Current Topics in Complement II 1st Edition

Visit the link below to download the full version of this book:

https://medipdf.com/product/current-topics-in-complement-ii-1st-edition/

Click Download Now

ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY
Editorial Board:
NATHAN BACK, State University of New York at Buffalo
IRUN R. COHEN, The Weizmann Institute of Science
ABEL LAJTHA, N.S. Kline Institute for Psychiatric Research
JOHN D. LAMBRIS, University of Pennsylvania
RODOLFO PAOLETTI, University of Milan

For other titles published in this series, go to

www.springer.com/series/5584
John D. Lambris
Editor

Current Topics
in Complement II
Editor
John D. Lambris
Department of Pathology
Laboratory of Medicine
Johnson Pavilion 410
University of Pennsylvania
Philadelphia, PA 19104
USA
[email protected]

ISBN: 978-0-387-78951-4 e-ISBN: 978-0-387-78952-1

DOI:10:1007/978-0-387-78952-1

Library of Congress Control Number: 2008925169

© 2008 Springer Science+Business Media, LLC

All rights reserved. This work may not be translated or copied in whole or in part without the written
permission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York, NY
10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in
connection with any form of information storage and retrieval, electronic adaptation, computer software,
or by similar or dissimilar methodology now known or hereafter developed is forbidden.
The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are
not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject
to proprietary rights.

Printed on acid-free paper

9 8 7 6 5 4 3 2 1

springer.com
Preface

Nearly 110 years after the term ‘Complement’ was coined by Paul Ehrlich,
this fascinating cascade within the innate immune system still offers many
surprises. Reports about new connections to diseases, links to other
physiological pathways, novel complement-binding molecules, and
microbial evasion proteins are emerging almost on a weekly base. With last
years’ FDA approval of the monoclonal antibody Eculizumab as the first
truly complement-specific drug (by targeting C5), this important field
regained even more momentum. Several promising clinical candidates
covering a wide area of potential treatment applications are in the pipelines
of both industrial and academic groups. This indicates an increasing interest
in complement as a therapeutic target. In view of these exciting discoveries,
scientists from around the world convened at the 4th Aegean Conferences
Workshop on Complement Associated Diseases, Animal Models, and
Therapeutics (June 10-17, 2007) in Porto Heli, Greece, to discuss recent
advances in this rapidly-evolving field. This volume represents a collection
of topics on the “novel” functions of complement, pathophysiology, protein
structures, and complement therapeutics discussed during the conference.
My sincere thanks to the contributing authors for the time and effort they
have devoted to writing what I consider exceptionally informative chapters
in a book that will have a significant impact on the complement field. I
would also like to express my thanks to Rodanthi Lambris for her assistance
in collating the chapters and preparing the documents for publication and I
gratefully acknowledge the generous help provided by Dimitrios Lambris in
managing the organization of this meeting. Finally, I also thank Andrea
Macaluso and Melanie Wilichinsky of Springer Publishers for their
supervision in this book’s production.

John D. Lambris, Ph.D.

Dr. Ralph and Sallie Weaver Professor
of Research Medicine, University of Pennsylvania
Contents

Preface .......................................................................................................................v

Contributors .........................................................................................................xvii

1. Adipokines and the Immune System: An Adipocentric

View ............................................................................................... 1
Robin MacLaren , Wei Cui and Katherine Cianflone

1 Introduction ............................................................................................................1
2 Endocrine Functions of Adipose Tissue in the Immune System ...........................2
3 Adipose Tissue Crosstalk: Adipocytes and Macrophages .....................................3
4 Adipose Tissue Micro-Environment ......................................................................5
4.1 Adipocyte-Mediated Recruitment, Differentiation and Macrophage
Differentiation .................................................................................................5
4.2 Effects of Macrophages on Adipocyte Function .............................................6
4.3 Effects of Adipocytes on Macrophage Function..............................................7
4.4 Contribution of Preadipocytes to Altered Adipocyte and Macrophage
Function...........................................................................................................7
4.5 Pros and Cons of Macrophage Infiltration .......................................................7
4.6 Effect of Weight Loss on Adipose Tissue Function.........................................8
5 The Role of C5L2: Adipose vs. Immune ...............................................................9
5.1 Metabolism, C3, and Acylation Stimulating Protein (ASP) ............................9
5.2 Identification of C5L2 and Ligand Binding in Transfected Cells..................10
5.3 Signalling of C5L2 in Transfected Cells ........................................................12
5.4 A DRY Motif is not Required for Signalling .................................................12
5.5 Endogenous Expression of C5L2 and Functionality......................................13
5.6 In vivo Role of C5L2 in Mice and Humans ...................................................15
6 Summary ..............................................................................................................15
References ...............................................................................................................16

2. The Role of Complement in Stroke Therapy ........................... 23

Ricardo J. Komotar, Grace H. Kim, Marc L. Otten, Benjamin Hassid,
J. Mocco, Michael E. Sughrue, Robert M. Starke, William J. Mack,
Andrew F. Ducruet, Maxwell B. Merkow, Matthew C. Garrett, and
E. Sander Connolly

1 Introduction ...........................................................................................................23
2 Inflammation Following Cerebral Ischemia ........................................................24
viii Contents

3 Complement Mediated Ischemia/Reprefusion Injury ..........................................24

4 Complement Mediated Cell Clearance ................................................................25
5 Implications of Complement Inhibition ...............................................................26
6 Complement and Neurogenesis/Neurorecovery ..................................................26
7 Steps Towards Clinical Translation .....................................................................27
8 Conclusion.............................................................................................................28
References ...............................................................................................................28

3. Food Intake Regulation by Central Complement System....... 35

Kousaku Ohinata and Masaaki Yoshikawa

1 Introduction ..........................................................................................................35
2 C3a Effect on Food Intake ....................................................................................36
2.1 Anorexigenic Action of Central C3a .............................................................36
2.2 C3a Agonist Peptides Derived from Natural Proteins ...................................37
2.3 Involvement of the PGE2-EP4 Receptor Pathway .........................................38
3 C5a Effect on Food Intake ....................................................................................41
3.1 Orexigenic Action of Central C5a..................................................................41
3.2 Involvement of PGD2-DP1 Receptor .............................................................41
References ...............................................................................................................42

4. A Pivotal Role of Activation of Complement Cascade

(CC) in Mobilization of Hematopoietic Stem/Progenitor
Cells (HSPC) ............................................................................... 47
Mariusz Z. Ratajczak, Marcin Wysoczynski, Ryan Reca, Wu Wan, Ewa
K. Zuba-Surma, Magda Kucia, and Janina Ratajczak

1 Introduction ...........................................................................................................47
2 Mobilization of HSPC and Problem of Poor Mobilizers ......................................48
3 G-CSF-Induced Mobilization Triggers Activation of CC ....................................50
4 Experimental Evidence that Ig-Deficient RAG2, SCID and Jh Mice, but not
T-Cell-Depleted Mice, Respond Poorly to G-CSF Induced Mobilization ..............52
5 Defective Mobilization in RAG2, SCID and Jh Mice is Restored by
Purified Immunoglobulins Supports Further a Pivotal Role of Ig in this
Process ..................................................................................................................54
6 Evidence that CC Activation and C3a Generation in Serum Correlate
with G-CSF Induced HSPC Mobilization ............................................................54
7 In Contrast to G-CSF-Mobilization, RAG2, SCID and Jh Mice Display
Normal Zymosan-Induced Mobilization .............................................................56
8 Impaired Mobilization in C5-Deficient Mice Supports a Pivotal Role
for CC in Egress of HSPC from BM and their Mobilization into PB..................56
9 Conclusions ...........................................................................................................58
References ...............................................................................................................59
Contents ix

5. Regulation of Tissue Inflammation by Thrombin-

Activatable Carboxypeptidase B (or TAFI) ............................. 61
Lawrence L.K. Leung, Toshihiko Nishimura, and Timothy Myles

1 Introduction ..........................................................................................................61
2 Procoagulant and Anticoagulant Properties of Thrombin ....................................62
3 Dissociation of Thrombin’s Procoagulant and Anticoagulant Properties ............62
4 Thrombin-Activatable Procarboxypeptidase B as a Physiological
Substrate for the Thrombin/Thrombomodulin Complex......................................63
5 Thrombin-Activatable Carboxypeptidase B as an Anti-inflammatory
Molecule ...............................................................................................................64
6 Carboxypeptidase B Reduces Bradykinin-Induced Hypotension In Vivo ...........66
7 Carboxypeptidase B Ameliorates C5a-Induced Alveolitis In Vivo......................66
8 ProCPB-Deficient Mice Are Predisposed to Abdominal Aneurysm
Formation and Arthritis In Vivo ..........................................................................67
9 Regulation of Thrombin’s Inflammatory Properties by Thrombin-
Activatable Procarboxypeptidase B .....................................................................67
References ................................................................................................................68

6. Interaction between the Coagulation and Complement

System ......................................................................................... 71
Umme Amara, Daniel Rittirsch, Michael Flierl, Uwe Bruckner,
Andreas Klos, Florian Gebhard, John D. Lambris, and Markus Huber-Lang

1 Introduction ...........................................................................................................71
2 Serine Protease Systems .......................................................................................72
2.1 Coagulation System........................................................................................72
2.2 Fibrinolytic System.........................................................................................74
2.3 Complement System.......................................................................................74
3 C3a and C5a Generation by Coagulation Factors.................................................75
4 Complement: New Activation Paths.....................................................................76
5 Interaction between the Coagulation and Complement Cascade After
Trauma..................................................................................................................76
6 Conclusion.............................................................................................................77
References ................................................................................................................77

7. Platelet Mediated Complement Activation............................... 81

Ellinor I.B. Peerschke, Wei Yin, Berhane Ghebrehiwet

1 Complement Activation on Platelets ....................................................................81

2 Complement Activation on Platelet Microparticles (PMP) ..................................83
x Contents

3 Pathophysiology of Platelet Mediated Complement Activation ..........................84

4 Regulation of complement Activity on Platelets ..................................................86
5 Summary and Conclusion .....................................................................................87
References ................................................................................................................88

8. Adrenergic Regulation of Complement-Induced Acute

Lung Injury................................................................................. 93
Michael A. Flierl, Daniel Rittirsch, J. Vidya Sarma,
Markus Huber-Lang, and Peter A. Ward

1 Introduction ...........................................................................................................93
2 Phagocytes: A New Adrenergic Organ ................................................................94
2.1 Evidence for de novo-Synthesis, Release and Inactivation
of Catecholamines by Phagocytes ..................................................................94
2.2 Modulation of Phagocyte Functions by Catecholamines ...............................96
3 Phagocyte-Derived Catecholamines Regulate Complement-Dependent
Acute Lung Injury ................................................................................................96
4 Outlook..................................................................................................................98
5 Conclusion...........................................................................................................100
References ..............................................................................................................100

9. Ficolins: Stucture, Function and Associated Diseases ........... 105

Xiao-Lian Zhang, Mohammed A.M. Ali

1 Introduction ........................................................................................................105
2 Structures of Ficolins ..........................................................................................107
3 Ficolin Genetics .................................................................................................108
4 Ficolin and Infectious Diseases ..........................................................................109
5 Single nucleotide Polymorphisms in Ficolins ....................................................110
6 Ficolins and Apoptosis........................................................................................110
7 Ficolins and Systemic Lupus Erythematosus .....................................................110
8 Ficolins and IgA nephropathy (IgAN) ...............................................................110
9 Ficolins and Preeclampsia ..................................................................................111
10 Ficolin and C-Reactive Protein .........................................................................111
11 Concluding Remarks.........................................................................................111
References ..............................................................................................................112

10. Complement Factor H: Using Atomic Resolution

Structure to Illuminate Disease Mechanisms....................... 117
Paul N. Barlow, Gregory S. Hageman, and Susan M. Lea

1 Introduction ........................................................................................................117
2 Involvement of Factor H in Human Disease ......................................................119
3 CFH Binding Sites ..............................................................................................121
Contents xi

4 The Structure of Factor H ...................................................................................122

4.1 Low Resolution Structural Information on CFH..........................................123
4.2 Atomic Structure of the CFH Carboxy-terminus .........................................123
4.3 Atomic Structures for Both Tyr and His variants of CCP 7.........................125
4.5 Atomic Structure for CFH-678.....................................................................125
4.6 Sulfated Sugar Recognition at the Polymorphic residue..............................127
4.7 Additional Binding Sites for Sulfated-Sugar Within CFH-6,7,8 .................128
5 Structure: Insights into Disease Mechanism .......................................................129
6 Options for Therapy ...........................................................................................130
References .............................................................................................................133

11. Role of Complement in Motor Neuron Disease: Animal

Models and Therapeutic Potential of Complement
Inhibitors ................................................................................. 143
Trent M. Woodruff, Kerina J. Costantini, Steve M. Taylor, and
Peter G. Noakes

1 Background .........................................................................................................143
2 Animal Models of Motor Neuron Disease..........................................................144
2.1 Early Models of Motor Neuron Disease.......................................................144
2.2 SOD1 Transgenic Model of Amyotrophic Lateral Sclerosis .......................144
3 Clinical Evidence for Complement Involvement................................................146
4 Experimental Evidence for Complement Involvement.......................................149
5 Therapeutic Possibilities .....................................................................................151
6 Summary .............................................................................................................153
References ..............................................................................................................153

12. The Role of Membrane Complement Regulatory

Proteins in Cancer Immunotherapy ..................................... 159
Jun Yan, Daniel J. Allendorf, Bing Li, Ruowan Yan, Richard Hansen,
and Rossen Donev

1 Complement System and its Activation..............................................................159

2 Membrane-Bound Complement Regulatory Proteins and their Expression
on Tumors ..........................................................................................................161
3 Antitumor mAb Therapy and mCRPs on Tumors ..............................................162
4 mCRPs and Adaptive T-Cell Responses.............................................................163
5 Modulation of mCRPs for Immunotherapy ........................................................164
5.1 Neutralizing mAbs ...........................................................................................164
5.2 Small Interfering RNAs or Anti-sense Oligos .................................................165
5.3 Chemotherapeutic Drugs..................................................................................166
5.4 Peptide Inhibitors of mCR Gene Expression ...................................................166
6 Concluding Remarks...........................................................................................167
References ..............................................................................................................167
xii Contents

13. Role of Complement in Ethanol-Induced Liver Injury........ 175

Michele T. Pritchard, Megan R. McMullen, M. Edward Medof,
Abram Stavitsky, and Laura E. Nagy

1 Alcoholic liver Disease .......................................................................................175

1.1 Innate and Adaptive Immunity in Ethanol-Induced Liver Injury ................176
2 Complement and Ethanol-Induced Liver Injury .................................................176
2.1 Ethanol and Complement Activation ...........................................................178
2.2 Role of Complement in Ethanol-Induced Liver Injury ................................178
3 C3 in the Development of Hepatic Steatosis ......................................................179
4 Complement and Inflammatory Cytokines in Ethanol-Induced Liver Injury........179
5 Complement Regulatory Proteins in Ethanol-Induced Liver Injury...................180
6 Membrane Attack Complex (MAC) and Ethanol-Induced Liver Injury ............181
7 Complement in Hepatocellular Proliferation ......................................................181
8 Complement and “Waste Disposal”: Complement and Ethanol-Induced
Apoptosis ...........................................................................................................182
9. Conclusions ........................................................................................................182
References ..............................................................................................................183

14. Immune Complex-Mediated Cytokine Production is

Regulated by Classical Complement Activation both
In Vivo and In Vitro ............................................................... 187
Johan Rönnelid, Erik Åhlin, Bo Nilsson, Kristina Nilsson-Ekdahl, and
Linda Mathsson

1 Introduction .........................................................................................................187
2 Down-Regulation of IC-Induced IL-12 Production by the Classical
Complement Pathway.........................................................................................188
3 Complement Blockade Induce Inverse Regulation of Cryoglobulin-
Stimulated TNF-α and IL-10 Production...........................................................192
4 In Vivo Complement Activation and Anti-SSA in SLE .....................................195
5 Discussion ...........................................................................................................197
6 Concluding Remarks...........................................................................................198
References ..............................................................................................................198

15. Subversion of Innate Immunity by Periodontopathic

Bacteria via Exploitation of Complement Receptor-3......... 203
George Hajishengallis, Min Wang, Shuang Liang, Muhamad-Ali K.
Shakhatreh, Deanna James, So-ichiro Nishiyama, Fuminobu
Yoshimura, and Donald R. Demuth

1 Introduction ........................................................................................................ 203

2 CR3 in Innate Immunity ..................................................................................... 204
3 P. gingivalis interacts with CR3 Through its Cell Surface Fimbriae................. 205
Contents xiii

4 Biological Significance of CR3-P. gingivalis Interactions: In Vitro

Mechanistic Studies.............................................................................................205
4. 1 P. gingivalis Stimulates CR3-Dependent Transendothelial Migration
of Monocytes................................................................................................207
4.2 P. gingivalis Enters Macrophages via CR3 and Resists Intracellular
Killing ........................................................................................................... 208
4.3 P. gingivalis Interaction with CR3 Downregulates IL-12 Induction ...........210
5 In vivo Evidence for CR3 exploitation by P. gingivalis and Implications
in Periodontitis....................................................................................................211
6 CR3 exploitation by P. gingivalis depends on TLR2 .........................................214
7 Conclusion...........................................................................................................214
References ..............................................................................................................215

16. Staphyloccocal Complement Inhibitors:

Biological Functions, Recognition of
Complement Components, and Potential
Therapeutic Implications........................................ 221
Brian V. Geisbrecht

1 S. aureus as a Model System for Immune Evasion ............................................221

2 The Anti-Complement Activities of S. aureus....................................................222
2.1 Inhibitors of Complement Activation and Amplification ..........................222
2.2 Inhibitors of Complement-induced Inflammatory Responses......................225
2.3 Remaining Questions....................................................................................225
3 Toward a Molecular Understanding of Complement Evasion ...........................226
3.1 Recognition of C3 by S. aureus Efb.............................................................226
3.2 Recognition of C3 by S. aureus Ehp ............................................................228
3.3 Inhibitory Mechanisms of the Efb Family ...................................................230
4 Potential Therapeutic Applications of the Efb Family........................................231
5 Conclusions .........................................................................................................233
6 References ...........................................................................................................233

17. Human Astrovirus Coat Protein: A Novel C1 Inhibitor ..... 237

Neel K. Krishna and Kenji M. Cunnion

1 Introduction .........................................................................................................237
2 C1, the First Complement Component ...............................................................239
3 C1 Inhibitors........................................................................................................240
3.1 C1-Inhibitor ..................................................................................................240
3.2 Decorin and Biglycan ...................................................................................240
3.3 Neutrophil Defensins....................................................................................240
3.4 C1q Receptor Proteins ..................................................................................241
4 The Astroviruses .................................................................................................241
xiv Contents

5 Inhibition of Complement Activity By Human Astrovirus Coat Protein

(HAstV CP).........................................................................................................242
5.1 HAstV CP Suppresses Classical Pathway Activity......................................243
5.2 HAstV CP Binds to the A-chain of C1q.......................................................244
5.3 HAstV CP Specifically Targets the C1 Complex ........................................245
5.4 HAstV CP Suppresses Complement Activation via an Inhibitory
Mechanism. .................................................................................................246
5.5 Hypothetical Mechanism of C1 Inhibition by HAstV CP ...........................247
6 Human Astrovirus Coat Protein: Potential as a Therapeutic for Complement-
Mediated Diseases ..............................................................................................247
7 Conclusions .........................................................................................................248
8 References ...........................................................................................................248

18. Hypothesis: Combined Inhibition of Complement and

CD14 as Treatment Regimen to Attenuate the
Inflammatory Response. ........................................................ 253
Tom Eirik Mollnes, Dorte Christiansen, Ole-Lars Brekke, and
Terje Espevik

1 Introduction .........................................................................................................253
2 Complement .......................................................................................................255
3 CD14 and Toll-Like Receptors ..........................................................................256
3.1 Toll-like Receptors are Essential Membrane Receptors in the
Inflammatory Response ..............................................................................256
3.2 TLR Signaling ..............................................................................................257
4 Rational for Combined Complement and CD14 Inhibition ...............................257
4.1 Escherichia Coli Bacteria .............................................................................257
4.2 Endotoxin (LPS) ...........................................................................................259
4.3 Gram Negative Sepsis ..................................................................................259
4.4 General Principles for the Inflammatory Reaction: Role of
Endogenous Ligands.....................................................................................259
5 Conclusion...........................................................................................................261
References ..............................................................................................................261

19. Targeting Classical Complement Pathway to Treat

Complement Mediated Autoimmune Diseases .................... 265
Erdem Tüzün, Jing Li, Shamsher S. Saini, Huan Yang, and Premkumar
Christadoss

1 Complement System in Myasthenia Gravis........................................................265

2 Classical Complement Pathway in EAMG.........................................................268
3 Anti-C1q Antibody Prevents and Treats EAMG ................................................268
Contents xv

4 Conclusion...........................................................................................................270
References ..............................................................................................................271

20. Compstatin: A Complement Inhibitor on its Way

to Clinical Application ............................................................ 273
Daniel Ricklin and John D. Lambris

1 Tackling Complement at its Core .......................................................................273

2 Discovery and Initial Characterization ...............................................................275
3 Tuning the Structure............................................................................................278
4 Exploring the Binding Site and Mode.................................................................280
5 First Steps Towards Therapeutic Applications ...................................................283
6 From Bench to Bedside: Clinical Development .................................................285
7 Conclusions and Perspectives ............................................................................286
References ..............................................................................................................288

21. Derivatives of Human Complement Component C3 for

Therapeutic Complement Depletion: A Novel Class of
Therapeutic Agents................................................................. 293
David C. Fritzinger, Brian E. Hew, June Q. Lee, James Newhouse,
Maqsudul Alam, John R. Ciallella, Mallory Bowers, William B. Gorsuch,
Benjamin J. Guikema, Gregory L. Stahl, and Carl-Wilhelm Vogel

1 Background and Concept ...................................................................................293

2 Development of C3 Derivatives for Therapeutic Complement Depletion .........296
3 Discussion and Outlook ......................................................................................301
References ..............................................................................................................304

Index ......................................................................................................................309