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Lecture 5: Antigen Recognition by B Cell Receptors (based on Lecture by Dr. Matthew Scharff, Einstein) Questions to Consider How can we make antibody to every possible pathogen-i.e. Diversity? How do we avoid making autoantibodies-i.e. Specificity? How do we rapidly increase amount of antibody-i.e. Mobilization? How do we switch from making IgM to IgG- i.e. Isotype Switching? How do we increase the the affinity of antibody-i.e. Affinity maturation? How do we generate memory? Antibody Molecules Use Different Mechanisms to Prevent Infection Antibody Levels and Affinity Are Increased by Immunization Structure of the Antibody Molecule Clonal Selection of Antigenspecific Lymphocytes V Domains of Heavy and Light Chains Contain Discrete Hypervariable Regions Hypervariable Regions Lie in Loops That Are Brought Together in the Folded Molecule Clonal Selection of Antigen-specific Lymphocytes V-region Gene Are Constructed From Discrete Gene Segments Germline Organization of the Immunoglobulin Heavy and Light-Chain Loci in the Human Genome V-region Gene Segments Are Joined by Recombination The Number of Functional Gene Segments for the V region Heavy and Light-Chains Germline Organization of the Immunoglobulin Heavy and Light-Chain Loci in the Human Genome Gene Segments Encoding the V Regions Are Flanked by Conserved Heptamer and Nonamer Sequences Introduction of P- and N-nucleotides at the Joints Between Gene Segments During Ig Gene Rearrangement Contribution of Factors to Antigen Receptor Diversity Clonal Selection of Antigen-specific Lymphocytes Neutralizing Antibodies Prevent Viral Infection of Cells Somatic Mutation Increases Affinity Abbas, Cellular and Molecular Immunology Progenitor B cell Pluripotent stem cell Immature B cell antigen mature B B cell activation Pre-B cell centroblast AID Th AID Dark Zone AID centrocyte SHM CSR Light Zone FDC selection memory B cell apoptotic cell plasma B cell anergic B cell modified from Luo, Ronai, and Scharff. J Allergy Clin Immunol. 2004 and Harrison’s Principles of Internal Medicine 16th ed Ch. 97. Activation-induced Cytidine Deaminase (AID) NLS N alpha helix Deficiency causes Hyper IgM type II F15X NES active site PS CSR C H56Y W68X C87R L106P C147X R174S R24W M139V L59F W80R W84X R112C F151S L181 R112H P182 C U G Luo, Ronai, and Scharff. J Allergy Clin Immunol. 2004 • AID is a cytidine deaminase whose in vitro substrate is ssDNA • AID may associate with RPA, RNAP II &? others • Transcription is required for somatic SHM and CSR R190X AID deaminates C to U followed by UNG and APE1 Somatic Hypermutation of Antibody V Regions J. Peled et al. Ann Rev Imm 2008 Somatic Hypermutation Error prone Polymerases 10-1 High fidelity Polymerases 10-3 death Proofreading 10-6 cancer Mismatch repair 10-9 cancer 10-11 health Mutation Frequency Biological consequence and yet also fitness After Philip Coffino Mutation Frequency = Mutations/bp/cell division After T-cell-dependent Activation, B cells Undergo Rounds of Mutation and Selection That Generates High Affinity Memory B Cells Humoral Immune Response Class Switch Recombination IgM IgG / IgE / IgA Antigen-binding site Effector arm Somatic Hypermutation Low affinity high affinity Janeway and Travers, Immunobiology Questions to Consider How can we make antibody to every possible pathogen-i.e. Diversity How do we avoid making autoantibodies-i.e. Specificity How do we rapidly increase amount of antibody-i.e. Mobilization How do we switch from making IgM to IgG- i.e. Isotype Switching How do we increase the the affinity of antibody-i.e. Affinity maturation How do we generate memory