Elsevier S & T

AID for Immunoglobulin Diversity: Advances in Immunology

Alt, Frederick W.

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Table of contents
  • Advances in Immunologyiii
  • Copyright Pageiv
  • Contentsv
  • Contributorsix
  • Prefacexiii
  • Chapter 1: Discovery of Activation-Induced Cytidine Deaminase, the Engraver of Antibody Memory1
  • 1. Introduction2
  • 2. Identification of AID as a Key Molecule in CSR and SHM4
  • 2.1. Cloning of AID4
  • 2.2. Disruption of AID Results in Loss of CSR and SHM5
  • 2.3. Enlarged Secondary Lymphoid Organs in AID-Deficient Mice8
  • 3. AID Is the Only B-Cell-Specific Factor Required for Both CSR and SHM8
  • 3.1. Ectopic Expression of AID Induces CSR of an Artificial Switch Construct in Fibroblasts9
  • 3.2. Ectopic Expression of AID Induces SHM of an Artificial Construct in Fibroblasts10
  • 4. Functional Domains of AID11
  • 4.1. The C-Terminal Domain of AID Is Required for CSR but Not for SHM11
  • 4.2. The N-Terminal Domain of AID Is Required for SHM but Not for CSR11
  • 4.3. AID Shuttles Between the Nucleus and Cytoplasm12
  • 4.4. AID Dimerization Is Necessary for CSR13
  • 5. AID Is Involved in a DNA Cleavage Step14
  • 6. Major Hypotheses for the Action of AID16
  • 6.1. RNA Editing Model17
  • 6.2. Evidence for the RNA Editing Model17
  • 6.3. DNA Deamination Model19
  • 7. Critical Examination of the DNA Deamination Model19
  • 7.1. In Vitro DNA Deamination19
  • 7.2. UNG Is Dispensable for DSBs22
  • 8. Evidence for a Novel Function of UNG in CSR24
  • 8.1. Catalytic Site Mutants of UNG Do Not Affect CSR24
  • 8.2. Replication-Coupling Motifs of UNG Are Dispensable for CSR25
  • 8.3. UNG Requires the WXXF Motif for CSR Function27
  • 9. Conclusion28
  • References29
  • Chapter 2: DNA Deamination in Immunity: AID in the Context of Its APOBEC Relatives37
  • 1. Introduction38
  • 2. AID: The DNA Deaminase Trigger for Antibody Diversification38
  • 3. The Zn-Dependent Deaminase Superfamily39
  • 3.1. Overview of Family Members39
  • 3.2. Correlation of Structure and Function Among Deaminases43
  • 4. Timeline of AID/APOBEC Evolution48
  • 5. APOBEC1: An RNA-Editing Enzyme That Can Also Act on DNA49
  • 6. APOBEC2: A Muscle-Specific Family Member of Unknown Function/Activity50
  • 7. APOBEC4: A Distant or Ancestral Member of the AID/APOBEC Family51
  • 8. APOBEC3s: DNA Deaminases Active in Viral Restriction52
  • 8.1. APOBEC3G52
  • 8.2. Other APOBEC3 Family Members55
  • 8.3. Action of APOBEC3 Family Members on Viruses Other Than Retroviruses56
  • 8.4. Action of APOBEC3 Family Members on LTR-Containing Endogenous Retroelements57
  • 8.5. Action of APOBEC3 Family Members on Non-LTR-Containing Endogenous Retroelements59
  • 8.6. Mechanism of APOBEC3-Mediated Restriction61
  • 9. Conclusion63
  • References63
  • Chapter 3: The Role of Activation-Induced Deaminase in Antibody Diversification and Chromosome Trans75
  • 1. Introduction76
  • 2. Events Preceding the DNA Lesion77
  • 2.1. Epigenetic Modifications and Transcription77
  • 2.2. Transcriptional Activation77
  • 3. The DNA Lesion78
  • 3.1. AID Function78
  • 3.2. Substrate ssDNA Is Liberated During Transcription80
  • 3.3. AID Transcriptional Regulation80
  • 3.4. The AID Protein81
  • 3.5. AID Nuclear Transport and Posttranslational Modification82
  • 3.6. AID Targeting83
  • 4. DNA Damage Detection and Resolution During CSR85
  • 4.1. Nonhomologous End-Joining and DSB Resolution During CSR85
  • 4.2. DNA Damage Response During CSR88
  • 5. AID and Lymphomagenic Lesions93
  • 5.1. Mutations in Non-Ig Genes93
  • 5.2. Non-Ig Mutations and Lymphomas93
  • 5.3. AID and Chromosome Translocations94
  • 6. Conclusions and Perspectives96
  • References96
  • Chapter 4: Targeting of AID-Mediated Sequence Diversification by cis-Acting Determinants109
  • 1. Introduction109
  • 2. The Link Between Transcription and AID-Mediated Sequence Diversification111
  • 2.1. Transcription Is Necessary for SHM, GCV, and CSR111
  • 2.2. Heterologous Promoters Can Substitute for Ig Promoters to Direct SHM and CSR in Mammalian Cells111
  • 2.3. Not All Heterologous Promoters Support Efficient GCV/SHM in DT40 Cells113
  • 2.4. Can Non-Ig Transcription Cassettes Be Targeted for AID-Mediated Sequence Diversification?114
  • 2.5. Correlation Between Transcription Levels and Frequencies of AID-Mediated Sequence Diversificati115
  • 2.6. Transcription and AID Deamination In Vitro116
  • 3. Other cis-Acting Determinants Involved in the Targeting of AID116
  • 3.1. Targeting DNA Elements in Ig Loci116
  • 3.2. DNA Newly Incorporated into the Genome Can Undergo a Transient Phase of Mutability117
  • 4. Future Outlook120
  • Acknowledgments120
  • References120
  • Chapter 5: AID-Initiated Purposeful Mutations in Immunoglobulin Genes127
  • 1. Introduction128
  • 2. Biochemical Basis of C Deamination by APOBEC Enzymes132
  • 2.1. AID Targets C Motifs on ssDNA132
  • 2.2. APOBEC-Targeting Mechanisms Involve Jumping and Sliding Along ssDNA139
  • 3. How and Why Might AID-Specific Mutations Be Targeted?141
  • 4. Selection of AID-Induced Mutations During Ab Maturation143
  • Acknowledgments149
  • References149
  • Chapter 6: Evolution of the Immunoglobulin Heavy Chain Class Switch Recombination Mechanism157
  • 1. Overview of Genetic Alterations in B Lymphocytes158
  • 2. Activation-Induced Cytidine Deaminase162
  • 2.1. AID Is the Major Specific Factor for CSR and SHM162
  • 2.2. AID Is Required Upstream of DNA Lesions163
  • 2.3. DNA Deamination Versus Putative RNA Editing Activities of AID163
  • 2.4. The RNA Editing Hypothesis164
  • 2.5. The DNA Deamination Model for AID Function164
  • 2.6. Experimental Findings Relevant to Consideration of the DNA Deamination Model for AID Function166
  • 2.7. AID Function: Conclusions169
  • 3. Role of Germ Line Transcription and Switch Regions in CSR169
  • 3.1. Overview169
  • 3.2. Organization of the IgH CH Locus170
  • 3.3. S Region Function in CSR170
  • 3.4. The Role of Germ Line CH Gene Transcription in Targeting CSR171
  • 3.5. Mechanisms by Which Transcription Through S Regions Promotes CSR174
  • 3.6. Open Questions Regarding AID Access to Transcribed dsDNA178
  • 4. Posttranscriptional Regulation of AID180
  • 4.1. Nuclear Versus Cytoplasmic Localization180
  • 4.2. AID Phosphorylation181
  • 5. Mechanisms Involved in Synapsis of AID Initiated DSBs in Widely Separated S Regions184
  • 5.1. Overview184
  • 5.2. CSR Versus Internal S Region Deletions as Mechanisms to Resolve S Region DSBs184
  • 5.3. CSR Has Adopted a General Repair Mechanism to Join/Synapse Distant DSBs186
  • 6. General DNA Repair Systems in the Joining Phase of CSR189
  • 6.1. DNA Damage Response189
  • 6.2. DSB Response Proteins in CSR192
  • 6.3. End Joining194
  • 7. Evolution of CSR197
  • Acknowledgments198
  • References198
  • Chapter 7: Beyond SHM and CSR: AID and Related Cytidine Deaminases in the Host Response to Viral Inf215
  • 1. Introduction215
  • 2. Evolution of the AID/APOBEC Cytidine Deaminase Family216
  • 3. APOBEC3: A Subfamily of Antiviral Cytidine Deaminases217
  • 3.1. APOBEC3G Restricts HIV Infection217
  • 3.2. APOBEC3G Can Act on a Variety of Viruses220
  • 3.3. Antiviral Activities of Other APOBEC3 Family Cytidine Deaminases223
  • 3.4. Endogenous Retroelements Can Be Suppressed by Many APOBEC3 Deaminases226
  • 4. AID in the Host Response to Viral Infection229
  • 4.1. AID Is a Host Response Factor Against Ab-MLV229
  • 4.2. AID and Other Viruses231
  • 5. Concluding Remarks235
  • Notes Added in Proof237
  • Acknowledgments237
  • References237
  • Chapter 8: Role of AID in Tumorigenesis245
  • 1. Introduction246
  • 2. AID Transgenic Mouse Models247
  • 3. Role of AID in Chromosomal Translocation and Subsequent Lymphomagenesis249
  • 4. AID Expression in Human B-Cell Malignancies252
  • 4.1. AID Expression in GC-Derived B-Cell Lymphomas252
  • 4.2. AID Expression in Non-GC-Derived B-Cell Lymphomas256
  • 4.3. Potential Importance of AID Expression in Human B-Cell Malignancies257
  • 5. Mechanism of AID Expression in Normal and Malignant B Cells259
  • 5.1. Regulation of AID Expression in Normal B Cells259
  • 5.2. Mechanism of AID Expression in B-Cell Malignancy260
  • 6. AID Expression in Normal and Malignant Nonlymphoid Cells263
  • 7. Concluding Remarks265
  • Acknowledgments265
  • References265
  • Chapter 9: Pathophysiology of B-Cell Intrinsic Immunoglobulin Class Switch Recombination Deficiencie275
  • 1. Introduction276
  • 2. Ig-CSR Deficiency Type 1 Caused by Activation-Induced Cytidine Deaminase Deficiency279
  • 2.1. Classical AID Deficiency280
  • 2.2. AID Deficiency Associated with Preserved SHM285
  • 2.3. Autosomal Dominant Transmission of AID Deficiency287
  • 3. Ig-CSR Deficiency Type 2 Caused by UNG Deficiency289
  • 4. Molecularly Undefined Ig-CSR Deficiency with Normal SHM292
  • 4.1. Ig-CSR Deficiency Type 3 Characterized by a CSR Block Located Upstream from the Smu Region DNA293
  • 4.2. Ig-CSR Deficiency Type 4 Characterized by a CSR Block Downstream from the Smu Region DNA Cleava294
  • 5. Concluding Remarks296
  • Acknowledgments298
  • References298
  • Index307
  • Contents of Recent Volumes317
Book details
  • Vendor Elsevier S & T
  • SKU 9780123737069
  • ISBN-13 9780080545929
  • Author Alt, Frederick W.
  • Category Medical
  • Subject Immunology

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Advances in Immunology, a long established and highly respected serial, presents current developments as well as comprehensive reviews in immunology. Articles address the wide range of topics that comprise immunology, including molecular and cellular activation mechanisms, phylogeny and molecular evolution, and clinical modalities. Edited and authored by the foremost scientists in the field, each volume provides up-to-date information and directions for future research.