Activators and Inhibitors of Complement PDF
Preview Activators and Inhibitors of Complement
ACTIVATORS AND INHIBITORS OF COMPLEMENT ACTIVATORS AND INHIBITORS OF COMPLEMENT edited by R. B. SIM M edical Research Council Scientific Staff and University Research Lecturer, University of Oxford, Oxford, U.K. SPRINGER SCIENCE+BUSINESS MEDIA, B. V. Library of Congress Cataloging-in-Publication Data Activators and inhibitors of complement/edited by R.B. Sim. p. cm. Includes bibliographical references and index. ISBN 978-94-010-5224-5 ISBN 978-94-011-2757-8 (eBook) DOI 10.l007/978-94-011-2757-8 1. Complement activation. 2. Complement inhibition. I. Sim, R. B. QRI85.8.C6.A28 1993 616.07'9--dc20 92-14814 ISBN 978-94-010-5224-5 printed on acid free paper All Rights Reserved © 1993 by Springer Science+Business Media Dordrecht Originally published by K1uwer Academic Publishers in 1993 Softcover reprint of the hardcover 1s t edition 1993 No part of the material protected by this copyright notice may be reproduced or utilized in any form or by any means, electronic or mechanical including photocopying, recording or by any information storage and retrieval system, without written permission from copyright owner. To Margaret Mathieson Braidwood 1914-1986 and Charles McIntosh Sim 1907-1988 Contents List of Contributors IX 1. The Complement System 1 M.A. McAleer and R.B. Sim 2. The Structure of Immunoglobulins and Their Interaction with Complement 17 D.R. Burton 3. Non-Immunoglobulin Activators of the Complement System 37 P.w. Taylor 4. Solid Phase Activators of the Alternative Pathway of Complement and Their Use in vivo 69 P.D. Cooper 5. Nucleophilic Compounds Acting on C3 and C4 107 E. Sim, K.E. Parker and A. Jones 6. Effects of Drugs, Venoms and Charged Polymers on the Comple ment System I. von Zabern 6a. Effects of Venoms of Different Animal Species on the Comple- ment System 127 6b. Drugs and Low Molecular Weight Compounds Affecting the Complement System 137 6c. Action of Polyionic Substances on the Complement System 149 7. Monoclonal Antibodies Against the Terminal Complement Com- ponents 167 R. Wiirzner 8. Autoantibodies Against Complement Components and Their Ef- fects on Complement Activity 181 M. Loos, J. Alsenz, U. Antes and H.-P. Heinz 9. Use of Synthetic Pep tides in Exploring and Modifying Comple- ment Reactivities 201 J.D. Lambris, J.D. Becherer, C. Servis and J. Alsenz Index 233 vii List of Contributors JOCHEM ALSENZ Institut fUr Medizinische Mikrobiologie, Johannes-Gutenberg Universitiit, Augustplatz/Hochhaus, 6500 Mainz, Germany. Present Address: Basel Insti tute for Immunology, Grenzacherstrasse 487, CH-4005 Basel, Switzerland URSULA ANTES Institut fUr Medizinische Mikrobiologie, Johannes-Gutenberg Universitiit, Augustplatz/Hochhaus, 6500 Mainz, Germany 1. DAVID BECHERER Basel Institute for Immunology, Grenzacherstrasse 487, CH-4005 Basel, Switzerland DENNIS R. BURTON Department of Biochemistry, University of Sheffield, Sheffield S10 2TN, U.K. Present Address: Research Institute for Scripps Clinic, Department of Immunology, Scripps Clinic and Research Foundation, 10666 North Torrey Pines Road, La Jolla, California 92037, USA PETER D. COOPER Division of Cell Biology, John Curtin School of Medical Research, Austra lian National University, Canberra, ACT 2601, Australia HANS-PETER HEINZ Institut fUr Medizinische Mikrobiologie, Johannes-Gutenberg Universitiit, Augustplatz/Hochhaus, 6500 Mainz, Germany ALISON JONES Department of Pharmacology, University of Oxford, Mansfield Road, Ox ford OXl 3QT, UK JOHN D. LAMBRIS Basel Institute for Immunology, Grenzacherstrasse 487, CH-4005 Basel, Switzerland. Present Address: Dept. of Pathology, Laboratory of Medicine, University of Pennsylvania, Johnson Pavilion 410, Philadelphia Pa 19104, USA ix x List of Contributors MICHAEL LOOS Institut fiir Medizinische Mikrobiologie, Johannes-Gutenberg Universitat, AugustplatzjHochhaus, 6500 Mainz, Germany MARCIA A. McALEER MRC Immunochemistry Unit, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OXl 3QU, u.K. Present Address: Nuffield Department of Surgery, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK KA Y E. PARKER Department of Pharmacology, University of Oxford, Mansfield Road, Ox ford OXl 3QT, U.K. Present Address: INSERM U-211, Plateau Technique du CHR, Quai Moncousu, 44035 Nantes Cedex 01, France CA THERINE SERVIS Basel Institute for Immunology, Grenzacherstrasse 487, CH-4005 Basel, Switzerland EDITH SIM Department of Pharmacology, Universty of Oxford, Mansfield Road, Ox ford OXl 3QT, UK ROBERT B. SIM MRC Immunochemistry Unit, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OXl 3QU, UK PETER W. TAYLOR CIBA-Geigy Pharmaceuticals, Wimblehurst Road, Horsham, West Sussex RHl2 4AB, UK REINHARD WURZNER MRC Immunochemistry Unit, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OXl 3QU, u.K. Present address: MRC Molecular Immunopathology Unit, MRC Centre, Hills Road, Cambridge CE2 2QH, UK INGE VON ZABERN Max-Planck-Institut fUr Experimentelle Medizin, Abteilung Biochemische Pharmakologie, Hermann-Rein-Strasse 3, 3400 Gottingen, Germany. Pres ent Address: Klinikfur Aniisthesiologie der Universitiit Heidelberg, 1m Neuen heimer Feld 110, 6900 Heidelberg, Germany 1. The complement system M. A. McALEER and R. B. SIM The complement system is concerned with host defence against infection. The system regulates the clearance or lysis of foreign cells, particles or macro molecules and tissue breakdown products. It is composed of a series of proteins, both membrane-bound and soluble, that interact with each other when the system is activated by a number of different stimuli. Activation of complement results in the assembly of bimolecular enzyme complexes (the C3 convertases), one component of which is covalently bound to the surface of the complement activator and the other is a catalytically active serine protease. This is able to cleave and activate C3, the most abundant complement component. The major fragment of activated C3, C3b, binds covalently to complement-activating surfaces (e.g. cells, viruses). Once large amounts of C3b or proteolytic fragments derived from C3b are deposited on activating surfaces phagocytosis of the coated substance can occur. This occurs through the interaction of the surface-bound C3 fragments with C3 receptors located on membranes of phagocytic cells. If the complement activating substance is a cell, lysis and cell death can also occur through a stepwise interaction involving the components C5, C6, C7, C8 and C9 which leads to assembly of the membrane attack complex (MAC). There are two pathways of activation, the classical pathway and the alternative pathway (Figure 1) [1]. Biochemical studies of complement proteins are far-advanced, and complete amino acid sequences are available for most components. There is now considerable interest in generating tertiary structures, so that the molecular details of the protein-protein interactions of the system can be understood. Since the system is involved in removal and killing of materials from the circulation and tissues, it has considerable capacity to damage host tissue. In addition to the beneficial effects of complement, undesirable complement-mediated tissue dam age occurs in a wide range of situations, including mechanical injury, viral infection, tissue damage initiated by autoantibodies, myocardial infarction and rheumatoid arthritis. Diminished activity of the complement system is asso ciated with susceptibility to infection and to inadequate removal of materials, e.g. immune complexes, from the circulation, leading to lupus-like conditions and possible damage to the small blood vessels particularly of the skin and kidneys. There is therefore considerable interest in being able to manipulate the R.B. Sim (ed.), Activators and Inhibitors of Complement, 1-15. © 1993 Kluwer Academic Publishers. 2 M.A. McAleer and R.B. Sim C3b deposition and C.:1b2a3b """ ""'""c.~{ ~ (6 tj (7 C4b2a ____- .j C3-C3b MAC .. Ct3b Activator surface C3(H20lBb and C3b deposition Figure 1. Activation of the complement system. Activation of the classical pathway occurs via Cl, an assembly of three proteins, Clq, Clr and CIs. Activated CIs cleaves C4 and C2, which form a complex, C4b2a (the C3 convertase enzyme), which cleaves C3, forming C3b. C3b molecules bind covalently to the surface of the complement activator, or react with water, and diffuse away. A C3b molecule binds covalently to C4b2a, forming C4b2a3b (the C5 convertase enzyme), which cleaves C5, forming C5b. C6,7,8 and 9 then bind to C5b, forming the membrane attack complex (MAC) or terminal complement complex (TCC). In the alternative pathway, C3b formed by the classical pathway, or by the enzyme C3(H 0)Bb, binds covalently to surfaces, via reaction with surface OH or NH2 groups. The 2 bound C3b may then be destroyed by control proteins (factor I and a cofactor such as CRl, MCP or factor H), or it may form a C3bB complex, which is activated by factor D, to form C3bBb, the alternative pathway C3 convertase enzyme, which converts more C3 to C3b. Covalent deposition of a C3b molecule onto the C3bBb enzyme converts it to C3b Bb 2 (also written as C3bBbC3b) which activates C5, with subsequent assembly of the MAC. Sites of action of the control proteins (boxed) are shown. Important biologically active fragments are released during proteolytic activation of the complement proteins: these include Ba and the anaphylotoxin and chemotactic factors C4a, C3a and C5a, released on activation of factor B, C4, C3, and C5 respectively. complement system for therapeutic purposes. The following chapters in this book indicate the range of materials, natural or synthetic, which affect the complement system, and illustrate some of the approaches used to alter the activity of the system, in vitro or in vivo. The classical pathway: activation and components The classical pathway of complement consists of a group of 11 plasma glycoproteins: C1q; C1r; C1s; C4; C2; C3; C5; C6; C7; C8 and C9. The irregularity in numbering of components reflects the order in which components were first The Complement System 3 identified. There are also several plasma glycoproteins that are involved in the regulation of activation of this pathway as well as a number of membrane associated molecules which act as reglators and/or receptors for fragments of activated complement [2]. The proteins C5-C9 (the late components of complement) are common to the alternative pathway and the glycoprotein C3 has a central role in both pathways (Figure 1). Properties of the soluble proteins of the system are summarised in Table 1. Table 1. Properties of the soluble complement proteins Protein mo!.wt serum conc. no of poly peptide homology group or (kD) (mgjlitre) chains homologues Clq 465 80-100 18 MBP, SPA Clr 85 35-50 1, cleaved to serine protease 2 on activation Cis 85 35-50 1, cleaved to serine protease 2 on activation C4 195 300-450 3 C3, C5, a2m C2 110 15-25 1, cleaved to abnormal serine protease 2 on activation homo!. to factor B C3 185 1000-1350 2 C4, C5, a2m C5 185 60-90 2 C3, C4, a2m C6 120 60-90 homologous to C7, C9 C8 a and fJ chains C7 115 50-80 homologous to C6, C9, C8 a and fJ chains C8 160 60-100 3 a and fJ chains homologous to C6, C7, C9 C9 75 50-80 homologous to C6, C7, C8 a and fJ chains Factor B 90 180-250 1, cleaved to abnormal serine protease 2 on activation homo!. to C2 Factor D 25 2 1 serine protease Properdin 220 20-30 oligomeric, usually thrombospondin tetramer of 56kD subunit Factor H 155 200-700 1 member of RCA family, with CRl, CR2, MCP, DAF Factor I 88 30-40 2 serine protease C4bp 540 200-400 7 x 70kD plus member of RCA family, 1 x 50kD with CRl, CR2, MCP, DAF CI-Inh 110 150-300 1 serpin Clq is the molecule that interacts with the activator, and so provides the specificity in activation of this pathway. Classical pathway activation is most commonly studied using immune complexes, containing IgG or IgM antibodies as the activator. Many other substances however, in the absence of antibody, such as viral membranes and Gram negative bacteria are also able to activate the classical pathway. Immunoglobulin and non-immunoglobulin activators are discussed in detail in chapters 2 and 3.
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