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The Major Histocompatibility Complex

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The Major Histocompatibility Complex. Antigen Presentation and Processing and the Relationship to Susceptibility and Resistance to Diseases;. Folder Title: MHC. Updated: November 25, 2012. Kuby Immunology, 6 th Edition, Chapter 8 Topics Listed vs Topics Covered in BIO 447, See Page 189

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The Major Histocompatibility Complex
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  1. The Major HistocompatibilityComplex Antigen Presentation and Processing and the Relationship to Susceptibility and Resistance to Diseases; Folder Title: MHC Updated: November 25, 2012

  2. Kuby Immunology, 6th Edition, Chapter 8 • Topics Listed vsTopics Covered in BIO 447, See Page 189 • General Organization and Inheritance of the MHC Genes • MHC Molecules and Genes • Detailed Genomic Map of MHC Genes (Not Covered in BIO 447) • Cellular Expression of MHC Molecules • Regulation of MHC Expression (Not Covered in BIO 447) • MHC and Disease Susceptibility • MHC and Immune Responsiveness • Self-MHC Restriction of T-Cells • Role of Antigen-Presenting Cells • Not Covered in BIO 447 • 10. Evidence of Different Antigen-processing and Presentation Pathways • 11. Endogenous Antigen: The Cytosolic Pathway • 12. Exogenous Antigens: The Endocytic Pathway • 13. Cross Presentation of Exogenous Antigens • 14. Presentation of Non-Peptide Antigens

  3. What we saw earlier in the course: What Affects Host Response to Potential Antigens?

  4. What else affects host response to potential antigens?

  5. What are we looking at? Groups of Mice with Same Collection of MHC Alleles (Haplotype) How do these groups respond to two different experimental antigens?

  6. Haplotype = Combination of MHC Genes Inherited from Each Parent Co-dominantly Expressed = both sets of alleles are expressed

  7. On a scale of 1 to 5:1 = I’m totally lost;2 I’m having a hard time but I get some of it.3 = I’m doing OK. I get a lot of it. I’ll figure the rest out later.4 = I’m doing fine. I get most of it; 5 = +2 = This is no problem. Please get moving before I get bored

  8. Both parents are of course histocompatible with their own tissues, and their progeny tolerate skin grafts from either parent because the progeny recognizes antigens from either parent as self. Transplanting hematopoietic stem cells from parent to mixed progeny could generate graft-vs-host reaction

  9. What happens if we transplant skin from one b/k progeny hybrid to another b/k hybrid? What happens if we transplant from a b/k hybrid back to either of the parental strains (b/b or k/k)?

  10. Why is this collection of genes controlling whether one can transplant a tissue from one mouse to another or from one human to another? Nature doesn’t do transplants. Why does Nature bother to generate genes that control transplantability of tissue?

  11. What are these genes controlling tissue compatability (“histocompatibility”)? “Histocompatability Complex or Major Histocompatability Genes = MHC Genes” What products are these genes coding for that control histocompatibility?

  12. Mouse H2 Complex Complement Proteins Some Cytokines Figure 8-1, Kuby 6th Edition, Top Half Human HLA (Histocompatibility Complex), Lower Half Next Slide

  13. In Humans the Genes Corresponding to MHC Region in Mice are Called Human Leukocyte Associated Antigens or HLA Genes

  14. Human HLA Loci Class I Loci Equivalent toK, D, and L in Mice Class II Loci Equivalent to IAa, IAb; IEa, IEb in Mice Kuby, 6th Edition, Figure 8.01, Bottom Half

  15. Recombinant Collection of HLA Genes not existing in this grouping in either parent

  16. k and b Haplotype “Team Members” See Table 7-1, Kuby 4th Edition, p. 175

  17. Haplotype and Team Members

  18. These H2 Genes Control Recognition of Self when cells from mouse strains with two different H2 Haplotypes are mixed together in cell culture. Mixed Lymphocyte Test in Cell Culture

  19. MLR Assay See Figure 14-16, p.367, Kuby, 6th Edition Strain X Cells are activated to proliferate by exposure to unmatched cells from Strain Y

  20. Strain X Cells are also activated by exposure to strain Y cells in the living mouse Strain X mouse makes T-cells that will lyse strain Y cells

  21. Cell-Mediated Lympholysis Assay (CML Assay) Strain X Cells are also activated by exposure to strain Y cells in the living mouse Strain X mouse makes T-cells that will lyse strain Y cells. Why is Strain X mouse doing this? What does the strain X mouse “think” it sees? CML Assay See Figure 14-17, Kuby 6th Edition, p. 368. For CML Assay See Figure 8-15, p. 207, Kuby, 6th Edition For MHC Restriction. MHC Restriction will be covered later Get lysis of Strain Y target cells

  22. CML Assay See Figure 14-17, Kuby 6th Edition, p. 368. For CML Assay See Figure 8-15, p. 207, Kuby, 6th Edition For MHC Restriction. MHC Restriction will be covered later

  23. Restriction to Self MHC Alleles In Vitro exposure of target cells to spleen cells from LCM virus-infected mouse.

  24. On a scale of 1 to 5:1 = I’m totally lost;2 I’m having a hard time but I get some of it.3 = I’m doing OK. I get a lot of it. I’ll figure the rest out later.4 = I’m doing fine. I get most of it; 5 = +2 = This is no problem. Please get moving before I get bored

  25. What Do MHC Class I and Class II Proteins Look Like? How do they bind and present peptide antigens?

  26. MHC-I See figure 8-3, Kuby, 6th Edition, p. 194, left

  27. MHC-II See figure 8-3, Kuby, 6th Edition, p. 194, right

  28. Class I MHC Protein Binding Cleft

  29. Ag Site Class I See figure 8-4, Kuby, 6th Edition, p. 195, right

  30. Ag-Bind See figure 8-9(a,b), Kuby, 6th Edition, p. 199

  31. See figure 8-9(c), Kuby, 6th Edition, p. 199 Ag in Site Class I

  32. Class I MHC Space-Filling

  33. H2K and Peptides See figure 7-12, Kuby 4th edition, p. 184

  34. Class I and Class II proteins have sequence differences inherited in the germ line (they are polymorphic) Where are the variations located in the Class I and Class II proteins?

  35. Amino Acids Positions of Polymorphic Variations in Class I MHC Proteins in Humans Trans- Membrane Residues Membrane Distal a1 and a2 Domains (Comprise Peptide-binding Cleft) Kuby, 6th Edition, Figure 8-10(a) p. 201; MHCIVary

  36. Kuby, 6th Edition Figure 8-10(b) p. 201 MHCIPoly MHC-Class I Polymorphisms Positions of Polymorphic Amino Acid Residues in a Human Class I MHC Protein

  37. MHC ClassI and Flu

  38. On a scale of 1 to 5:1 = I’m totally lost;2 I’m having a hard time but I get some of it.3 = I’m doing OK. I get a lot of it. I’ll figure the rest out later.4 = I’m doing fine. I get most of it; 5 = +2 = This is no problem. Please get moving before I get bored