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 Beta β2-microglobulin 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 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. In contrast, MHC molecules are fixed in the genes
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 Class II MHC are blue
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 Pathway Exogenous

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