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Immunoglobulins

Immunoglobulins. Harry W Schroeder Jr MD PhD Division of Developmental and Clinical Immunology Departments of Medicine, Microbiology, and Genetics University of Alabama at Birmingham. Immunoglobulin Has Two Roles. Antigen Receptor

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Immunoglobulins

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  1. Immunoglobulins Harry W Schroeder Jr MD PhD Division of Developmental and Clinical Immunology Departments of Medicine, Microbiology, and Genetics University of Alabama at Birmingham

  2. Immunoglobulin Has Two Roles • Antigen Receptor • Recognition of and binding to antigens such as toxins, viruses, and exposed molecules on the surface of pathogenic organisms • V domain function • Effector Molecule • Elimination or inactivation of the foreign antigen or the cell that bears the antigen • C domain function

  3. Immunoglobulins are HeterodimersComposed of Two H chains and Two L chains

  4. Human Igk Locus • V domain is created by the joining of a Variable (V) and a Joining (J) gene segment • Contains only one C gene, with only one exon IGKC: 1 IGKJ: 5 IGHV:40 Lefranc M.-P. Immunologist8:80,2000

  5. Human vs Mouse

  6. Creation of a k chain

  7. Human Igl Locus • V domains composed of V and J segments • Four or more equivalent single domain C genes, each with its own J IGHV:32 IGKJ: 4 IGJC: 4 Lefranc M.-P. Immunologist8:80,2000

  8. Human vs Mouse

  9. The Human IgH Locus • Includes Diversity (D) as well as V and J gene segments • Contains multiple, different C genes each with three or domains IGHC: 9 IGHJ: 6 IGHD:27 IGHV:39 Lefranc M.-P. Immunologist8:80,2000

  10. Human vs Mouse

  11. Primary Structure - H chain V Domain

  12. Non-Homologous End-Joining • Site-specific cleavage • RAG 1, RAG 2, HMG1, 2 • Recognition of cut ends • DNA PK • Ku 70/80 • Repair of the ends • XRCC4 • DNA ligase IV • Artemis • Modified repair • TdT

  13. Recombination Signal Sequences • RSS - Conserved sequence flanking V (D) J gene segments • Consists of a highly conserved seven bp sequence (heptamer), a less conserved nine bp sequence (nonamer), and a 12 or 23 bp (spacer) • One-turn/two-turn rule (12/23 rule) – Recombination occurs only between a 12 bp spacer RSS and a 23 bp spacer RSS

  14. Rearrangement

  15. TdT • Adds nucleotides at random to the 3’ terminus of DNA • Expressed in fetal liver, bone marrow, and thymus

  16. Junctional Diversity

  17. Combinatorial Diversification

  18. Junctional Diversification

  19. A Nested Gradient of Diversity

  20. Class switching • During an immune response, B cells can replace an ‘upstream’ C domain with a ‘downstream’ C domain  ‘class-switching’ • B cells can thus produce IgG, IgA or IgE with the same antigen specificity as the original IgM

  21. Class Switching • Occurs by gene rearrangement • Mediated by AID instead of RAG • Involves non-homologous recombination between a pair of “switch sites” rather than pairs of RSS • The switch sites are composed of multiple nucleotide repeats • Transcription of the switch site is required • Initiation of transcription is driven by T cell cytokines (e.g., IL-4 drives IgE and IgG4 in human)

  22. Recombination Occurs by Deletion • Initial recombination occurs between Sm and a downstream S site • Allows switching from IgM to IgG, IgA or IgE • IgD is an exception (no switch region)

  23. Effector Functions • Typically Inflammatory Reactions Complement Fixation • Complement Activation • Binding to Fc Receptors • Basophils • Monocytes • Platelets

  24. IgM • First Ig to be produced • Can exist as a monomer or a pentamer • Excellent for agglutination, complement activation

  25. IgG bound to FcRn • Igs can function as the antigen binding component for many receptors and signal transduction proteins on many types of cells • B cells, membrane Ig binds Iga and Igb • Granulocytes, secretory Ig binds Fc receptors

  26. Effector functions of human isotypes • Igs can kill in one of two ways: • ADCC (antibody dependent cell-mediated cytotoxicity, Fc receptor driven • Complement lysis www.path.cam.ac.uk/~mrc7/igs/mikeimages.html

  27. IgA • Major Ig class in secretions, critical to mucosal immunity • Can exist as a monomer or dimer • Transported by means of secretory component

  28. IgE bound to FceRI Nature406, 259 - 266 (2000)

  29. Ontogeny of Serum Ig IgM, IgG, IgA IgG Subclasses

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