Antibody Fc

Antibody Fc

Linking Adaptive and Innate Immunity

1st Edition - August 6, 2013
This is the Latest Edition
  • Editors: Margaret Ackerman, Falk Nimmerjahn
  • Hardcover ISBN: 9780123948021
  • eBook ISBN: 9780123948182

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Antibody Fc is the first single text to synthesize the literature on the mechanisms underlying the dramatic variability of antibodies to influence the immune response. The book demonstrates the importance of the Fc domain, including protective mechanisms, effector cell types, genetic data, and variability in Fc domain function. This volume is a critical single-source reference for researchers in vaccine discovery, immunologists, microbiologists, oncologists and protein engineers as well as graduate students in immunology and vaccinology. Antibodies represent the correlate of protection for numerous vaccines and are the most rapidly growing class of drugs, with applications ranging from cancer and infectious disease to autoimmunity. Researchers have long understood the variable domain of antibodies, which are responsible for antigen recognition, and can provide protection by blocking the function of their target antigen. However, recent developments in our understanding of the protection mediated by antibodies have highlighted the critical nature of the antibody constant, or Fc domain, in the biological activity of antibodies. The Fc domain allows antibodies to link the adaptive and innate immune systems, providing specificity to a wide range of innate effector cells. In addition, they provide a feedback loop to regulate the character of the immune response via interactions with B cells and antigen-presenting cells.

Key Features

  • Clarifies the different mechanisms of IgG activity at the level of the different model systems used, including human genetic, mouse, and in vitro
  • Covers the role of antibodies in cancer, infectious disease, and autoimmunity and in the setting of monoclonal antibody therapy as well as naturally raised antibodies
  • Color illustrations enhance explanations of the immune system


vaccinologists, immunologists, microbiologists, oncologists, protein engineers, in academic and industrial research institutions; graduate students in immunology and vaccinology.

Table of Contents

  • List of Contributors

    1: Effector Mechanisms

    Chapter 1. Antibody-Dependent Cellular Cytotoxicity (ADCC)

    Brief History of ADCC

    Effector Cells

    Receptors Involved

    Mechanisms of ADCC

    ADCC in Monoclonal Antibody Therapy of Cancer

    ADCC in Infectious Disease: A Correlate of Protection?

    Rational Modification of ADCC Activity

    Enhancing the Link between ADCC and Adaptive Immunity

    Perspectives: Future Directions



    Chapter 2. Antibody-Dependent Cellular Phagocytosis and Its Impact on Pathogen Control


    Phagocytic Cells and Their Fcγ Receptors

    Fcγ Receptor-Mediated Phagocytosis by Phagocytes

    Role of FcγR-Mediated Phagocytosis for Pathogen Uptake, Cellular Localization, and Pathogen Control

    Concluding Remarks


    Chapter 3. Interactions Between the Complement System and Fcγ Receptors

    Preliminary Comments

    Complement Fragment C3b Mediates Binding of IgG Immune Complexes to Primate Erythrocytes: Immune Adherence

    Complement Fragment C3d Mediates Binding of Substrates to CR2 on B Cells: Antigen Trafficking and its Significance in HIV Disease

    Cooperation/Synergy between Fcγ Receptors and Complement Receptors on Effector Cells

    Cross-Talk between the C5a Receptor and FcγR on Effector Cells

    Concluding Remarks



    2: Effector Cells

    Chapter 4. Natural Killer Cells

    Inhibitory Receptor Modules Inform a Useful and Self-Tolerant NK Cell Repertoire

    Activating Immunoreceptors Mediate NK Cell Recognition of Tumors and Infected Cells

    Adaptive Features of NK Cells


    Chapter 5. Phagocytes and Immunoglobulins

    Antibodies in the Context of Innate and Acquired Immune Recognition

    General Characteristics of Mononuclear Phagocytes: Macrophages, Monocytes, and Dendritic Cells

    General Characteristics of Granulocytes

    Opsonic and Non-Opsonic Recognition in Phagocytes

    Non-Opsonic Recognition: Pattern Recognition Receptors

    Phagocyte Activation in Response to Non-Opsonic Recognition

    Opsonic Recognition: FcRs and Complement Receptors

    Phagocyte Cooperation During Inflammation


    Antigen Presentation by DCs, Role of FcγRs

    Collaboration Between FcR and Non-Opsonic Receptors

    Concluding Remarks


    Chapter 6. B Cells: Development, Differentiation, and Regulation by Fcγ Receptor IIB in the Humoral Immune Response

    B Cell Development and Selection in the Bone Marrow

    B Cell Selection, Activation, and Tolerance in the Peripheral Immune System

    Generation of Plasma Cells and Memory B Cells in the Germinal Center

    FcγRIIB Regulates B-Cell Activation and Apoptosis

    FcγRIIB Inhibits Autoantibody Production

    FcγRIIB as a Regulator of Long-Term Survival of Plasma Cells in the Bone Marrow


    3: FcR

    Chapter 7. Structural Recognition of Immunoglobulins by Fcγ Receptors


    Structures of Fcγ Receptors

    Structure of the IgG Fc Domain

    Structure of FcγRIII–Fc Complex

    FcγRIII–Fc Binding Interface

    FcγR Specificities for IgG Subclasses

    Fc Receptor Isoform Affinities to IgG

    Influence of FcR Polymorphism on IgG Recognition

    Role of Fc Glycosylation in the Recognition of Antibodies by Fcγ Receptors

    Recognition of Fc Receptors by Pentraxins



    Chapter 8. FcγRs Across Species


    Human FcγRs

    Mouse FcγRs

    Human Versus Mouse FcγRs

    Macaque FcγRs

    Human Versus Macaque FcγRs




    4: Variability of the Fc Domain

    Chapter 9. Human IgG Subclasses

    Introduction: Immunoglobulins and Humoral Immunity



    Binding to Effector Molecules

    IgG Antibody Responses

    Therapeutic Considerations



    Chapter 10. Antibody Glycosylation

    Human Antibody: An Overview of Structure and Function

    Human IgG Fc Structure and Function

    Human IgG Fc Glycosylation

    Role of IgG Fc Glycosylation in Fc Structure

    Activities of IgG Glycoforms

    Glycan Engineering of Antibodies

    Endoglycosidases in Immune Evasion and Therapeutics

    Variations of Antibody Glycosylation in Disease

    Conclusion and Perspectives


    5: Genetic Associations

    Chapter 11. Activating and Inhibitory FcγRs in Autoimmune Disorders


    A Question of Balance: Co-expression of Activating and Inhibitory Fc Receptors

    Establishing the Threshold for Cell Activation: Activating and Inhibitory Fc Receptor Signaling

    Signaling Pathways of Activating Fc Receptors

    Inhibitory Signaling Pathways

    Disturbing the Threshold: Horror Autotoxicus

    Changing the Expression Level of the Inhibitory Receptor on B Cells

    FcγRIIB as a Regulator of Dendritic Cell Activity

    The Role of FcγRIIB in the Efferent Response: Controlling Innate Immune Effector Cell Activation

    The Activating Fc Receptors in the Efferent Response

    Exogenous Factors Modulating the Balance: Cytokines and Sugar

    Regaining the Balance: Therapeutic Interventions that Modulate FcR Expression




    Chapter 12. Fcγ Receptor Polymorphisms and Susceptibility to Infection


    The Fcγ Receptor Family Genes

    FcγR Distribution and Function

    Genetic Variation in Human FcγRs

    FcγRs and Infection: Evidence Base

    FcγRs and Defense Against Infection


    Acknowledgments and Funding


    Chapter 13. Role of IgG Fc Receptors in Monoclonal Antibody Therapy of Cancer

    Mechanisms of Action of Monoclonal Antibodies in Oncology

    Development of Therapeutic Monoclonal Antibodies for the Treatment of Cancer

    Fc-Mediated Effector Functions, Preclinical Data

    Role for FcγR-Mediated Effector Functions, Clinical Data

    Polymorphisms in FcγRs

    Impact of FcγR Polymorphisms on mAb Treatment, Preclinical in Vitro Data

    Impact of FcγR Polymorphisms in mAb Treatment, Clinical Data

    Opportunities to Enhance FcγR-Mediated Effector Functions

    Future Perspectives


    6: Evolving Areas

    Chapter 14. No Mechanism is an Island: Interactions Among Monoclonal Antibody Mechanisms of Action


    In Vitro Analysis

    Animal Models

    Clinical Trials

    Individual Mechanisms of Action

    Interacting Mechanisms



    Chapter 15. Fc Receptor-Dependent Immunity

    Fc Receptors and Signaling Mechanisms in Immune Effector Cells

    Contribution of FcR-Mediated Immune Effector Functions of Antibodies to Protective Acquired Immunity

    The Immune Effector Mechanisms of FcR-Dependent Functional Processes and their Applications in Immunotherapy and Immunomodulation



    Chapter 16. Fcγ Receptors as Therapeutic Targets


    The A/I Ratio

    Fc Glycan Control of FcγR Interactions

    Activating and Inhibitory FcγR Expression

    Anti-Inflammatory IgG Modulates FcγR Expression

    FcγR Regulation During Autoimmune Disease

    FcγR Regulation During Infection

    FcγR Regulation During Cancer

    Engineering IgG Immune Responses

    Targeting Fcs to FcγRs

    Engineering the Fc Peptide Backbone

    Outlook and Perspectives


    Chapter 17. Fc Protein Engineering


    The IgG Subclasses

    IgG-Fc Binding Ligand: An Overview

    Evaluation of IgG-Fc Engineered Proteins

    IgG1 and IgG3 Binding and Activation of FcγR

    IgG2 Binding and Activation of FcγR

    IgG4 Binding and Activation of FcγR

    The Neonatal Receptor FcγRn: Transcytosis and Catabolism

    Classical Pathway of Complement Activation

    Immunogenicity and Adverse Events

    Human IgG-Fc Binding Ligands in Nature

    Concluding Remarks


    Chapter 18. Bacterial Modulation of Fc Effector Functions


    Immunoglobulin-Binding Proteins

    Immunoglobulin Proteases

    Immunoglobulin Glycan Hydrolases

    Concluding Remarks



    Chapter 19. Pathogenic Exploitation of Fc Activity


    ADE in Viruses

    ADE in Protozoan Parasites of Macrophages: Leishmania

    ADE in Other Intracellular Parasites and Bacteria

    Concluding Thoughts


    Chapter 20. Mechanisms of Immunoglobulin-Mediated Mucus Entrapment of Pathogens at Various Mucosal Surfaces


    Structure of Mucus

    Mechanisms of Immunity at Mucosal Surfaces





Product details

  • No. of pages: 358
  • Language: English
  • Copyright: © Academic Press 2013
  • Published: August 6, 2013
  • Imprint: Academic Press
  • Hardcover ISBN: 9780123948021
  • eBook ISBN: 9780123948182
  • About the Editors

    Margaret Ackerman

    Margaret Ackerman
    Margaret E. Ackerman studied molecular engineering at the Massachusetts Institute of Technology under K. Dane Wittrup, followed by postdoctoral studies at the Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University under Galit Alter. She was appointed an Assistant Professor of Engineering at Dartmouth College’s Thayer School of Engineering in 2011, and an Assistant Professor in the Department of Microbiology and Immunology at Dartmouth’s Geisel School of Medicine in 2012. Her research group applies protein engineering, molecular biology, and mathematical modelling tools to design enhanced antibody therapeutics and and vaccines.

    Affiliations and Expertise

    Thayer School of Engineering, Dartmouth College Department of Microbiology and Immunology, Geisel School of Medicine

    Falk Nimmerjahn

    Falk Nimmerjahn
    Falk Nimmerjahn studied Biology at the Universities of Bayreuth, Erlangen-Nuernberg and Munich in Germany. After his postdoctoral studies in the laboratory of Jeffrey Ravetch at the Rockefeller University in New York from 2004-2007, he was appointed as an Associate Professor at the University Hospital of Erlangen in 2007. Since 2010 he has been a full Professor of genetics and chairman of the Institute of Genetics at the University of Erlangen-Nuernberg in the Department of Biology. His research focuses on understanding the molecular and cellular mechanisms of mouse and human IgG activity. He authored more than 80 peer reviewed papers and several chapters in text books. For his work on immunoglobulin activity he was awarded several prizes, among them the Paul-Ehrlich and Ludwig Darmstädter Award for young scientists.

    Affiliations and Expertise

    Institute of Genetics, Department of Biology, University of Erlangen-Nürnberg