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Antibody Fc - 1st Edition - ISBN: 9780123948021, 9780123948182

Antibody Fc

1st Edition

Linking Adaptive and Innate Immunity

Editors: Margaret Ackerman Falk Nimmerjahn
eBook ISBN: 9780123948182
Hardcover ISBN: 9780123948021
Imprint: Academic Press
Published Date: 6th August 2013
Page Count: 358
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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






No. of pages:
© Academic Press 2013
6th August 2013
Academic Press
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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


"…highly recommended reading for all students of immunology and scientists involved in the research and development of therapeutic antibodies and vaccines because of its comprehensive coverage of relevant topics…also recommended as an excellent resource for academic, government and company libraries."--mAbs, May/June 2014
"Antibody Fc: Linking Adaptive and Innate Immunity is highly recommended reading for all students of immunology and scientists involved in the research and development of therapeutic antibodies and vaccines because of its comprehensive coverage of relevant topics…The book is also recommended as an excellent resource for academic, government and company libraries."--mAbs, March 21, 2014
"Ackerman and Nimmerjahn offer this volume on the immunological functions of the Fc antibody region. The first two parts discuss effector mechanisms and their mediating cells including antibody-dependent cytotoxicity, the complement system, phagocytosis, natural killer and B cells. Parts III-IV cover general properties of Fc immune receptors, receptor variation amongst species, and the structural variations and glycoside modifications of the Fc domain.", February 2014

Ratings and Reviews