1. Principles of Immunology Major Histocompatibility Complex 2/28/06 “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: 1.Intercellular recognition 2.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

8. 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

9. 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

10. Fig 7-5

11. 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

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

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

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

15. 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

16. 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?

19. 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