The Complement System

1 Complement and Complement Reactions.- 1.1 The Components.- 1.1.1 Properties of the Components.- 1.1.2 Purification Procedures.- 1.1.2.1 Unified Protocol for Resolution of Complement Components from Inhibitor- Treated Plasma Using DEAE-Sephacel.- 1.1.2.2 Single Protocols for Purification of Individual Components.- 1.1.3 Complement Biosynthesis.- 1.1.3.1 Factors of the Classical Pathway.- 1.1.3.2 Factors of the Alternative Pathway.- 1.1.4 Genetics and Polymorphism of the Complement Components.- 1.1.4.1 Introduction.- 1.1.4.2 Methodology.- 1.1.4.3 C3 Polymorphism.- 1.1.4.4 C4 Polymorphism.- 1.1.4.5 Factor B Polymorphism (BF).- 1.1.4.6 C2 Polymorphism.- 1.1.4.7 C5 Polymorphism in Man.- 1.1.4.8 C6 Polymorphism.- 1.1.4.9 C7 Polymorphism in Man.- 1.1.4.10 C81 (Alpha-Gamma) and C82 (Beta) Polymorphism in Man.- 1.1.4.11 Factor D in Man.- 1.1.4.12 Factor H Polymorphism in Man.- 1.1.4.13 C4BP Polymorphism.- 1.1.4.14 Factor I Polymorphism in Man.- 1.1.4.15 CR1 (C3b/C4b Receptor) Polymorphism in Man.- 1.1.4.16 Conclusions.- 1.2 Reactivity in Immune Hemolysis.- 1.2.1 "Classical" Pathway of Activation.- 1.2.1.1 Recognition Phase.- 1.2.1.2 Activation of the C1 Esterase, C1s.- 1.2.1.3 Formation of the C3/C5 Convertase (C4b, 2a).- 1.2.1.4 Reactions of the Third Complement Component, C3.- 1.2.1.5 Reaction of the Fifth Complement Component, C5.- 1.2.2 Alternative Pathway of Activation.- 1.2.2.1 Introduction.- 1.2.2.2 Initiation of the Pathway.- 1.2.2.3 The Amplification C3 Convertase.- 1.2.2.4 The C5 Convertase.- 1.2.2.5 Control Mechanisms.- 1.2.2.6 Biological Role of the Alternative Pathway.- 1.2.3 Control Mechanisms.- 1.2.3.1 C1 Inhibitor.- 1.2.3.2 Regulation of the C3 Convertases.- 1.2.3.3 Regulation of the Late-Acting Components C5-C9.- 1.2.3.4 C1q Inhibitor (C1q-I).- 1.2.3.5 Other Complement Inhibitors.- 1.2.4 Species-Dependent Incompatibilities.- 1.2.4.1 Incompatibility of Antibody with Complement.- 1.2.4.2 Incompatibilities Between Heterologous Components of the Classical Pathway.- 1.2.4.3 Incompatibilities Between Heterologous Components of the Alternative Pathway.- 1.2.4.4 Incompatibilities Between Regulatory Proteins and Heterologous Components.- 1.2.4.5 Incompatibilities of Complement Components with Target Cells.- 1.2.5 The Complement Attack Phase.- 1.2.5.1 Interaction of the Late Components with Each Other and with the Membrane.- 1.2.5.2 Complement-Mediated Killing of Nucleated Cells.- 1.2.5.3 Factors that Modulate the Efficiency of Complement-Mediated Damage.- 1.2.5.4 Other Biological Activities of the Late Complement Components.- 1.2.5.5 Innocent Bystander Lysis by C5-C9.- 1.2.6 Similarities Between Complement Lysis and Killing by Lymphocytes.- 1.2.6.1 Introduction.- 1.2.6.2 Direct Involvement of Complement Factors in Cell-Mediated Lysis.- 1.2.6.3 Kinetics and Stages of Lymphocyte-Mediated Killing.- 1.2.6.4 Recognition.- 1.2.6.5 Postbinding Events in CTL, ADCC, and NK.- 1.2.6.6 Additional or Alternative Putative Lytic Mechanisms.- 1.3 The Receptors.- 1.3.1 Introduction.- 1.3.2 Receptor for C1q.- 1.3.3 Receptor for a Fragment of C2.- 1.3.4 Receptors for Fragments of C4.- 1.3.5 Receptor for C3 Fragments.- 1.3.5.1 Receptor for C3a.- 1.3.5.2 Receptor for C3b (Complement Receptor 1, CR1).- 1.3.5.3 Receptor for C3d, g and C3d (Complement Receptor 2, CR2).- 1.3.5.4 Receptor for iC3b (Complement Receptor 3, CR3).- 1.3.5.5 Receptor for C3e.- 1.3.5.6 Modulations of Receptors for C3 Fragments.- 1.3.6 Receptor for Factor H.- 1.3.7 Receptor for C5a.- 1.4 Complement Determinations in Clinical Diagnosis.- 1.4.1 Laboratory Complement Analysis.- 1.4.1.1 Screening Procedure.- 1.4.1.2 Disorders of the Classical Pathway.- 1.4.1.3 Complement Disorders Pointing to Disturbances of the Feedback Cycle of the Alternative Pathway and/or the Terminal Components.- 1.4.1.4 Conclusions.- 1.4.2 New Approaches to Evaluate Complement Activation.- 1.4.2.1 Assays for Quantitation of C1 Activation.- 1.4.2.2 Assays for Quantitating the Activation of the Alternative Pathway.- 1.4.2.3 Quantitation of the Fluid Phase Terminal Complex (SC5b-9).- 1.4.2.4 Methods for Detecting Cleavage Products of Complement Components.- 1.4.2.5 Determination of the Anaphylatoxins C3a, C4a, and C5a.- 1.4.3 C1 Inhibitor Functional Test.- 1.4.4 Detection and Measurement of Free C1q.- 1.4.5 Detection and Estimation of Proenzyme C1r-C1s Complexes.- 1.4.6 Concluding Remarks.- 1.4.7 Demonstration of Complement Deposits in Tissue.- 1.4.7.1 Introduction.- 1.4.7.2 Physiological Deposition of Complement Components.- 1.4.7.3 Deposition of C Components Under Pathological Conditions.- 1.4.7.4 Pathogenetic Implications of C Activation In Situ.- 1.4.7.5 Technical Limitations of C Detection in Tissue.- 2 Biological Functions.- 2.1 Role of Complement in the Induction of Antibody Responses.- 2.1.1 Introduction.- 2.1.2 Role of Complement in Primary Antibody Responses.- 2.1.2.1 In Vitro Studies.- 2.1.2.2 In Vivo Studies.- 2.1.3 Role of C3 in the Generation of Immunological Memory.- 2.1.3.1 General Aspects.- 2.1.3.2 Importance of Antigen Trapping in Lymphoid Follicles.- 2.1.3.3 Mechanisms of Follicular Trapping.- 2.1.4 Concluding Remarks.- 2.2 Complement Interaction with Effector Cell Systems.- 2.2.1 Lysosomal Enzyme Release.- 2.2.2 Stimulation of Arachidonate Metabolism and Prostanoid Liberation by C3b, C3a, and Factor H.- 2.2.3 Reduction of Ia Antigens on Macrophages.- 2.2.4 Deactivation of Macrophages.- 2.3 Complement-Dependent Neutralization of Viruses.- 2.3.1 Introduction.- 2.3.2 Natural and Induced Immunity to Viruses and Virus-Infected Cells.- 2.3.3 Direct and Antibody-Dependent Complement Activation by Viruses and Virus-Infected Cells.- 2.3.4 Antibody and Complement-Dependent Viral Neutralization.- 2.3.5 Complement-Dependent Effects on Virus-Infected Cells.- 2.3.6 Conclusions.- 2.4 Leukocyte-Mobilizing Factor (LMF).- 2.5 Chemotactic Factors.- 2.5.1 Introduction.- 2.5.2 Complement-Derived Chemo tactic Factors.- 2.5.3 Trimolecular Complex of C567.- 2.5.4 C3-Derived Chemotactic Activity.- 2.5.5 C5-Derived Chemotactic Activity.- 2.5.6 Activity of the Alternative Complement Pathway.- 2.6 The Anaphylatoxins.- 2.6.1 Definition.- 2.6.2 Historical Survey.- 2.6.2.1 Phase 1.- 2.6.2.2 Phase 2.- 2.6.2.3 Phase 3.- 2.6.3 Present and Future.- 2.6.4 Chemical Structure.- 2.6.4.1 Carbohydrate Content.- 2.6.4.2 Antigenic Properties.- 2.6.4.3 Synthetic Peptides.- 2.6.4.4 Receptors.- 2.6.5 Biological Functions.- 2.6.5.1 Acute Respiratory Distress Syndrome.- 2.6.5.2 Anaphylatoxin-Peptide-Mediated Regulation of Humoral Immune Responses.- 2.6.6 In Vitro Test Systems.- 2.6.7 Conclusion.- 2.7 Opsonization, Phagocytosis, and Intracellular Microbial Killing.- 2.7.1 Introduction.- 2.7.2 Opsonization.- 2.7.3 Phagocytosis.- 2.7.3.1 Generation and Transmission of the Phagocytic Signal.- 2.7.3.2 Particle Ingestion.- 2.7.4 Cooperative Roles of Fc Receptors and Complement Receptors in Host Defense Against Microbial Infection.- 2.7.5 Intracellular Microbial Killing.- 2.7.6 Summary of the Roles of Complement Receptors in Opsonization, Phagocytosis, and Microbial Killing.- 2.8 Complement-Dependent Maintenance of Immune Complex Solubility.- 2.8.1 Introduction.- 2.8.2 Solubilization of Immune Aggregates by Complement.- 2.8.3 Inhibition of Precipitation by Complement.- 2.8.4 Nature of C3b and C4b Incorporation into Immune Complexes.- 2.8.5 Interaction of Immune Complexes with Cells: Role of Cell Membranes.- 2.8.6 Clinical Implications.- 3 Pathology.- 3.1 Complement-Deficient Animals.- 3.2 Disturbances of Control Mechanisms.- 3.2.1 Inherited and Acquired Deficiencies of C1 Esterase Inhibitor in Man.- 3.2.1.1 Introduction.- 3.2.1.2 Structural Properties of C1-INH.- 3.2.1.3 Procedures for Determination of C1-INH.- 3.2.1.4 Role of C1-INH in the Complement Cascade.- 3.2.1.5 Role of C1-INH in HF-Dependent Pathways.- 3.2.1.6 Inherited Deficiency of C1-INH of Man.- 3.2.1.7 Laboratory Diagnosis.- 3.2.1.8 Therapy.- 3.2.1.9 Acquired C1-INH Deficiency.- 3.2.2 Deficiencies of Factor I and Factor H.- 3.2.2.1 Introduction.- 3.2.2.2 First Factor I Deficient Patient: TJ.- 3.2.2.3 Other Patients with Factor I Deficiency.- 3.2.2.4 Factor H Deficiency.- 3.2.3 C3 Nephritic Factor.- 3.2.3.1 Studies on Whole Serum Containing C3NeF.- 3.2.3.2 Functional Studies of C3NeF.- 3.2.3.3 Studies on Purified C3NeF.- 3.3 Immunopathological Aspects of the Complement System.- 3.3.1 Defense Against Bacterial Infections.- 3.3.1.1 Introduction.- 3.3.1.2 Bactericidal Activity of Serum.- 3.3.1.3 Pathways of the Complement Activation by Bacteria.- 3.3.1.4 Resistance to Serum Bactericidal Activity.- 3.3.1.5 The Pathophysiological Significance of the Serum Bactericidal Activity and Serum Resistance of Bacteria.- 3.3.2 The Role of Complement in Immune Complex Induced Tissue Injury.- 3.3.2.1 Introduction.- 3.3.2.2 Experimental Models of Immune Complex Mediated Tissue Injury.- 3.3.2.3 Mediators in Immune Complex Tissue Injury.- 3.3.2.4 Conclusion.- 3.3.3 Shock and Shock Fragments.- 3.3.4 Adverse Reactions to Drugs.- 4 In Vivo Manipulation of the Complement System.- 4.1 Natural Proteinaceous Inhibitors.- 4.2 Simple Chemical Compounds.