Molecular Biology of B Cells Tasuku Honjo Frederick W. Alt Michael S. Neuberger Editors Elsevier Academic Press Molecular Biology of B Cells Molecular Biology of B Cells Edited by Tasuku Honjo Department of Medical Chemistry Kyoto University Faculty of Medicine Kyoto, Japan Frederick W. Alt Howard Hughes Medical Institute The Center for Blood Research The Children’s Hospital, Boston, Massachusetts Michael S. Neuberger MRC Laboratory of Molecular Biology Protein and Nucleic Acid Chemistry Division Cambridge, United Kingdom AMSTERDAM • BOSTON • HEIDELBERG • LONDON NEWYORK • OXFORD • PARIS • SAN DIEGO SAN FRANCISCO • SINGAPORE • SYDNEY• TOKYO Elsevier Academic Press 84 Theobald’s Road, London WC1X 8RR, UK 525 B Street, Suite 1900, San Diego, California 92101-4495, USA Copyright ©2004, Elsevier Ltd. All rights reserved. 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ISBN: 0-12-053641-2 For all information on all Academic Press publications visit our Web site at http://books.elsevier.com Printed in the United States of America 03 04 05 06 07 08 9 8 7 6 5 4 3 2 1 Contributors Dr. Frederick W. Alt Howard Hughes Medical Institute, The Children’s Dr. Adolfo Ferrando Department of Pediatrics, Children’s Hospital, Dana- Hospital, The Center for Blood Research, Boston, MA, USA Farber Cancer Institute, Boston, MA, USA Dr. Barbara Birshtein Department of Cell Biology, Albert Einstein Dr. Martin F. Flajnik Department of Microbiology and Immunology, Uni- College of Medicine, Bronx, NY, USA versity of Maryland, Baltimore, MD, USA Dr. Constantin A. Bona Department of Microbiology, The Mount Sinai Dr. Raif S. Geha Department of Pediatrics, Harvard Medical School, School of Medicine, New York, NY, USA Boston, MA, USA Dr. Francisco Bonilla Division of Immunology, Children’s Hospital, Dr. Deborah LHardie Medical Research Council Centre for Immune Reg- Boston, MA, USA ulation, The University of Birmingham Medical School, Birmingham, England, UK Dr. Per Brandtzaeg Laboratory of Immunohistochemistry and Immunopathology (LIIPAT), Institute of Pathology, University of Oslo, Dr. Linda Hendershot Tumor Cell Biology, St Jude Children’s Research Rikshospitalet, Oslo, Norway Hospital, Memphis, TN, USA Dr. Marianne Bruggemann Laboratory of Developmental Immunology, The Babraham Institute, Babraham Hall, Babraham, Cambridge, UK Dr. Tasuku Honjo Department of Medical Chemistry, Kyoto University Faculty of Medicine, Yoshida, Sakyo-ku, Kyoto, Japan Dr. PeterBurrows Department of Microbiology, University of Alabama at Birmingham, 383 Wallace Tumor Institute, Birmingham, USA Dr. Ellen Hsu Department of Physiology & Pharmacology, The State Uni- versity of New York Health Science Center at Brooklyn, Brooklyn, NY, Dr. Kathryn Calame Departments of Microbiology and Biochemistry & USA Molecular Biophysics, Columbia Unversity, Collge of Physicians and Surgeons, New York, NY, USA Dr. John F. Kearney Division of Developmental and Clinical Immunol- ogy, Department of Microbiology, University of Alabama at Birming- Dr. Michael C. Carroll Department of Pediatrics, Harvard Medical ham, 6th Avenue South, Birmingham, AL, USA School, The Center for Blood Research, Boston MA, USA Dr. Paul W. Kincade Immunobiology and Cancer Research Program, Dr. Michel Cogné Laboratoire d’Immunologie, Faculte de Medecine, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA Limoges Cedex, France Dr. Kazuo Kinoshita Department of Medical Chemistry, Graduate School Dr. Max D. CooperHoward Hughes Medical Institute, The University of of Medicine, Kyoto University, Yoshida-Konoe, Sakyo-ku, Kyoto, Japan Alabama at Birmingham, 378 Wallace Tumor Institute, Birmingham AL, USA Dr. Katherine L. Knight Department of Microbiology and Immunology, Loyola University Stritch School of Medicine, Maywood, IL, USA Dr. Jason Cyster Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California San Francisco, Dr. Michael Krangel Department of Immunology, Duke University San Francisco, CA, U.S.A. Medical Center, Jones Bldg, Research Drive, Durham, NC, USA Dr. Nadia Danilova Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA Dr. Michael E. Lamm Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA Dr. Randall S. DavisDivisions of Developmental and Clinical Immunol- ogy and Hematology/Oncology, Department of Medicine, University of Dr. Dennis Lanning Department of Microbiology and Immunology, Alabama at Birmingham, Birmingham, AL, USA Loyola University Stritch School of Medicine, Maywood, IL, USA Dr. Douglas T. Fearon Department of Medicine, University of Cambridge Dr. Tucker W. LeBien University of Minnesota Cancer Center, Min- School of Clinical Medicine_Addenbrookes Hospital, Cambridge, UK neapolis, MN, USA v vi Contributors Dr.Gerard Lefranc Laboratoire d’Immunogenetique Moleculaire, Institut Dr. Michael Reth Department of Molecular Immunology, Faculty of de Genetique Humaine, Universite Montpellier II, Montpellier Cedex 5, Biology III, University of Freiburg and Max Planck Institute for France Immunobiology, Freiburg, Germany Dr. Marie-Paul Lefranc Laboratoire d’Immuno Genetique Moleculaire, Dr. Roy Riblet Torrey Pines Institute for Molecular Studies, San Diego, LIGM, Universite Montpellier II, UPR CNRS Institut de Genetique CA, USA Humaine, Montpellier Cedex 5, France Dr. Matthew Scharff Department of Cell Biology, Albert Einstein College Dr. Susanna Lewis Genetics and Genomic Biology, Hospital for Sick Chil- of Medicine, Bronx, NY, USA dren Research Institute, Toronto, Ontario, Canada Dr. Mark S. Schlissel Department of Molecular and Cellular Biology, Division of Immunology, University of California-Berkeley, Berkeley, Dr. Gary W. Litman Department of Molecular Genetics, All Children’s CA, USA Hospital, St. Petersburg, FL, USA Dr. JoAnn Sekiguchi Howard Hughes Medical Institute, The Children’s Dr. A. Thomas Look Department of Pediatrics, Children’s Hospital, Dana- Hospital, The Center for Blood Research, Boston, MA, USA Farber Cancer Institute, Boston, MA, USA Dr. Ranjan Sen Department of Biology, Brandeis University, Waltham, Dr. Ian C. M. MacLennan Medical Research Council Centre for Immune MA, USA Regulation, The University of Birmingham Medical School, Birming- ham, UK Dr. Mark Shlomchik Section of Immunobiology, Yale University School of Medicine, New Haven, CT, USA Dr. Nancy Maizels Departments of Immunology and Biochemistry, Uni- versity of Washington Medical School, Seattle, WA, USA Dr. Robero Sitia Department of Molecular Pathology and Medicine, Uni- versita Vita-Salute San Raffaele, DIBIT-HSR Scientific Institute, Milan, Dr. Roy Mariuzza Center for Advanced Research in Biotechnology, W. M. Italy Keck Laboratory for Structural Biology, University of Maryland Biotechnology Institute, Rockville, MD, USA Dr. Janet M. StavnezerDepartment of Molecular Genetics and Microbi- ology, University of Massachusetts Medical School, Worcester, MA, Dr. Jim Marks Department of Anesthesia, San Francisco General Hospi- USA tal, San Francisco, CA, USA Dr. Lisa A. Steiner Department of Biology, Massachusetts Institute of Dr. Fumihiko Matsuda Centre National de Genotypage, Evry Cedex, Technology, Cambridge, MA, USA France Dr. Freda Stevenson Molecular Immunolgy Group, Tenovus Laboratory, Southampton University Hospitals Trust, Southampton, UK Dr. Fritz Melchers Deptartmen of Cell Biology, Biozentrum, University of Basel, Basel, Switzerland Dr. Eric Sundberg Center for Advanced Research in Biotechnology, W. M. Keck Laboratory for Structural Biology, University of Maryland Dr. Herbert C. Morse III Laboratory of Immunopathology, National Insti- Biotechnology Institute, Rockville, MD, USA tutes of Health, Bethesda, MD, USA Dr. Naoya Tsurushita Protein Design Labs, Inc., Fremont, CA, USA Dr. H. Craig Morton Laboratory of Immunohistochemistry and Immunopathology (LIIPAT), Institute of Pathology, University of Oslo, Dr. Maximiliano Vásquez Protein Design Labs, Inc., Fremont, CA, USA Rikshospitalet, Oslo, Norway Dr. Ulrich H. von Andrian The Center for Blood Research and the Depart- Dr. Masamichi Muramatsu Department of Medical Chemistry, Graduate ment of Pathology, Harvard Medical School, Boston, MA, USA School of Medicine, Kyoto University, Yoshida-Konoe, Sakyo-ku, Kyoto, Japan Dr. Urich H. von Andrian Department of Pathology, The Center for Blood Research, Boston, MA, USA Dr. Lars Nitschke Institute of Virology and Immunobiology, Wuerzburg, Dr. Gregory W. WarrDepartment of Biochemistry, and Center for Marine Germany Biomedicine and Environmental Sciences, Medical University of South Dr. Marjorie A. OettingerDepartment of Molecular Biology, Massachu- Carolina, Charleston, SC, USA setts General Hospital, Boston, MA, USA Dr. Jurgen Wienands Department of Biochemistry & Molecular Immunol- ogy, Universität Bielefeld, Abteilung Biochemie I, Bielefeld, Germany Dr. Barbara A. Osborne Department of Veterinary and Animal Science, University of Massachusetts, Amherst, MA, USA Dr. Catherine Willett Phylonix Pharmaceuticals, Inc., USA Dr. Andreas Radbruch Deutsches Rheumaforschungszentrum Berlin, Dr. Gillean Wu Dean, Faculty of Pure and Applied Science, York Univer- 10117 Berlin, Germany sity, Toronto, Ontario, Canada Dr. Klaus Rajewsky Harvard Medical School, Center for Blood Research, Dr. Hans G. Zachau Adolf-Butenandt-Institut Molekularbiologie, 200, Longwood Avenue, Boston, MA, USA Muenchen, Germany Dr. Jeffrey V. Ravetch Laboratory of Molecualr Genetics and Immunol- Dr. Zhixin Zhang Howard Hughes Medical Institute, University of ogy, The Rockefeller University, New York, NY, USA Alabama at Birmingham, Birmingham, AL, USA Contents Preface xiii 5. The Mechanisms of V(D)J Recombination JOANN SEKIGUCHI, FREDERICK W. ALT, AND 1. Human Immunoglobulin Heavy MARJORIE OETTINGER Chain Locus Antigen Receptor Gene Assembly 62 FUMIHIKO MATSUDA Mutational Analyses of Recombination Signal Sequences 64 Organization of the Human V Locus 2 H “Beyond 12/23” Restriction of V(D)J Analysis of Human V Segments 7 H Rearrangements 64 Evolution of the Human V Locus 10 H Influence of Coding Flanks 65 Human C Locus 12 H The Biochemistry of V(D)J Cleavage 65 RAG1/2-RSS Binding 66 2. Immunoglobulin Heavy Chain Genes RAAG1/2 Post-Cleavage Complex 67 of Mouse ARole for HMG1 (or HMG2) in V(D)J Recombination 67 ROY RIBLET ACloser Look at RAAG1 and RAG2 68 Colding and Signal Joint Formation Requires the NHEJ Igh-Vor V Genes of the Igh Haplotype 19 H b Pathway 71 Polymorphism in VH Genes 20 Evolution 24 Genomic Considerations 24 6. Transcription of Immunoglobulin Genes 3. Immunoglobulin K Genes of Human KATHRYN CALAME AND RANJAN SEN and Mouse Transcriptional Regulatory Elements in Immunoglobulin HANS G. ZACHAU Heavy and Light Chain Genes 83 Proteins Binding in Ig Transcriptional Regulatory General Features of Human and Mouse K Genes 27 Elements 86 Human Immunoglobulin K Genes 27 Areas of Current Research 89 Mouse Immunoglobulin K Genes 30 Discoveries Resulting from the Study of Ig Gene Aspects of Evolution of the K Genes 33 Transcription 93 4. Immunoglobulin Lambda (IGL) Genes of Human and Mouse 7. Early B Cell Development to a Mature, Antigen-Sensitive Cell MARIE-PAULE LEFRANC AND GÉRARD LEFRANC FRITZ MELCHERS AND PAUL KINCADE IGLGenes and IMGT-ONCOLOGY 37 The Human IGLGenes 40 Three Waves of Hematopoiesis During Embryonic The Mouse IGLGenes 50 Development 101 vii viii Contents Pluripotent Hematopoietic Stem Cells 103 10. Development and Function of B Pathways of Hematopoietic Progenitor Cells Toward Cell Subsets B Lymphocyte Lineage Commitment and JOHN T. KEARNEY Differentiation 106 Control of Lymphoid Cell Development by Transcription Selection and Differential Survival Mechanisms—B Cell Factors 107 Receptor Signaling 156 Plasticity if PAX-5–Deficient Pre-B Cells 109 Compartmentalization of B Cell Subsets 157 The Surrogate Light Chain 110 Other Factors Involved in Formation of B Cell Pre-B Cells and Their Differentiation to More Mature B Subsets 157 Lineage Cells 112 Rearrangements at the LChain Loci at the Transition from Large to Small Pre-B-II Cells 114 11. Structure and Function of B Cell Antigen Immature B Cells 116 Receptor Complexes Selections of Immature B Cells 117 MICHAEL RETH AND JURGEN WIENANDS Structure of the BCR Complex 161 Coupling Between the BCR and SYK 162 Redox Regulation of BCR Signaling 162 8. Allelic Exclusion, Isotypic Exclusion, ITAM- and Non-ITAM-Controlled Signaling Pathways to and the Developmental Regulation of SLP-65 163 V(D)J Recombination ITAM-Independent Signaling and Fine-Tuning 165 MICHAEL S. KRANGEL AND MARK S. SCHLISSEL 12. Regulation of Antigen Receptor Signaling Rag Expression 127 The 12/23 Rule 128 by the Co-Receptors, CD19 and CD22 Accessibility Hypothesis 128 LARS NITSCHKE AND DOUGLAS T. FEARON Enhancer and Promoter Control of V(D)J Recombination 128 CD19 171 Trans-Acting Factors 130 Inhibitory Co-Receptors on B Cells 177 Chromatin Dynamics and V(D)J Recombination 130 Ordered Rearrangement Within Ig and TCR Loci 132 13. The Dynamic Structure of Allelic Exclusion at Ig and TCR Loci 133 Ig Light Chain Isotypic Exclusion 136 Antibody Responses Future Directions 136 IAN C. MACLENNAN AND DEBORAH L. HARDIE Three Routes to Antibody Production 187 Stages of Adaptive Antibody Responses 187 How and Where B Cells Encounter Antigen 188 9. The Development of Human Primary Cognate Interaction of B Cells with Primed T B Lymphocytes Cells 189 Exponential Growth of Activated B Cells 190 PETER D. BURROWS, TUCKER LEBIEN, ZHIXIN ZHANG, RANDALL S. DAVIS, AND MAX D. COOPER Proliferation, Hypermutation, and Selection in GC 192 Sustained Survival of Memory B Cell Clones and Plasma Stages of Human B Cell Differentiation 141 Cells 197 Sites of Human B Cell Development 143 Human Immunoglobulin Genes 143 14. Dynamics of B Cell Migration to and The Role of Surrogate Light Chains in Human B Cell Development 144 within Secondary Lymphoid Organs Repertoire Diversification via Receptor Editing and VH JASON G. CYSTER AND ULRICH H. VON ANDRIAN Replacement 145 Regulation of Antibody Production by B Cell Lymphoid Organ Entry 203 Receptors 147 Compartmentalization of Mature B Cells 209 Immunodeficiency Diseases 148 B Cells at Sites of Inflammation 213 B Lineage Leukemia 149 Homing of Antibody Secreting Cells (ACSs) 213 Contents ix 15. Characteristics of Mucosal B Cells with 19. Regulation of Class Emphasis on the Human Secretory Switch Recombination Immune System MICHEL COGNÉ AND BARBARA K. BIRSHTEIN PER BRANDTZAEG, H. CRAIG MORTON, AND CSR Requires Specific Stimuli Occurring in a Defined MICHAEL E. LAMM Germinal Center (GC) Microenvironment 289 Immune-Inductive Tissue Compartments 223 Proximal CIS Regulatory Elements for GT 291 Characteristics of B Cells in Secretory Effector Distant Regulatory Region for GTand CSR: The 3¢IGH Tissues 226 Enhancers 293 B-Cell Stimulation in MALTStructures 229 Mechanisms for 3¢IGH Regulatory Region-Mediated Class Switch and Ig AIsotype Promotion 232 Regulation of GT 295 Mechanisms Directing Homing and Retention of Mucosal Coordinated Regulation of Transcription, Recombination, B Cells 234 and Replication 300 What Is Actually Known About Human Mucosal B Cells? 238 20. Molecular Mechanisms of Class 16. The Cellular Basis of B Cell Memory Switch Recombination KLAUS RAJEWSKY AND ANDREAS RADBRUCH JANET STAVNEZER, KAZUO KINOSHITA, MASAMICHI MURAMATSU, AND TASUKU HONJO Generation of B Cell memory and Memory B Cells in T Cell-Dependent Antibody Responses 247 Outline of Mechanisms for CSR 307 Memory Plasma Cells 252 Isotype Specificity of CSR 312 Adaptive B Cell Memory 254 AID, The Sole B Cell-Specific Factor Required for CSR 313 Cleavage of the S Region 314 Processing and Joining of DNAEnds After 17. Immunoglobulin Assembly Cleavage 315 and Secretion Comparison of CSR with SHM 319 LINDA M. HENDERSHOT AND ROBERTO SITIA Mechanisms of IG Synthesis and Assembly 261 Multiple Layers of Quality Control Exist to Aid and Monitor the Assembly of Functional IGs 264 21. Molecular Mechanisms Transport of Assembled IG Molecules to the Golgi 267 of Hypermutation Degradation of Misfolded and Unassembled IG NANCY MAIZELS AND MATTHEW D. SCHARFF Subunits 267 Differentiation to Plasma Cell 268 Characteristics of Somatic Hypermutation of Immunoglobulin Variable Regions 327 Activation and Targeting of Hypermutation by Transcription and CIS-Elements 329 18. Fc and Complement Responses Hypermutation Occurs Within a Limited Window of B Cell development 330 JEFFREY V. RAVETCH AND MICHAEL C. CARROLL The AIDGene Is Critical for Hypermutation 331 Consequences of FCgRIIB Deficiency 275 Phase One of Hypermutation: C ÆU Deamination and Consequences of Complement and Complement Receptor Base Excision Repair 332 Deficiencies 276 Mismatch Repair Factors in Phase Two of Fc Receptors 2276 Hypermutation 332 Complement Receptors 280 DNABreaks in Hypermutation 334 Co-Receptor Signaling Versus Antigen Localization to Competing Pathways of Repair: Error-Prone DNA FDC 281 Synthesis or Strand Transfer 335 Frontiers: Complement Versus Fc Receptors 285 Evolution and Hypermutation 335