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Principles of Immunology Major Histocompatibility Complex 2/28/06

Principles of Immunology Major Histocompatibility Complex 2/28/06. “Change is not merely necessary for life. It is life.” A Toffler. Word List. Congenic Haplotype HLA complex MHC Polygenic Syngeneic. MHC. Cluster of genes that influence: Intercellular recognition Self vs. non-self

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Principles of Immunology Major Histocompatibility Complex 2/28/06

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  1. Principles of ImmunologyMajor Histocompatibility Complex2/28/06 “Change is not merely necessary for life. It is life.” A Toffler

  2. Word List • Congenic • Haplotype • HLA complex • MHC • Polygenic • Syngeneic

  3. MHC • Cluster of genes that influence: • Intercellular recognition • Self vs. non-self • HLA complex in humans

  4. HLA Complex • Three regions • Class I genes • MHC I molecules • Nucleated cells • T cytotoxic cells (CD8) • Class II genes • MHC II molecules • APCs • T helper cells (CD4) • Class III genes • Complement components (C2 and C4) plus TNF

  5. MHC I Molecules • Membrane bound glycoprotein (Ig super family) • Alpha chain • Three domains • Encoded by HLA complex • Anchored in cell membrane • Cytoplasmic tail • Beta chain • A single domain • Encoded by a different gene on another chromosome • Not anchored in cell membrane • Bound to alpha chain non covalently • Necessary for MHC I expression

  6. MHC I Molecules • Antigen presenting features • Alpha 1 and alpha 2 domains form peptide-binding cleft • 8-10 amino acid peptides can bind to MHC I molecule • Alpha 3 interacts with CD 8 on T cytotoxic cells

  7. MHC II Molecules • Membrane bound glycoprotein (Ig super family) • Alpha chain • Two domains • Encoded by HLA complex • Anchored in cell membrane • Cytoplasmic tail • Beta chain • Two domains • Encoded by HLA complex • Anchored in cell membrane • Cytoplasmic tail

  8. MHC II Molecules • Antigen presenting features • Alpha 1 and beta 1 domains form peptide-binding pocket • 13-18 amino acid peptides can bind to MHC II molecule • Alpha 2 and beta 2 interact with CD 4 on T helper cells

  9. Fig 7-5

  10. MHC I – Peptide Interaction • Stable associations • Endogenously processed antigens • Up to six allelic variants • ~100,000 MHC molecule variants per cell • ~ 100 MHC-peptide complexes required for T cytotoxic cell recognition

  11. MHC II – Peptide Interaction • Stable associations • Exogenously processed antigens • Up to 12 allelic variants

  12. MHC Diversity • Genetically determined • Polygenic characteristic • Different alleles • Genes with overlapping functions • ~12 million haplotypes • Diversity in HLA type

  13. MHC I Expression • Varies by cell type • Lymphocytes high • Hepatocytes low • Regulated by cytokines • Interferons • TNF • Suppressed by viruses • Herpes family • Hepatitis B

  14. Inheritance of MHC(HLA) Type • Polymorhisms • Many allelic types within a species • Haplotype • The genetic loci of MHC are closely linked • Inherited as a group (haplotype) • One haplotype from each parent • Co-dominant expression

  15. Inheritance of MHC • Inbred mice • Homozygous parents • F 1 generation has MHC loci from both (heterozygous) • F1 generation can accept grafts from either parent • Neither parent can accept graft from F1 offspring • WHY?

  16. Inheritance of MHC • Humans • Heterozygous parents • F 1 generation has MHC loci from both (heterozygous) • Four combinations • F1 generation can not accept grafts from either parent • Neither parent can accept graft from F1 offspring • 1 in 4 F1 generation are HLA compatible

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