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Genetics of I mmunoglobulins

Genetics of I mmunoglobulins. TUMS MD Class , 20-Farvardin -1393 Presented by: Dr F Noorbakhsh. Receptors for self- nonself recognition. VH. VH. B-cell receptor (antibody). T-cell receptor (TCR). VL. VL. V α. V β. CL. CL. CH. CH. C β. C α. Epitope (HIV gp120). Fab

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Genetics of I mmunoglobulins

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  1. Genetics of Immunoglobulins TUMS MD Class, 20-Farvardin-1393 Presented by: Dr F Noorbakhsh

  2. Receptors for self-nonself recognition VH VH B-cell receptor (antibody) T-cell receptor (TCR) VL VL Vα Vβ CL CL CH CH Cβ Cα

  3. Epitope (HIV gp120) Fab (Heavy and light chains) No 2- 3SE9 G: gp120 H: heavy chain L: Light chain Dr F Noorbakhsh, Dept of Immunology, TUMS

  4. Microbial diversity, the challenge of the immune system Dr F Noorbakhsh, Dept of Immunology, TUMS

  5. Even the smallest pathogens have a lot of antigens! Dengue virus Dr F Noorbakhsh, Dept of Immunology, TUMS

  6. Dengue hemorrhagic fever (DHF) Dr F Noorbakhsh, Dept of Immunology, TUMS

  7. Dengue virus structure Dr F Noorbakhsh, Dept of Immunology, TUMS

  8. How to cope with this diversity? Dr F Noorbakhsh, Dept of Immunology, TUMS

  9. Genes make proteins; diverse genes make diverse proteins! Dr F Noorbakhsh, Dept of Immunology, TUMS

  10. Is there any biological precedence for dealing with diverse molecules? And to make receptors for them?

  11. Dealing with molecular diversity; The problem of olfaction! Dr F Noorbakhsh, Dept of Immunology, TUMS

  12. Humans can recognize approximately 10,000 odours

  13. One neuron, one receptor!

  14. Genes for olfactory receptors are everywhere in the genome!

  15. But we need at least 10,000,000 antibodies to cover for all pathogens! Total number of genes in human genome is around 23,000! So “one gene, one protein” strategy would need around 400 times the size of human genome!

  16. Combinatorial diversity, the solution to generate diversity in immune molecules!

  17. A painting with lots of colors; how to show it on a monitor? Dr F Noorbakhsh, Dept of Immunology, TUMS

  18. Dr F Noorbakhsh, Dept of Immunology, TUMS

  19. Combinatorial diversity in RGB color space Dr F Noorbakhsh, Dept of Immunology, TUMS

  20. Combinatorial diversity in RGB color space Makes 1000 combinations 10 degrees for each color Dr F Noorbakhsh, Dept of Immunology, TUMS

  21. 256 degrees for each color makes a 16,777, 216 combinations Dr F Noorbakhsh, Dept of Immunology, TUMS

  22. How to make diverse antibodies? (or TCRs?) We need around 10,000,000 (107) at least! Dr F Noorbakhsh, Dept of Immunology, TUMS

  23. 1- Break the variable part into segments V Region J Region J Region D Region V Region V: Variable J: Joining D: Diversity Dr F Noorbakhsh, Dept of Immunology, TUMS

  24. 2-Give each segment multiple choices V Region D Region J Region V1 V2 V2 V3 V3 V4 Vn D1 D1 D2 D3 D3 D3 Dn J1 Jn Jn J2 J2 Constant region Combination 2 Combination 1 Dr F Noorbakhsh, Dept of Immunology, TUMS

  25. Enzymes do the work! Recombination Activating Gene-1 (RAG1) Lymphocyte-specific enzymes Recombination Activating Gene-2 (RAG2) Dr F Noorbakhsh, Dept of Immunology, TUMS

  26. Genetic Recombination between 2 DNA molecules (cross-over) Dr F Noorbakhsh, Dept of Immunology, TUMS

  27. Genetic Recombination inside 1 DNA molecule Somatic recombination Dr F Noorbakhsh, Dept of Immunology, TUMS

  28. Recombination Signal Sequences V Region D Region J Region V1 V2 V2 V3 V3 V4 Vn D1 D1 D2 D3 D3 D3 Dn J1 Jn Jn J2 J2 Constant region V3 D2 9mer 7mer 9mer 7mer Dr F Noorbakhsh, Dept of Immunology, TUMS

  29. Recombination Signal Sequences V Region D Region V1 V2 Vn V3 D1 D2 Dn 7 7 7 7 9 9 9 9 RAG1/2 9 9 9 7 7 7 Dr F Noorbakhsh, Dept of Immunology, TUMS

  30. Recombination Signal Sequences V Region D Region V1 V2 D1 D2 Dn Vn V3 7 7 7 7 9 9 9 9 RAG1/2 9 9 9 7 7 7 Dr F Noorbakhsh, Dept of Immunology, TUMS

  31. Recombination Signal Sequences V Region D Region V1 V2 D2 Dn 7 9 RAG1/2 9 7 Dr F Noorbakhsh, Dept of Immunology, TUMS

  32. V…D…J V....DJ  VDJ V Region D Region J Region V1 V2 V2 V3 V3 V4 Vn D1 D1 D2 D3 D3 Dn J1 Jn Jn J2 Constant region V4 D3 J2 Dr F Noorbakhsh, Dept of Immunology, TUMS

  33. Dr F Noorbakhsh, Dept of Immunology, TUMS

  34. Kappa light chain Heavy chain Lambda light chain VDJ Area Dr F Noorbakhsh, Dept of Immunology, TUMS

  35. VDJ Space; for a Heavy Chain J =6 =16200 V =100 D =27 Dr F Noorbakhsh, Dept of Immunology, TUMS

  36. VJ Space; for a light Chain J =5 =175 V =35 D =27 Dr F Noorbakhsh, Dept of Immunology, TUMS

  37. 2,835,000 But 107-108 Abs are needed! Dr F Noorbakhsh, Dept of Immunology, TUMS

  38. We need more diversity! V13 D2 J4 Dr F Noorbakhsh, Dept of Immunology, TUMS

  39. Happy Exonucleases! V13 D2 J4 AGCTG…ATGCAGT GGCG…GTGC ACCG…TTC RAG1/2 Dr F Noorbakhsh, Dept of Immunology, TUMS

  40. V13 D2 J4 AGCTG…ATGCAGT GGCG…GTGC ACCG…TTC Dr F Noorbakhsh, Dept of Immunology, TUMS

  41. TdT TdT TdT TdT V13 D2 J4 ACA TTGTA TTC AGCTG…ATGTTAT GGCG…GTGC CC ACCG…TTC RAG1/2 Dr F Noorbakhsh, Dept of Immunology, TUMS

  42. Junctional diversity TdT TdT TdT TdT V13 D2 J4 V13 V13 V13 V13 D2 D2 D2 D2 J4 J4 J4 J4 Dr F Noorbakhsh, Dept of Immunology, TUMS

  43. Combinatorial diversity Junctional diversity ~ 1011 Forms of Ab Dr F Noorbakhsh, Dept of Immunology, TUMS

  44. Our Antibody Space (VDJ X VJ X JunctD) ~ 1011 Forms of Ab Normal people have about 107-108Ab forms Dr F Noorbakhsh, Dept of Immunology, TUMS

  45. Dr F Noorbakhsh, Dept of Immunology, TUMS

  46. Removing autoreactive clones makes a lot of “holes” in the antibody space Dr F Noorbakhsh, Dept of Immunology, TUMS

  47. “Holes” in RGB color space Dr F Noorbakhsh, Dept of Immunology, TUMS

  48. Our painter DOES NOT WANT some of the colors! Dr F Noorbakhsh, Dept of Immunology, TUMS

  49. What next? Dr F Noorbakhsh, Dept of Immunology, TUMS

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