Inflammation and Retinal Disease: Complement Biology and Pathology (eBook)

John D. Lambris, Anthony P. Adamis (Herausgeber)

eBook Download: PDF

2010 | 2010
XIV, 170 Seiten
Springer New York (Verlag)
978-1-4419-5635-4 (ISBN)

Infos

Numerous studies have pointed to the key role of complement in the pathogenesis of retinal disease, particularly age-related macular degeneration (AMD). Reports about new gene associations and links to other physiological pathways are emerging almost on a weekly base. 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 First Aegean Conferences Conference on Inflammation and Retinal Disease: Complement Biology and Pathology (June 10-17, 2007) in Crete, Greece, to discuss recent advances in this rapidly-evolving field. This volume represents a collection of topics on the functions of complement in eye diseases, pathophysiology, protein structures, and complement therapeutics discussed during the conference. Our 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. We 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 of Springer Publishers for her supervision in this book's production. John D. Lambris Anthony P.

Inhalt

Preface 6
Contents 8
Contributors 10
Chapter 1: The Case for Complement and Inflammationin AMD: Open Questions 16
1 Introduction 16
1.1 Epidemiology 17
2 Drusen 18
3 Geographic Atrophy 18
4 Choroidal Neovascularization 19
References 21
Chapter 2: The Role of Complement in AMD 23
1 Age-Related Macular Degeneration 24
1.1 The Disease 24
1.2 AMD: A Chronic Inflammatory Disease 24
2 Age-Related Macular Degeneration: A Genetic Disorder 25
3 Effect of the Reported SNPs for Protein Function 28
3.1 Factor H and Other Complement Proteins 28
3.1.1 Factor H and FHL1 28
3.1.2 Complement Factor H Related Proteins 29
3.1.3 Other Complement Proteins Associated with AMD: C2, Factor B and C3 30
3.2 Gene Products of the Chromosome 10q26: ARMS-2 and HRTA1 31
4 Lessons Learned from Rare Disorders (HUS, MPGN) 32
5 Outlook 33
References 33
Chapter 3: Multiple Interactions of Complement Factor H with Its Ligands in Solution: A Progress Report 39
1 Complement Factor H 40
2 Structure of Factor H 41
3 Self-Association of Factor H 43
4 Interaction of Factor H with Zinc 46
5 Interaction of Factor H with C-Reactive Protein 47
6 Interaction of Factor H with Heparin 51
7 Interaction of Factor H with C3d 53
8 Conclusions and Future Considerations 56
References 58
Chapter 4: Genetic Control of Complement Activation in Humans and Age Related Macular Degeneration 62
1 Genes Associated with AMD 62
2 Non-Genetic Factors Increasing the Risk of AMD 65
3 Complement Proteins and AMD 65
4 Conclusions 71
References 71
Chapter 5: Bisretinoids of RPE Lipofuscin: Triggerfor Complement Activation in Age-Related Macular Degeneration 76
1 RPE Lipofuscin and Macular Degeneration 76
2 Age-Related Macular Degeneration and the Complement System 78
3 Complement Activation by Photoproductsof the RPE Bisretinoid A2E 78
4 Complement Activation by OxidizedAll-trans-Retinal-Dimer 79
5 Complement Activation by Bisretinoid Photoproducts is Dependent on Factor B 80
6 C-Reactive Protein Modulates Complement Activation by RPE Bisretinoids 81
7 Suppression by POT-4, a C3 Cleavage Inhibitor 82
8 Summary 82
References 83
Chapter 6: The Role of the Classical Complement Cascade in Synapse Loss During Developmentand Glaucoma 88
1 Introduction 88
2 Current Opinion on Glaucoma 89
3 Animal Models of Glaucoma 89
4 Pathological Progression of Glaucoma 91
5 Role of Glial Activation in Glaucoma 93
6 Neural-Immune and Neuron-Glia Signalingin Glaucoma 96
7 Complement Cascade Upregulation and Activationin Glaucoma 97
8 Parallels Between Complement-Mediated Synapse Elimination and Synapse Loss 98
9 Conclusions and Perspectives 100
References 102
Chapter 7: A Role for Complement in Glaucoma? 107
1 Introduction 107
2 Complement and Glaucoma 110
References 112
Chapter 8: The ATP-Binding Cassette Transporter ABCA4: Structural and Functional Properties and Role in Retinal Disease 117
1 Introduction to ABC Transporters 117
2 Human ABC Transporters 118
3 ABCA4 and Vision Diseases 118
4 Molecular View of ABCA4 119
4.1 Primary Structure 119
4.2 Localization 120
4.3 Insights into Topology, Structure and Posttranslational Modifications 122
4.4 Structural Features of Individual Domains 123
5 Biological Role of ABCA4 125
5.1 Identification of Substrate: Biochemical Evidence 125
5.2 Proposed General Model of Transport 126
5.3 Abca4 Knockout Mice 127
5.4 Proposed Role of ABCA4 in the Visual Cycle 129
5.5 Unresolved Issues 131
6 ABCA4 Mutations and Autosomal Recessive Macular Degeneration 132
7 Conclusions 133
References 133
Chapter 9: Suppression of Drusen Formation by Compstatin, a Peptide Inhibitor of Complement C3 activation, on Cynomolgus Monkeywith Early-Onset Macular Degeneration 138
1 AMD and Association of Complement Related Genes 138
2 Activated Complement Component in Drusen 139
3 Cynomolgus Monkey with Early-Onset Macular Degeneration 140
4 Suppression and Reversal of Drusen Formation by Compstatin 142
References 144
Chapter 10: A Targeted Inhibitor of the Complement Alternative Pathway Reduces RPE Injury and Angiogenesis in Models of Age-Related MacularDegeneration 147
1 Age-Related Macular Degeneration and Complement Activation 147
2 Targeted Complement Inhibition 149
3 Oxidative Stress Renders RPE Susceptible to Complement Attack 150
4 Choroidal Neovascularization is Amenable to CR2-fH Therapy 153
5 Summary 155
References 156
Chapter 11: Complement Depletion with Humanized Cobra Venom Factor in a Mouse Model of Age-Related Macular Degeneration 160
1 Introduction 160
2 Materials and Methods 162
2.1 Mice 162
2.2 CVF Transgenic Mice 163
2.3 Animal Study 163
2.4 Humanized CVF 164
2.5 Laser Coagulation Surgery 164
2.6 Funduscopy 164
2.7 Histopathology 164
2.8 Hemolytic Complement Activity 165
3 Results 165
4 Discussion 166
References 169
Index 172

Produkt-Details

• Erscheint lt. Verlag: 14.8.2010
• Reihe/Serie: Advances in Experimental Medicine and Biology
• Reihe/Serie: Advances in Experimental Medicine and Biology
• Zusatzinfo: XIV, 170 p.
• Verlagsort: New York
• Sprache: englisch
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete ► Augenheilkunde
• Themenwelt: Studium ► 1. Studienabschnitt (Vorklinik) ► Biochemie / Molekularbiologie
• Schlagworte: Eye • macular degeneration • pathogenesis • Pathology • retina
• ISBN-10: 1-4419-5635-2 / 1441956352
• ISBN-13: 978-1-4419-5635-4 / 9781441956354