Chapter 9 Major Histocompatibility Complex (MHC)

1. Chapter 9Major Histocompatibility Complex(MHC)

2. Contents • PartⅠ Several important concepts • PartⅡ Composition of HLA complex • PartⅢ Genetic characteristics of HLA • PartⅣ Molecular structure and distribution of HLA • PartⅤ Interaction of MHC molecules and antigen peptide • PartⅥ Biological functions of MHC • PartⅦ Application of HLA in medicine

3. PartⅠ Several important concepts • Transplantation antigen(Histocompatibility antigen): Antigens which cause immune response to the graft and determine the survival of the graft.They are alloantigen which is specific for each individual.

4. MHS(Major histocompatibility antigen system )： A group of complex histocompatibility antigens which cause rapidand strong immunoreaction to the graft. • mHS(Minor histocompatibility antigen system)： A group of complex histocompatibility antigens which cause slow and weak immunoreaction to the graft.

5. MHC (Major histocompatibility complex)： A large cluster of linked genes located in some chromosome of human or other mammalsencode for MHS and relate to allograft rejection, immune response, immune regulation and cell-cell recognition.

6. HLA (Human leucocyte antigen)： The MHS of human which is associated with allograft rejection, immune response, immune regulation and cell-cell recognition. • HLA complex： The MHC of human,a cluster of the genes which encode for HLA and relate to allograft rejection immune response, immune regulation and cell-cell recognition.

7. H-2 complex: The MHC of mouse (chromsome 17)

8. Class III 第六对 染色体 Class II Class I Class II Class III Class I DP DQ DR C4B C4A Bf C2 HSP TNF B C E A F G RING DP DM LMP2 LMP7 DQ DR B2 A2 B1 A1 A B TAP1 TAP2 B2 A2 B3 B1 A1 B* A PartⅡ Composition of HLA complex HLA complex is located on chromosome 6 and divided into three regions

9. Ⅰ. ClassⅠgene region • Classical HLA classⅠgenes-------HLA-A,B,C • Non-classical HLA classⅠgenes-----HLA-E,F,G • MHC classⅠ chain related genes Ⅱ. Class Ⅱ gene region • Classical HLA classⅡ genes---HLA-DP,DQ,DR • Genes associated with antigen processing Ⅲ. Class Ⅲ gene region • Complement genes-----C4,C2,Bf • Inflammation-associated genes----TNF,HSP70

10. Ⅰ. Class Ⅰ gene region • Classical HLA class Ⅰ genes ------HLA-A,B,C Participate in endogenous antigen presenting and immune regulation.

11. 2. Non-classical HLA classⅠ genes ----HLA-E,F,G • Participate in immune regulation • Associated with maternal-fetal immune tolerance. 3. MHC classⅠchain-related genes(MIC) • MICA,MICB,MICC,MICD,MICE • Associated with cytotoxicity effect of NK cell.

12. Ⅱ. Class Ⅱ gene region 1. Classical class Ⅱ genes----HLA-DP,DQ,DR Participate in exogenous antigen presenting and immune regulation.

13. 2. Genes associated with antigen processing • The genes associated with endogenous antigen-processing and presenting • TAP（Transporter associated with antigen processing,抗原加工相关转运体） • LMP（Large multifunctional proteasome,巨大多功能蛋白酶体）or （ low molecular weight polypeptide 低分子量多肽）

14. (2)The genes associated with exogenous antigen-processing and presenting • HLA-DM----Processing and presenting of exogenous Ag • HLA-DO----Inhibit the function of HLA-DM

15. Ⅲ. Class Ⅲ gene region 1. Encoded genes of complement ------C4B,C4A,Bf,C2

16. 2. TNF genes family 3. Heat-shock protein(HSP) genes family

17. PartⅢ Genetic characteristics of HLA • Haplotype inheritance • Polymorphism • Linkage disequilibrium

18. 1. Haplotype inheritance • Haplotype • Genotype • Phenotype

21. 2. Polymorphism Polymorphism means there are multiple alleles at a gene locus of MHC in a population so that an individual may have variant allele. ------multiple allele ------codominance: The two alleles at a gene locus of MHC in the two homogenous chromosomes are expressed together.

24. 3. Linkage disequilibrium • The distribution of haplotypes is not random in a population. • The probability in which two or more than two alleles present together in one chromosome is greater than the probability in which they present randomly.

25. PartⅣ Molecular structure and distribution of HLA molecules

26. Ⅰ. Molecular Structure of HLA molecules 1. Class Ⅰ HLA molecules (1)Class Ⅰ HLA molecules contain two separate polypeptide chains • HLA-encoded alpha (or heavy) chain • Non-HLA-encoded beta chain (beta2 microglobulin,β2m)---15 chromosome (2) Only alpha chain is trans-membrane HLA

27. (3)Class Ⅰ HLA molecules have four regions • Peptide binding region----α1, α2 • IgSF region----α3, β2m • Trans-membrane region • Cytoplasmic region

29. (4) Function of each domain • 1 and 2 domains: Interact to form a peptide-binding region which is a groove(cleft) having a "floor"of 8 beta-pleated strands and two "walls" with alpha-helices. ( Containing a peptide of 8-11 aa in the groove)

31. 3 domain: Binding to CD8 on Tc cells • 2 microglobulin domain: To maintain proper conformation of class Ⅰ HLA molecules. • Trans-membrane region: Anchoring class Ⅰ HLA molecules • Intra-membrane region: Transmitting the signal

33. 2. Class Ⅱ HLA molecules (1) Class Ⅱ HLA molecules consist of a non-covalent complex of two chains:  and . (2) Both  and  chain span the membrane. (3) Both  and  chain are HLA-encoded HLA

34. (4) Class Ⅱ HLA molecules have four regions • Peptide binding region----α1, β1 • IgSF region----α2, β2 • Trans-membrane region • Cytoplasmic region

36. (5) Function of each domain • α1 and 1: Interact to form the peptide-binding region which is a groove having a "floor" of 8 beta-pleated strands and two "walls" with alpha-helices. (Containing a peptide of 10-30aa in the groove)

38.  2 and  2 domain : Form the immunoglobulin-like region. •  2 domain can bind to CD4on Th cells • Trans-membrane region: Anchoring class Ⅱ HLA molecules • Intra-membrane region: Transmitting the signal

39. β α

40. Ⅱ. Distribution of HLA molecules 1.Class Ⅰ HLA molecule: Expressed on nucleate cells 2.Class Ⅱ HLA molecule Expressed on professional antigen-presenting cell(macrophage, dentritic cell and B cell), activated T cell, thymus epithelial cell et al. 3.sHLA

41. PartⅤ Interaction between MHC molecule and antigenic peptide Class I MHC molecule -antigenic peptide complex Class II MHC molecule-antigenic peptide complex

42. Ⅰ. Molecular basis of interaction between MHC molecule and antigenic peptide

43. Interaction between MHC and antigen • Anchor sites: Two or more sites on antigenic peptide bind to “groove” or “pocket” of MHC molecules. • Anchor residues: The amino acid residues on anchor sites of antigenic peptide.

44. Interaction between MHC and antigen • Certain MHC molecule binds the corresponding anchor residue of antigenic peptides. • Antigenic peptides which can combine with the same kind of MHC molecule have same or similaranchor sites and anchor residues (consensus motif)

47. Ⅱ. Characteristics of interaction Relative specificity (1) Specificity: • Certain MHC molecule recognizes corresponding consensus motif (2) Flexibility: • Amino acids “x” and anchor residues are variable • Different MHC molecules can recognize similar consensus motif

48. MHC restriction: T cell only recognize antigenic peptide combining with MHC molecules. That is to say, interaction of T cell and antigen-presenting cell(APC) or target cell need restriction by MHC molecules.

49. Interaction of Th(CD4+T) cell and antigen-presenting cell (APC) is restricted by class Ⅱ molecules. • Interaction of Tc(CD8+T) cell and antigen-presenting cell (APC) or target cell is restricted by class Ⅰ molecules.

50. CD8+T cell(Tc) CD4+T cell(Th) T cell Receptor T cell Receptor Peptide Peptide CD4 CD8 MHC Class II MHC Class I Antigen Presenting Cell Antigen Presenting Cell