immunology

1. Chapter 8 Major Histocompatibility Complex Dr. Capers immunology

2. Antibodies can recognize antigen alone • T-cell receptors can only recognize antigen that has been processed and presented by Major Histocompatibility Complex (MHC) • Involves: • Antigen processing • Antigen presentation

5. Inheritance of MHC • MHC coded by cluster of genes • Rejection of foreign tissue is due to immune response against cell surface molecules, histocompatibility antigens

6. Inheritance of MHC • Collection of genes on chromosome 6 in humans (HLA complex) and chromosome 17 in mice (H-2 complex) • Class I MHC genes • Encode glycoproteins expressed on all nucleated cells • Class II MHC genes • Encode glycoproteins expressed on antigen-presenting cells (macrophages, B cells, dendritic cells) • Class III MHC genes • Encode various products involved in complement and inflammation

7. Inheritance of MHC

8. Inheritance of MHC • Many different alleles exist at each locus among the population • Each set of alleles is called a haplotype • Genes of MHC lie close together so crossing over during meiosis occurs infrequently • Individual inherits one haplotype from mom, one from dad • Many in the population are heterozygous • Alleles are codominant so expressed simultaneously

9. Inheritance of MHC • Inbred strains will express identical haplotypes – homozygous • Inbred mice are solid colors

11. Inheritance of MHC

12. MHC molecules • Both Class I and Class II are membrane-bound glycoproteins • Antigen-presenting molecules

13. Class I MHC • Alpha α chain • Transmembrane • Encoded by A, B, and C regions in human MHC complex • Beta β2-microglobulin • Encoded by highly conserved gene on different chromosome

14. Class II Molecule • α1 and α2 chain • Transmembrane • β1 and β2 chain • transmembrane

15. Figure b shows top View of peptide cleft

16. Every individual expresses small number of different Class I and Class II • Limited number of MHC must be able to present enormous array of different antigens • MHC does not display specificity of Antibodies • MHC is “promiscuous” 

17. Generation of B-cell receptors (antibodies) and T-cell receptors is dynamic, changing over-time • Gene rearrangement • In contrast, MHC molecules are fixed in the genes • Differences in population due to large number of alleles • In humans, ~370 A alleles, 660 B alleles, 190 C alleles

18. Location of genes • Human • Class I MHC are red • Telomeric end of HLA complex • Class II MHC are blue • Centromeric end of HLA complex

19. Cellular Expression of MHC

20. MHC Restriction • CD8+ Tc cells are MHC Class I restricted • Can only recognize antigen presented by MHC Class I molecules • Therefore, cells with MHC Class I are called “taget cells”, killed by cytotoxic T cells • CD4+ TH cells are MHC Class II restricted • Cells with MHC Class II are called antigen-presenting cells (APCs)

21. MHC Restriction • Mice immunized with lymphocytic choriomenigitis virus (LCM) • Animal’s spleen cells were extracted (containing Tc cells) • Cells were labeled with radioactive chromium, if lysed the chromium is released

22. Antigen Presenting Pathways • Cystolic Pathway • Endogeneous antigens – produced in cell, in infected cell • Antigens presented on MHC Class I to Tc cells • Endocytic Pathway • Exogeneous antigen – taken in by endocytosis by antigen-presenting cells and presented to TH cells by MHC Class II

23. Ubiquitin – targets protein for proteolysis TAP – transporter protein that takes the target molecule into the RER to join with forming MHC

24. Figure below: • (a) shows degradation of misfolded protein in infected cell • (b) shows intact proteins linked to ubiquitin to be degraded in antigen presenting cells

26. Endocytic PathwayExogenous

27. Invariant chain – since APCs have both MHC I and II, there Must be way to prevent antigen meant for MHC I from binding To MHC II