products in Gingival Fluid Before and After Treatment of Chronic periodontitis in Humans Christine Elizabeth Niekrash Follow this and additional works at: https://opencommons.uconn.edu/sodm_masters Recommended Citation Niekrash, Christine Elizabeth, "Longitudinal Assessment of Complement Components C3, C4, and B and Their leC avage Products in Gingival Fluid Before and After Treatment of Chronic periodontitis in Humans" (1983). SoDM Masters Theses. 97. https://opencommons.uconn.edu/sodm_masters/97 LONGITUDINAL ASSESSMENT OF COMPLEMENT COMPONENTS C3, C4 AND B AND "-EIR CLEAVAGE PRODUCTS IN GINGIVd] FLUID BEFORE AND AFTER TREATMENT OF CHRONIC PERIODONTITIS IN HUMS Christine Elizabeth Niekrash ScaB., Brown University, 1975 D.M.D., University of Connecticut, 1981 A Thesis Submitted in Partial Fulfillment of the Requirements for the Degree of Master of Dental Science at The University of Connecticut 1983 APPROVAL PAGE Masters o Dental Science Thesis LONGITUDINAL ASSESSMENT OF COMPLEMENT COMPONENTS C3, C4, AND B AND THEIR CLEAVAGE PRODUCTS IN GINGIVAL FLUID BEFORE AND AFTER TREATMENT OF CHRONIC PERIODONTITIS IN HUMANS Presented by Christine Elizabeth Niekrash, Sc.B., D.M.D. The University of Connecticut 1983 ii ACKN_GNTS This research effort would not have been possible without the guidance and support of Dr. Mark R. Patters. His excellence as a teacher and his high standards were properly balanced by a superb sense of humor and a deep friendship. It was a rewarding and pleasurable experience to have worked with him. I am also grateful to Dr.
    [Show full text]
  • "Complement System and Its Role in Immune
    Complement System and Introductory article Its Role in Immune Article Contents . Introduction Responses . Complement Activation Pathways . Phylogeny of the Complement System . Complement Effector Functions Katerina Oikonomopoulou, University of Pennsylvania, School of Medicine, . Regulatory Proteins of Complement Activation Philadelphia, Pennsylvania, USA . Complement Dysregulation in Clinical Settings Edimara S Reis, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania, USA . Complement Therapeutics John D Lambris, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania, Online posting date: 15th August 2012 USA Based in part on the previous version of this eLS article ‘Complement’ (2005) by M Claire H Holland and John D Lambris. The complement system is a network of more than 50 first-line defence against microbial invaders (for review plasma proteins and receptors, which have the role of see Refs. (Ricklin et al., 2010; Lambris et al., 2008)). mediating innate and adaptive host defence mechanisms, As early suspected, complement also contributes to whereas they also participate in various (patho)physio- humoral immune responses by potentiating the production of antibodies and B cell memory (Carroll, 2008). Later logical processes. The primary functions mediated by studies suggested that complement has additional nonin- complement proteins include phagocytosis of foreign flammatory roles participating in several physiological elements (bacteria, viruses, particles etc.), cell lysis, processes, such
    [Show full text]
  • A Dissertation Entitled Role of Complement Regulatory Protein
    A Dissertation entitled Role of Complement Regulatory Protein Properdin in Complement Activation on Platelets and in the Formation of Platelet-Leukocyte Aggregates by Gurpanna Saggu Submitted to the Graduate Faculty in partial fulfillment of the requirements for the Doctor of Philosophy Degree in Biomedical Sciences ___________________________________________________ Viviana P. Ferreira, D.V.M., Ph.D., Committee Chair ___________________________________________________ Stanislaw Stepkowski, D.V.M., Ph.D., Committee Member ___________________________________________________ R. Mark Wooten, Ph.D., Committee Member ___________________________________________________ Z. Kevin Pan, M.D., Ph.D., Committee Member ___________________________________________________ Guillermo Vazquez, Ph.D., Committee Member ___________________________________________________ Patricia R. Komuniecki, Ph.D., Dean College of Graduate Studies The University of Toledo May, 2014 Copyright 2014, Gurpanna Saggu This document is copyrighted material. Under copyright law, no parts of this document may be reproduced without the expressed permission of the author. An Abstract of Role of Complement Regulatory Protein Properdin in Complement Activation on Platelets and in the Formation of Platelet-Leukocyte Aggregates by Gurpanna Saggu Submitted to the Graduate Faculty in partial fulfillment of the requirements for the Doctor of Philosophy Degree in Biomedical Sciences University of Toledo, May 2014 Patients with inflammatory cardiovascular disease have an increased number
    [Show full text]
  • Complement in Human Disease
    Clinical and Developmental Immunology Complement in Human Disease Guest Editors: Michael A. Flierl, Daniel Rittirsch, Markus S. Huber-Lang, and Philip F. Stahel Complement in Human Disease Clinical and Developmental Immunology Complement in Human Disease Guest Editors: Michael A. Flierl, Daniel Rittirsch, Markus S. Huber-Lang, and Philip F. Stahel Copyright © 2013 Hindawi Publishing Corporation. All rights reserved. This is a special issue published in “Clinical and Developmental Immunology.” All articles are open access articles distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Editorial Board B. Dicky Akanmori, Ghana H. Inoko, Japan G. Opdenakker, Belgium R. Baughman, USA David Kaplan, USA Ira Pastan, USA Stuart Berzins, Australia W. Kast, USA Berent Prakken, The Netherlands Bengt Bjorksten, Sweden Taro Kawai, Japan Nima Rezaei, Iran K. Blaser, Switzerland Michael H. Kershaw, Australia Clelia M. Riera, Argentina Federico Bussolino, Italy Hiroshi Kiyono, Japan Luigina Romani, Italy Nitya G. Chakraborty, USA Shigeo Koido, Japan Aurelia Rughetti, Italy Robert B. Clark, USA Guido Kroemer, France Takami Sato, USA Mario Clerici, Italy H. Kim Lyerly, USA Senthamil R. Selvan, USA Edward P. Cohen, USA Enrico Maggi, Italy Naohiro Seo, Japan Robert E. Cone, USA Stuart Mannering, Australia E. M. Shevach, USA Nathalie Cools, Belgium Eiji Matsuura, Japan George B. Stefano, USA Mark J. Dobrzanski, USA C. J. M. Melief, The Netherlands Trina J. Stewart, Australia Nejat Egilmez, USA Jiri Mestecky, USA Helen Su, USA Eyad Elkord, UK C. Morimoto, Japan Jacek Tabarkiewicz, Poland Steven E. Finkelstein, USA Hiroshi Nakajima, Japan Ban-Hock Toh, Australia Richard L.
    [Show full text]
  • Mjusko THESIS APPROVED
    Complement evasion strategies of human pathogens - the evolutionary arms race Jusko, Monika 2014 Link to publication Citation for published version (APA): Jusko, M. (2014). Complement evasion strategies of human pathogens - the evolutionary arms race. Protein Chemistry, Lund University. Total number of authors: 1 General rights Unless other specific re-use rights are stated the following general rights apply: Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal Read more about Creative commons licenses: https://creativecommons.org/licenses/ Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. LUND UNIVERSITY PO Box 117 221 00 Lund +46 46-222 00 00 Download date: 09. Oct. 2021 Complement Evasion Strategies of Human Pathogens The evolutionary arms race Monika Jusko Department of Laboratory Medicine Malmö Division of Medical Protein Chemistry Faculty of Medicine, Lund University
    [Show full text]
  • Preparation and Evaluation of Immunoglobulin Free Sera for Biomaterial-Induced Complement Activation Studies
    School of Natural Sciences Degree project work Preparation and Evaluation of Immunoglobulin Free Sera for Biomaterial-Induced Complement Activation Studies Nadia Vickius Subject: Biomedical Science Level: Advanced level Nr: 2010:BV2 Preparation and Evaluation of Immunoglobulin Free Sera for Biomaterial-Induced Complement Activation Studies Nadia Vickius Degree Project Work, Biomedicine 30 ECTS Master of Science Supervisor: Prof. Kristina Nilsson Ekdahl School of Natural Sciences Linnaeus University SE-391 82 KALMAR SWEDEN Examiner: Prof. Bengt Persson School of Natural Sciences Linnaeus University SE-391 82 KALMAR SWEDEN The Degree Project Work is included in the Study programme Biomedical Chemistry 240 ECTS Abstract As the need for and usage of biomaterials in medicine constantly increase, so do the requirements for increased biocompatibility and hemocompatibility. Initially in blood- biomaterial interactions, the surface of an implanted biomaterial is enclosed with adsorbed host proteins and the composition of the adsorbed protein layer depends mainly on the physical-chemical properties of the biomaterial. It is known that the adsorption of proteins on the biomaterial surface may be followed by conformational changes of the adsorbed proteins and subsequent activation of the complement system. For example, binding of complement component C1q to IgG and IgM associated with biomaterial surfaces mediates complement classical pathway activation. The aim of this degree project work was to prepare and evaluate IgG and IgM free sera with functional complement activity for complement activation studies. Further complement studies necessitated IgG and IgM free sera, since two novel polymers with different compositions needed evaluation regarding their ability to induce antibody-independent complement classical pathway activation.
    [Show full text]
  • Uva-DARE (Digital Academic Repository)
    UvA-DARE (Digital Academic Repository) Assessment of complement activation in human disease Wouters, D. Publication date 2008 Link to publication Citation for published version (APA): Wouters, D. (2008). Assessment of complement activation in human disease. General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl) Download date:24 Sep 2021 General Introduction Chapter 1 General Introduction 9 Chapter 1 The complement system As a major effector mechanism, the complement system plays a central role in innate immunity. It consists of more than 30 plasma- and membrane bound proteins constituting a first line of defence against many pathogens (1, 2). The importance of complement is illustrated by the fact that patients with complement deficiencies show an increased predisposition for infections and auto-immune disease.
    [Show full text]
  • Initiation and Regulation of Complement During Hemolytic Transfusion Reactions
    Hindawi Publishing Corporation Clinical and Developmental Immunology Volume 2012, Article ID 307093, 12 pages doi:10.1155/2012/307093 Review Article Initiation and Regulation of Complement during Hemolytic Transfusion Reactions Sean R. Stowell,1 Anne M. Winkler,1 Cheryl L. Maier,1 C. Maridith Arthur,2 Nicole H. Smith,3 Kathryn R. Girard-Pierce,1 Richard D. Cummings,2 James C. Zimring,4 and Jeanne E. Hendrickson1, 3 1 Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA 2 Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA 3 Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University, Atlanta, GA 30322, USA 4 Puget Sound Blood Center Research Institute, Seattle, WA 98102, USA Correspondence should be addressed to Jeanne E. Hendrickson, [email protected] Received 7 July 2012; Accepted 7 September 2012 Academic Editor: Michael A. Flierl Copyright © 2012 Sean R. Stowell et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Hemolytic transfusion reactions represent one of the most common causes of transfusion-related mortality. Although many factors influence hemolytic transfusion reactions, complement activation represents one of the most common features associated with fatality. In this paper we will focus on the role of complement in initiating and regulating hemolytic transfusion reactions and will discuss potential strategies aimed at mitigating or favorably modulating complement during incompatible red blood cell transfusions. 1. Introduction discoveries provided the first example of significant poly- morphisms within the human population long before DNA As pathogens began to evolve elaborate antigenic structures was recognized as the molecular basis of inheritance [5– to avoid innate immunity, vertebrates evolved an equally im- 8].
    [Show full text]
  • Membrane Attack and Therapy in Autoimmune Disease: Modulating Pathology Whilst Retaining Physiology
    Membrane attack and therapy in autoimmune disease: modulating pathology whilst retaining physiology By Marieta Milkova Ruseva A thesis submitted to Cardiff University in Candidature for the Degree of Doctor of Philosophy. Department of Infection, Immunity and Biochemistry, School of Medicine, Cardiff University, Cardiff Wales, United Kingdom December 2010 UMI Number: U564B00 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. Dissertation Publishing UMI U564300 Published by ProQuest LLC 2013. Copyright in the Dissertation held by the Author. Microform Edition © ProQuest LLC. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 DECLARATION This work has not previously been accepted in substance for any degree and is not concurrently submitted in candidature for any degree. Signed... Date JS,. 93; M i / ........... STATEMENT 1 This thesis is being submitted in partial fulfillment of the requirements for the degree of PhD. Signed .. Date . l . i .......... STATEMENT 2 This thesis is the result of my own independent work/investigation, except where otherwise stated. Other sources are acknowledged by explicit references. Signed .. Date . Q??:pU?.. i i ............. STATEMENT 3 I hereby give consent for my thesis, if accepted, to be available for photocopying and for inter-library loan, and for the title and summary to be made available to outside organisations.
    [Show full text]
  • Immunochemistry and Immunobiology of the Complement System
    THE JOURNAL OF INVESTIGATIVE DERMATOLOGY, 67: 346-353. 1976 Vol. 67 , No.3 Copyright © 1976 by The Williams & Wilkins Co. Printed in U.S.A. IMMUNOCHEMISTRY AND IMMUNOBIOLOGY OF THE COMPLEMENT SYSTEM IRMA GIGLI, M.D. Departments of Dermatology and Medicine, Irvington House Institute, New York University School of Medicine, New York , New York, U.S.A. The complement system, a complex mixture of centrations in blood and in their physicochemical at least 15 sequentially activated plasma proteins, characteristics (Tab.). constitutes one of the primary effector systems of immunologically induced inflammatory reactions. The First Component (Cl) The proteins are present in plasma in nonactivated form. Activation is by a series of specific proteo­ The first component of the classic pathway is present in its inactivated form as a calcium­ lytic reactions, which can be initiated by dependent macromolecular complex of three sub­ antigen-antibody complexes, fungal and bacterial units, C1q, Clr, and CIs [4]. There have been substances, and certain cellular and humoral pro­ reports of another subcomponent necessary for full teolytic enzymes. C1 hemolytic activity [5]; however, C1 has been The molecular events in the activation of the totally reconstituted from highly purified prepara­ complement system can be divided between those tions of C lq and the proenzyme forms of C lr and involved in the classic activation mechanism (C1 , CIs at concentrations comparable to those of the C4, C2, and (:3) and those which participate in the subunits in the euglobulin fraction of serum con­ alternative or properdin pathway (IF, P , B, D). taining Cl [6]. Clq is a glycoprotein with an The latter pathway functions independently of C1, unusual amino acid composition, containing C4, and C2 but requires C3.
    [Show full text]