Molecular Biology of B Cells

3rd Edition - January 10, 2024
Imprint: Academic Press
Editors: Tasuku Honjo, Michael Reth, Andreas Radbruch, Frederick Alt, Alberto Martin
Language: English
Hardback ISBN:
9 7 8 - 0 - 3 2 3 - 9 5 8 9 5 - 0
eBook ISBN:
9 7 8 - 0 - 3 2 3 - 9 5 8 9 6 - 7

Molecular Biology of B Cells, Third Edition provides a comprehensive reference on how B cells are generated, selected, activated, and engaged in antibody production. These develo… Read more

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Molecular Biology of B Cells, Third Edition provides a comprehensive reference on how B cells are generated, selected, activated, and engaged in antibody production. These developmental and stimulatory processes are described in molecular, immunological, and genetic terms to give a clear understanding of complex phenotypes. The book offers an integrated view of B cells to produce a normal immune response as a constant, and the molecular basis of numerous diseases due to B cell abnormality. This new edition provides updated research on B cell development and function, the use of therapeutic antibodies in cancer and infectious disease, and more. With updated research and continued comprehensive coverage of all aspects of B cell biology, Molecular Biology of B Cells, this updated release is a definitive resource, vital for researchers across molecular biology, immunology, and genetics.

Cover image
Title page
Table of Contents
Copyright
Contributors
Preface
Chapter 1. The Structure and Regulation of the Immunoglobulin Loci
1. Introduction
2. Genomic Organization of the Mouse Immunoglobulin Heavy Chain Locus
3. Genomic Organization of the Mouse Immunoglobulin Kappa Light Chain Locus
4. Genomic Organization of the Mouse Immunoglobulin Lambda Light Chain Locus
5. B Cell Development and Regulation of V(D)J Recombination
6. Junctional Diversity
7. Combinatorial Diversity
8. Noncoding Transcription and Immunoglobulin Locus Rearrangement
9. The Process of Dh–Jh Recombination
10. Epigenetics and Immunoglobulin Locus Rearrangement
11. Insulators and Immunoglobulin Locus Rearrangement
12. 3D Structure and Compaction of the Immunoglobulin Heavy Chain Locus
13. Conclusion
Chapter 2. The Mechanism, Regulation and Evolution of V(D)J Recombination
1. Introduction
2. RAG 1/2 Activity in V(D)J Recombination
3. The Joining Phase of V(D)J Recombination
4. Regulation of V(D)J Recombination
5. Evolution of V(D)J Recombination
Chapter 3. The Origin of V(D)J Diversification
1. Introduction
2. The Alien Seed
3. The Evolution of BCR and TCR Loci
4. Considerations on the Ur-V Gene
5. Concluding Remarks
Chapter 4. The Variable Lymphocyte Receptor B System of the Jawless Vertebrates
1. Introduction
2. The Structure of VLRB Protein
3. Structure and Evolution of the Germline VLRB Gene
4. Characteristics of Lamprey B Cells
5. Sites of Lamprey B Cell Development
6. The Sea Lamprey VLRB Antibody Response
7. VLRB Monoclonal Antibodies
8. Commonalities and Differences of Vertebrate Adaptive Immune Systems
9. Outstanding Questions About the Jawless Vertebrate VLRB System
Chapter 5. Structure and Signalling Function of the B-Cell Antigen Receptor and Its Coreceptors
1. Introduction
2. Basic Structure of the BCR Complex
3. The Resting BCR and the Three-Dimensional Topography of the B-Cell Surface
4. BCR Activation Models
5. The BCR Coreceptors CD19 and CD22
6. CD22: An Inhibitory Receptor
7. Initial Antigen-Induced Events in BCR Signalling
8. The BCR Signalosome and Phospholipase Cγ2 Activation
9. NFAT Activation and Function
10. NF-κB Activation
11. Activation of Phosphoinositide 3-Kinase (PI3K)
12. Akt, a Multifunctional Transducer of PI3K Signalling
13. Phosphoinositide Regulation
14. GTPase Activation and GTPase-Regulated Signalling Pathways
15. BCR Signalling to the Cytoskeleton
16. Immune Synapse Formation and Function
Chapter 6. Fc Receptors
1. Introduction
2. Structural Determinants of IgG–FcR Interactions
3. B-cell IgG Fc Receptors
4. FcγR Function and Properties
5. Animal and Clinical Studies on B-Cell FcR Function
Chapter 7. Transcriptional Regulation of Early B-Cell Development
1. Introduction
2. The Trajectory of B-Cell Development
3. Early B-Lineage Specification Regulated by Transcription Factors
4. Defining Transcription Factor Function
5. EBF1: A COE Family Transcription Factor
6. E Proteins
7. PAX Transcription Factors
8. ETS Family Transcription Factors
9. Forkhead O (Foxo) Transcription Factors
10. Zinc Finger Transcription Factors
11. Interferon Regulatory Factors
12. MYC Family Proteins
13. Conclusions
Chapter 8. Relationship between B-Cell Populations, Development and Function of B-Cell Subsets
1. Introduction
2. B-Cell Populations and Development
3. Conclusions
Chapter 9. B-Cell Development to Immunity and Tolerance
1. Introduction
2. B Cells Have Two Major Functions
3. Successive Embryonic Development of B1-a Cells in Foetal Liver and B2 Cells in Foetal Bone Marrow
4. Pre-B1-a Cell Lines and Clones with Extraordinary Proliferation Capacities
5. Establishment of Life-Long B2 Cell Development in the Bone Marrow
6. Surrogate L Chain Guides the Development of Pre-B Cells During Their V(D)J Rearrangements on the H-Chain Locus
7. Autoantigen-Reactive BcR Repertoires of B1-a and B2 Cells
8. B1-a Cells, but Not B2 Cells Express the Negative Regulator of T Cell Function: CTLA-4
9. Conclusion
Chapter 10. The Role of the BAFF and Lymphotoxin Pathways in B Cell Biology
1. BAFF/APRIL: Important Regulators of B Cell Survival, Homoeostasis, and Function
2. The Lymphotoxin Pathway: Shaping B Cell Environments
3. Conclusions and Perspectives
Chapter 11. Mechanism and Regulation of Immunoglobulin Class Switch Recombination
1. Introduction
2. Overview of Genomic Alterations in B Cells
3. Activation-Induced Cytdine Deaminase
4. Germline Transcription
5. From Base Lesions to DSBs
6. DNA End-Joining During CSR
7. DSB Damage Response and End-Joining
8. Chromosomal Translocations and AID-Induced Collateral Damage
9. Evolution of CSR Mechanism
10. Concluding Remarks
Chapter 12. Somatic Hypermutation
1. Introduction
2. A Mutagenic Enzyme Initiates SHM
3. Transcriptional and Epigenetic Features that Favour SHM at Ig Genes
4. B-Cell Intrinsic Regulation of SHM Frequency by AID Regulation
5. AID Substrates
6. DNA Repair Pathways Downstream of AID
7. Cell Cycle Regulation During SHM
8. Concluding Remarks
Chapter 13. Molecular Mechanism of Activation-Induced Cytidine Deaminase
1. Introduction
2. Features and Properties of AID
3. Molecular Mechanism for DNA Cleavage and Recombination by AID
4. Regulation of DNA Cleavage, Repair and Recombination
5. The Regulation of AID Expression
6. Conclusions
Chapter 14. Molecular Pathogenesis of B-Cell Lymphomas
1. Introduction
2. The Cell of Origin of Lymphomas
3. Mechanisms of Genetic Lesion in Lymphoma
4. Molecular Pathogenesis of Most Common Lymphoma Types
Chapter 15. Human Immunodeficiencies Caused by Inborn Errors of B-Cell Development or Function
1. Introduction
2. B-Cell Development and Function
3. Naïve B Cells Differentiate into Memory and Plasma Cells During Germinal Centre Reactions
4. Inborn Errors of Immunity
5. Inborn Errors of Immunity Reveal the Fundamental Roles of B Cells in Host Defence
6. Agammaglobulinemia and B-Cell Deficiency
7. Inborn Errors Affecting B-Cell Differentiation and Humoral Immunity
8. Insights into Regulation of IgE Production from IEI Affecting Cytokine Signaling
9. Molecular Requirements for Generating Human CD21loCD11chiT-bet+ B Cells
10. B Cells Are Key Antigen-Presenting Cells to Induce Effective Cell-Mediated Immunity Against EBV
11. Conclusion
Chapter 16. Memory B Cells and Plasma Cells
1. Introduction
2. Heterogeneity of Memory B Cells
3. Heterogeneity of Plasma Cells
4. Maintenance of Memory B Cells and Long-Lived Plasma Cells
5. The Interplay of Humoral and Reactive Memory in Adaptive Immunity
6. Antibody-Mediated Diseases
Chapter 17. Homoeostatic Versus Pathogenic Autoantibodies: Origin, Structure and Effector Functions
1. Introduction
2. Natural Autoantibodies and Their Biological Effects
3. Immuno-Suppressive Versus Immuno-Activating Antibodies: IgM, IgG and Their Receptors
4. Glycosylation of Antibodies Regulates Their Pro- or Anti-inflammatory Effect
5. B-Cell Subsets Enriched for Homoeostatic Autoreactivity
6. B Cells Development, Selection and Tolerance
7. B Cell Differentiation
8. Mechanisms that Breach B-Cell Tolerance – Why Pathogenic Autoantibodies Arise in Inflammatory Conditions?
9. Mechanisms of Pathogenicity of Autoreactive Antibodies
10. Therapeutic Strategies Targeting Pathogenic B Cell-Mediated Autoreactivity
11. Conclusion
Chapter 18. Anti-Tumour Necrosis Factor and New Paradigms for Therapies Using Antibodies
1. Introduction
2. Brief Overview of TNF Immunobiology
3. Overview of Anti-TNF Biologics
4. Successes and Failures of Anti-TNF Therapy
5. Importance of Mouse Models
6. B Cells and Anti-TNF Therapy
7. Conclusions/Perspectives
Glossary
Chapter 19. Therapeutic Targeting of B Cells and Plasma Cells with a Focus on Multiple Sclerosis and Other Autoimmune Conditions
1. Introduction
2. The Roles of B-Cell Lineage Cells in MS and Other Autoimmune Conditions
3. Therapeutic Targeting of B-Lineage Cells
4. Future Approaches and Opportunities
Chapter 20. IMGT Immunoglobulin Repertoire Analysis and Antibody Humanization
1. Introduction
2. IMGT and the Birth of Immunoinformatics
3. Fundamental Information from IMGT-ONTOLOGY Concepts
4. IMGT Immunoglobulin Repertoire Analysis
5. IMGT Antibody Engineering and Humanization
6. Conclusion
7. Availability and Citation
Chapter 21. Mucosal Immunity to Bacteria and Immunoglobulin A Synthesis
1. Introduction
2. Overview of Different Functional Aspects of IgA Biology
3. IgA Synthesis and Regulation
4. IgA Repertoire Features
5. Molecular Targets
6. Functional Insights of Secretory IgA
7. Mouse-Human Species Differences and IgA Relevance in Systemic Disease
8. Concluding Remarks
Chapter 22. B-Cell Metabolism
1. Introduction
2. Basics in Cell Metabolism
3. Signalling Pathways Regulating B-Cell Metabolism
4. Crosstalk Between Metabolism and Signalling
5. Metabolic Requirements During B-Cell Development and Differentiation
6. Metabolism in Malignant and Autoreactive B Cells
7. Consequences of Disrupted Metabolism
8. Conclusions
Index

Tasuku Honjo

Dr. Tasuku Honjo graduated from Kyoto University Faculty of Medicine in 1966 (M.D.). After obtaining his Ph.D. in Biochimistry (Dr. O. Hayaishi), he spent 4 years in the U.S.A. as a postdoctoral fellow first in Carnegie Institution of Washington (Dr. D. Brown), and then in NIH (Dr. P. Leder) where he initiated studies on immunoglobulin genes. He returned to Tokyo University as an assistant professor in 1974, and then moved to Osaka University School of Medicine as Professor of Genetics in 1979. He succeeded to Dr. O. Hayaishi after his retirement at the Department of Medical Chemistry in Kyoto University. He also served as Dean of Medical School (1996-2000 and 2004-2005), and Executive Member of Council for Science and Technology Policy, Cabinet Office (2006-2012). Currently, he is Professor of Department of Immunology and Genomic Medicine, Kyoto University, and also Chairman of Board of Directors, Shizuoka Prefectural University Corporation.

Dr. Honjo is well known for his discovery of activation-induced cytidine deaminase that is essential for class switch recombination and somatic hypermutation. He has established the basic conceptual framework of class switch recombination starting from discovery of DNA deletion (1978) and S regions (1980), followed by elucidation of the whole mouse immunoglobulin heavy-chain locus. His contribution further extended to cDNA cloning of IL-4 and IL-5 cytokines involved in class switching and IL-2 receptor alpha chain. Aside from class switching recombination, he discovered PD-1 (program cell death 1), a negative coreceptor at the effector phase of immune response and showed that PD-1 modulation contributes to treatments of viral infection, tumor and autoimmunity. In addition, he is known to be a discoverer of RBP-J, a nuclear protein that interacts with the intracellular domain of Notch in the nucleus. Notch/RBP-J signaling has been shown to regulate a variety of cell lineage commitment including T and B cells.

For these contributions, Dr. Honjo has received many awards, including the Noguchi Hideyo Memorial Prize for Medicine (1981), Imperial Prize, Japan Academy Prize (1996), Robert Koch Prize (2012), and Order of Culture (2013). He is an honorary member of the American Association of Immunologists. He has been honored by the Japanese Government as a person of cultural merits (2000). He has also been elected as a foreign associate of National Academy of Sciences, USA in 2001, as a member of Leopoldina, the German Academy of Natural Scientists in 2003, and as a member of Japan Academy in 2005.

Affiliations and expertise

Professor of Department of Immunology and Genomic Medicine, Kyoto University, Japan; Chairman of Board of Directors, Shizuoka Prefectural University Corporation, Japan

Michael Reth

Prof. Dr Michael Reth has won the Paul Ehrlich and Ludwig Darmstaedter Prize, awarded by the Paul Ehrlich Foundation, for his research on the immune system. For the first time since 1996, the prize goes to a scientist working in Germany. Dr Reth is Professor for Molecular Immunology at the Institute of Biology III of the University of Freiburg and Scientific Director of the Cluster of Excellence BIOSS, Centre for Biological Signalling Studies. He is also head of the department for Molecular Immunology at the Max Planck Institute of Immunobiology and Epigenetics (MPI-IE). The prize is endowed with €100,000 and is one of the highest honours in science in Germany. By awarding the prize to Dr Reth, the Foundation has chosen to honour a scientist who, like Nobel laureate Paul Ehrlich, decodes how immunity operates at a molecular level, in order to find new therapies for cancer and infectious diseases.

“This award is a great honour for me, because I deeply admire Paul Ehrlich’s work in immunology,” Dr Reth said. “He was one of the first scientists to consider the molecular level in this field.” Following Ehrlich’s scientific tradition, Dr Reth chose to focus his research on how the human body recognises foreign substances. “Due to the success of vaccinations, which was one of the greatest achievements in medicine, immunology has been an applied science from the beginning. However, we still do not fully understand the processes that underlie immunisation,” Dr Reth remarks. That is why his research revolves around the B cell component of the immune system. When activated, these blood cells produce antibodies to fight off infection. Dr Reth investigates the structure and organisation of the B cell antigen receptors. These molecules on the surface of B cells recognise foreign substances, so-called antigens, and trigger the activation of the immune system. Dr Reth was able to describe the basic structure of the antigen receptor of B cells for the first time in 1989. Together with his research group, he developed a new model for the activation of this receptor and recently provided further experimental evidence for this model.

Furthermore Dr Reth has shown that receptors on the plasma membrane have a more complex structure than previously assumed. They are not freely diffusing on the cell surface but are organized in 50 to 150 nanometre sized membrane patches also called protein islands. The detailed analysis of the organization of receptors on the cellular membrane is a focus of research at the BIOSS Centre for Biological Signalling Studies, the cluster of excellence directed by Dr Reth since 2007.

Located in the Signalhaus in Freiburg, BIOSS brings together engineers and biologists to investigate signalling processes using methods of synthetic biology. In the spirit of BIOSS’s motto “from analysis to synthesis”, researchers re-construct signalling cascades or develop new kinds of systems altogether – for example, hydrogels that release medication in a temporally controlled way, or signalling proteins that can be switched on and off with light.

About Michael Reth:

In 1989 Michael Reth joined Nobel laureate George Köhler’s laboratory at the MPI and later on was appointed Chair of Molecular Immunology at the University of Freiburg. He was awarded the Gottfried Willhelm Leibniz Prize of the German Research Foundation in 1995 and the EFIS-Schering-Plough European Immunology Prize in 2009.

In 2012, Michael Reth was awarded an advanced grant by the European Research Council (ERC).

Affiliations and expertise

Professor for Molecular Immunology, Institute of Biology III, University of Freiburg, Germany

Andreas Radbruch

Andreas Radbruch did his PhD at the Genetics Institute of the Cologne University, Germany, with Klaus Rajewsky. He later became Associate Professor there and was a visiting scientist with Max Cooper and John Kearney at the University of Alabama, Birmingham. In 1996, he became Director of the German Rheumatism Research Centre Berlin, a Leibniz Institute, and in 1998, Professor of Rheumatology at the Charité, the Medical Faculty of the Humboldt University of Berlin.

A biologist by education, Andreas Radbruch early on worked on somatic variants in myeloma and hybridoma cells lines, modeling antibody class switching and somatic hypermutation. In this context, his lab originally developed the MACS technology. Andreas Radbruch then showed that recombination is the physiological mechanism of class switching in vivo, in plasmablasts isolated ex vivo. Moreover, he could show that in vivo, class switch recombination is targeted to the same Ig class on both IgH loci of a cell, reflecting a tight control of targeting of recombination. An essential element of this control is transcription of recombinogenic sequences, and the processing of these switch (germline) transcripts, as became evident from targeted deletion of the control regions involved. The switch transcripts are induced by cytokines of T helper cells, e.g. interleukin-4. The Radbruch lab contributed essentially to our current understanding of the polarization and imprinting of T helper cells expressing interleukin-4 (Th2) versus those expressing interferon- (Th1).

The lab then addressed the organization of immunological memory as such. First they identified longlived (memory) plasma cells, mostly residing in bone marrow but also in secondary lymphoid organs and in inflamed tissues. They could show that these cells individually persist in dedicated survival niches, organized by CXCL12-expressing mesenchymal stroma cells. They identified different, dedicated niches for CD4+ and CD8+ memory T cells in the bone marrow, too, and could show that, at least in immune responses to vaccines, memory T cells are mostly maintained in bone marrow, resting in terms of proliferation and gene expression. Thus memory niches organize and maintain memory, and bone provides a privileged environment for resting memory cells. In chronic antibody-mediated diseases, Andreas Radbruch´s lab identified pathogenic antibody-secreting memory plasma cells as critical mediators of chronicity, refractory to conventional immunosuppression, and thus representing a novel therapeutic target. Similarly, in chronic T cell-mediated diseases, the pathogenic T cells induce and adapt to chronicity. Recently, the Radbruch group has identified Twist1, HopX and the microRNAs miR-182 and miR148a as molecular adaptations of proinflammatory T cells to chronicity, and innovative therapeutic targets.

Andreas Radbruch´s work has been recognized by the Carol Nachman Prize for Rheumatology (2011), an Advanced Grant of the European Research Council (ERC, 2010), the Federal Cross of Merit (2008) and the Aronson Award (2000). He is a member of the Berlin-Brandenburg Academy of Sciences and Humanities (BBAW), the European Molecular Biology Organization (EMBO) and the German National Academy of Sciences Leopoldina.

Affiliations and expertise

Professor of Rheumatology, Charite, Medical Faculty, Humboldt University of Berlin, Germany

Frederick Alt

Frederick W. Alt is a Howard Hughes Medical Institute (HHMI) Investigator and Director of the Program in Cellular and Molecular Medicine (PCMM) at Boston Children's Hospital (BCH). He is the Charles A. Janeway Professor of Pediatrics and Professor of Genetics at Harvard Medical School. He works on elucidating mechanisms that generate antigen receptor diversity and, more generally, on mechanisms that generate and suppress genomic instability in mammalian cells, with a focus on the immune and nervous systems. Recently, his group has developed senstive genome-wide approaches to identify mechanisms of DNA breaks and rearrangements in normal and cancer cells. He has been elected to the U.S. National Academy of Sciences, the U.S. National Academy of Medicine, and the European Molecular Biology Organization. His awards include the Albert Szent-Gyorgyi Prize for Progress in Cancer Research, the Novartis Prize for Basic Immunology, the Lewis S. Rosensteil Prize for Distinugished work in Biomedical Sciences, the Paul Berg and Arthur Kornberg Lifetime Achievement Award in Biomedical Sciences, and the William Silan Lifetime Achievement Award in Mentoring from Harvard Medical School.

Affiliations and expertise

Professor of Pediatrics and Professor of Genetics, Harvard Medical School, Boston, MA, USA

Alberto Martin

Dr. Alberto Martin received his MSc and PhD from the Department of Immunology at the University of Toronto. He is current a Professor at the same university. He also is the Sanofi Pasteur Chair in Human Immunology. Dr. Martin was a Section editor for the Encyclopedia of Immunobiology (2016) and is the Editor for PLoS Genetics, the Journal of Immunology, Frontiers in B cell Biology, and BMC Immunology. He has received a number of awards including the 2008 Canadian Society for Immunology New Investigator Award, the Top 10 funded research of 2014 from the Canadian Cancer Society, and the 2017 Canadian Society for Immunology Investigator Award.

Affiliations and expertise

University of Toronto, Department of Immunology, St. George Campus, Medical Sciences Building, Toronto, ON, Canada

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Tasuku Honjo

Michael Reth

Andreas Radbruch

Frederick Alt

Alberto Martin

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