The Antibody Enigma

1. The Nature of the Problem.- 1.1. Introduction.- 1.2. Antibody Synthesis.- 1.3. Historical Roots.- 1.3.1. Introduction of the Germline Concept of Immunologic Specificity.- 1.3.2. Introduction of the Somatic Concept of Immunologic Specificity.- 1.4. Clonal Selection.- 1.5. Effector Functions.- >1.6. The Extent of Diversity—The Problem in a Nutshell.- 1.7. Scope of the Book.- 1.8. Precis.- References and Bibliography.- 2. The Serologist’s Approach to the Problem.- 2.1. Introduction.- 2.2. Rabbit Allotypes.- 2.2.1. Discovery.- 2.2.2. Variable-Region Allotypes.- 2.3. Human Allotypes.- 2.3.1. Discovery.- 2.3.2. Allotypes and Isotypes.- 2.3.3. Haplogroups.- 2.4. Allotypes of the Mouse and the Rat.- 2.4.1. Mouse Allotypes.- 2.4.2. Allotypes of the Rat.- 2.5. Individual Antigenic Specificity and Idiotypy.- 2.5.1. Idiotypes of Human Immunoglobulins.- 2.5.2. Idiotypes of Rabbit Antibodies.- 2.5.3. Presence of Idiotypes on IgG and IgM.- 2.5.4. Idiotype versus IAS.- 2.6. Idiotypes as Markers for Antibody-Binding Regions.- 2.6.1. Idiotypic Cross-Specificity.- 2.6.2. Antigen Inhibition of Idiotype Reactions.- 2.6.3. Exceptions to the Correlation of Idiotypy and Binding Site.- 2.7. The Inheritance of Idiotypes.- 2.7.1. Discovery.- 2.7.2. The Mouse Idiotype Systems.- 2.8. Conclusion.- References and Bibliography.- 3. The Biochemist’s Approach to the Problem.- 3.1. Biochemical Studies on Heterogeneous Antibodies.- 3.2. Biochemical Studies on Homogeneous Antibodies.- 3.2.1. Human Myeloma.- 3.2.2. Mouse Myeloma.- 3.2.3. Other Homogeneous Antibodies.- 3.2.4. Hybridomas.- 3.3. Structural Features of Immunoglobulin Isotypes and Allotypes.- 3.3.1. The Human Immunoglobulin Classes.- 3.3.2. The Carbohydrate Structures of Human Immunoglobulins.- 3.3.3. Comparisons of Immunoglobulins from Different Species.- 3.3.4. Immunoglobulin Allotypes.- 3.4. Structural Features of V Regions.- 3.4.1. V-Region Subgroups.- 3.4.2. Framework and Hypervariable Regions.- 3.4.3. The Antibody-Combining Site.- 3.5. Are the C Regions Really Constant?.- 3.6. Structural Analysis of Selected V Regions.- 3.6.1. Mouse V?.- 3.6.2. Mouse V?21.- 3.6.3. The Mouse V Ars Kappa Chains.- 3.7. Precis.- References and Bibliography.- 4. Unique Features of the Antibody Problem.- 4.1. Introduction.- 4.2. Structural Variability of Antibodies.- 4.2.1. Immunoglobulins and Major Histocompatibility Complex Proteins.- 4.2.2. Immunoglobulins and Hemoglobin.- 4.3. Two Genes-One Polypeptide Chain.- 4.3.1. The Todd Phenomenon.- 4.3.2. Structural Differentiation of V and C Regions.- 4.3.3. Statement of the Two-Gene Hypothesis.- 4.3.4. Cis or Trans Synthesis.- 4.3.5. Genetic Recombination between V- and C-Region Allotypes.- 4.3.6. Biclonal Myeloma Proteins.- 4.3.7. Cross-overs between Idiotypes and C Regions.- 4.3.8. Theoretical Impact of the Two-Gene Hypothesis.- 4.4. Allelic Exclusion.- 4.4.1. The Lyon Hypothesis.- 4.4.2. Selective Expression of Immunoglobulin Alleles.- 4.5. The Three Loci for Immunoglobulins.- 4.5.1. Kappa versus Lambda Light Chains.- 4.5.2. Expression of V-Region Subgroups.- 4.5.3. Allelic Selection of Immunoglobulin Genes.- 4.6. Conclusion.- References and Bibliography.- 5. The Polar Solutions.- 5.1. Introduction.- 5.2. The Germline Theory.- 5.3. The Somatic Mutation Theory.- 5.4. Data Favoring Germline Theories.- 5.4.1. V-Region Subgroups.- 5.4.2. Evolutionary Divergence (Trees).- 5.4.3. Inheritance of Idiotypes.- 5.5. Data Favoring Somatic Mutation Models.- 5.5.1. Phylogenetically Associated Residues.- 5.5.2. Mouse Lambda Light Chains.- 5.5.3. Rabbit Group a Allotypes.- 5.5.4. A V-Region Allotype for the Mouse Kappa Chain.- 5.6. Waiting for the Answer.- References and Bibliography.- 6. The Maverick Solutions.- 6.1. Introduction.- 6.2. Data Difficult to Rationalize with Either Germline or Somatic Theories.- 6.2.1. V-Region Subgroup Distinctions Are Not Evident throughout the V Regions.- 6.2.2. The Rabbit Allotypes Are Not Evident throughout the V Regions.- 6.2.3. Phylogenetically Associated Residues Are Not Evident throughout the V Regions.- 6.2.4. Shared Idiotypes Occur in Molecules of Differing V-Region Subgroup.- 6.2.5. Identical Hypervariable Regions Occur in Proteins of Differing V-Region Subgroup.- 6.2.6. The Framework Portions of the V Region Do Not Occur in Absolute Linkage.- 6.3. The Maverick Solutions.- 6.3.1. Kabat and Wu’s Episomal Insertion-Mini-Gene Model.- 6.3.2. Capra and Kindt’s Gene Interaction Hypothesis.- 6.3.3. Smithies’ Networks of Branched DNA Hypothesis.- 6.3.4. Edelman and Gally’s Somatic Recombination Model.- 6.4. Precis.- References and Bibliography.- 7. The Molecular Biologists Attack the Problem.- 7.1. Introduction.- 7.2. Gene Counting by Liquid Hybridization.- 7.2.1. Early Evidence Favors the Germline Theory.- 7.2.2. Mouse V? Studies Favor Fewer Genes.- 7.2.3. Mouse V? Studies Favor Fewer Genes.- 7.2.4. Cautions on Interpretation of Liquid Hybridization.- 7.3. Recombinant DNA Methods.- 7.3.1. The Principle of Cloning.- 7.3.2. Restriction Endonucleases.- 7.3.3. Southern Filter Hybridization.- 7.3.4. DNA Sequencing.- 7.3.5. The Antibody Question Redefined.- 7.4. The Two-Gene Hypothesis Reinvestigated.- 7.4.1. Gene Rearrangements.- 7.4.2. The J Region of the Light Chain.- 7.5. Heavy Chain Genes.- 7.5.1. The VDJ Arrangement.- 7.5.2. The D Segment.- 7.6. The V Gene Segment.- 7.6.1. Mouse V?.- 7.6.2. Mouse V?.- 7.6.3. The VH Gene Segment.- 7.6.4. Pseudogenes.- 7.7. Heavy Chain C-Region Genes.- 7.8. Allelic Exclusion.- 7.9. Mapping the Immunoglobulin Genes.- 7.10. Conclusions.- References and Bibliography.- 8. Antibody Diversity: A Contemporary Solution.- 8.1. Introduction.- 8.2. There Are a Modest Number of Germline Genes.- 8.2.1. V Gene Segments.- 8.2.2. J and D Gene Segments.- 8.3. Combinatorial Joining of V/J and V, D, and J Gene Segments.- 8.3.1. Mouse V?.- 8.3.2. Mouse VH.- 8.4. Junctional Diversity Is Created by Alternate Frames of Recombination between Germline V, D, and J Gene Segments.- 8.5. Somatic Mutation in All Gene Segments Leads to Further Diversity.- 8.5.1. Mouse V?.- 8.5.2. Mouse V?.- 8.5.3. Mouse VH.- 8.6. The Number of C-Region Genes Is Limited and Varies Considerably among the Species.- 8.6.1. Human and Mouse Kappa.- 8.6.2. Mouse Lambda.- 8.6.3. Human Lambda.- 8.6.4. Mouse CH.- 8.6.5. Human CH.- 8.7. Further Considerations for Antibody Diversity.- 8.7.1. Gene Conversion May Account for Additional Antibody Diversity.- 8.7.2. Pseudogenes.- 8.7.3. VH/D and D/JH Recombination May Generate Additional Diversity through a Novel Mechanism.- 8.7.4. Combinatorial Pairing of Heavy and Light Chains Further Amplifies Diversity.- 8.8. Gene Families and Specificity.- 8.9. V-Region Polymorphism.- 8.10. Evolution of V and J Gene Segments.- 8.11. Somatic Mutation Revisited.- 8.12. Why Do We Have Certain Germline Genes?.- 8.13. Horizons.- 8.14. Precis.- References and Bibliography.