Section 7 major histocompatible complex (MHC) major histocompatible complex (MHC) Chapter 1 structure and genetics of MHC structure and genetics of MHC Rejection Related definitions Histocompatibility Histocompatibility whether individuals accept or reject grafts from one another Histocompatibility antigens Histocompatibility antigens : the rejection of foreign tissue is the result of an IR to cell-surface molecules Donor 1 receptor Donor 2 Major histocompatibility antigens Major histocompatibility antigens induce fast and strong rejection Minor histocompatibility Ag Minor histocompatibility Ag induce weaker rejection donor receptor major histocompatibility complex (MHC) the genes encoding minor histocom- patibility Ag an extended genetic locus containing closely-linked, highly polymorphic genes that determined the outcome of tissue graft exchanged between individuals donor receptor The human leukocyte Ag (HLA) The human MHC is refered to as HLA complex The human MHC is refered to as HLA complex MHC molecules or MHC antigens The products of MHC The products of MHC Classical MHC gene complex HLA complex spans 3.6 million basepairs on the short arm of chromosome 6 HLA complex spans 3.6 million basepairs on the short arm of chromosome 6 Organized into regions encoding 3 classes of molecules Organized into regions encoding 3 classes of molecules Class loci Class loci Class loci Class loci Class loci Class loci Simplified map of the HLA region Maximum of 9 types of antigen presenting molecule allow interaction with a wide range of peptides. Class III MHC Class II DP LMP/TAPDM DQ DR 11 BCA MHC Class I Polygeny CLASS I: 3 types HLA-A, HLA-B, HLA-C (sometimes called class Ia genes) CLASS II: 3 types HLA-DP HLA-DQ HLA-DR. 44 55 33 3 extra DR genes in some individuals can allow 3 extra HLA-DR molecules Class loci Include HLA-A, -B and C loci Include HLA-A, -B and C loci Highly polymophic Highly polymophic Encode classical class molecules expressed on the surface of nearly all nucleated cells Encode classical class molecules expressed on the surface of nearly all nucleated cells Class loci Include HLA-DP, -DQ and DR loci Include HLA-DP, -DQ and DR loci Encode classical class molecules expressed mainly on APC (macrophages, dendritic cells, B cells) Encode classical class molecules expressed mainly on APC (macrophages, dendritic cells, B cells) MHC molecules About class and class molecules Contain 2 noncovalently linked polypeptide chains Contain 2 noncovalently linked polypeptide chains Are membrane-bound glycoproteins Are membrane-bound glycoproteins Highly specialized Ag-presenting molecules, forming MHC-peptides complex on the cell surface for recognition by T cell Highly specialized Ag-presenting molecules, forming MHC-peptides complex on the cell surface for recognition by T cell Cell Membrane Peptide MHC class IMHC class II MHC molecules Peptide binding groove MHC molecules Structure of class molecules -chain: polymorphic -chain: polymorphic 2 - microgrobuline: nonpolymorphic 2 - microgrobuline: nonpolymorphic 4 domains 4 domains 3 formed from -chain ( 1, 2, 3 ) 3 formed from -chain ( 1, 2, 3 ) 1 formed from 2 - microgrobuline 1 formed from 2 - microgrobuline Structure of class molecules Only the -chain spans the plasma membrane 12 Peptide-binding site: 1 -chain and 2 - chain 11 33 22 MHC-encoded -chain of 43kDa Overall structure of MHC class I molecules 3 domain & 2m have structural & amino acid sequence homology with Ig C domains Ig GENE SUPERFAMILY 2m2m 2-microglobulin, 12kDa, non-MHC encoded, non-transmembrane, non covalently bound to - chain Peptide antigen in a groove formed from a pair of -helicies on a floor of anti-parallel strands -chain anchored to the cell membrane Distribution of class molecules Expressed on the vast majority of cells Expressed on the vast majority of cells Recognized by CD8 T cells Recognized by CD8 T cells Structure of class molecules 2 12 - 1 2 2 -chains ( 1 -chain and 2 -chain ) and 2 -chains ( 1 -chain and 2 - chain ) Both chains are similar in size Both chains anchored in the surface membrane 1 1 Peptide-binding site: 1 -chain and 1 -chain 22 11 and a -chain of 29kDa MHC-encoded, -chain of 34kDa 22 11 Overall structure of MHC class II molecules and chains anchored to the cell membrane 2 & 2 domains have structural & amino acid sequence homology with Ig C domains Ig GENE SUPERFAMILY No -2 microglobulin Peptide antigen in a groove formed from a pair of -helicies on a floor of anti-parallel strands Distribution of class molecules On antigen presenting cells (APC) On antigen presenting cells (APC) Dendritic cells Dendritic cells Macrophages Macrophages B lymphocytes B lymphocytes A few other cell types A few other cell types Make peptides available for recognition by CD4 T cells Make peptides available for recognition by CD4 T cells Chapter 2 MHC polymorphism MHC polymorphism Concept of polymorphism There are many different alleles present among the different individuals in the population There are many different alleles present among the different individuals in the population MHC is one of the most polymorphic genetic systems known in higher vertebrates MHC is one of the most polymorphic genetic systems known in higher vertebrates BCADPDQDR 11 Polygeny BCADPDQDR 11 Polygeny BCADPDQDR 11 Polygeny BCADPDQDR 11 Polygeny The presence of multiple alleles at a given genetic locus within the species The presence of multiple alleles at a given genetic locus within the species Codominant expression in each individual Codominant expression in each individual Multiple alleles Multiple different alleles of each locus exist in the human population Multiple different alleles of each locus exist in the human population There are many alternative versions of each MHC gene that yield proteins There are many alternative versions of each MHC gene that yield proteins BCADPDQDR 11 Polygeny BCADPDQDR 11 Polygeny BCADPDQDR 11 Polygeny BCADPDQDR 11 Polygeny BCADPDQDR 11 Polygeny BCADPDQDR 11 Variant alleles polymorphism Genes in the MHC are tightly LINKED and usually inherited in a group The combination of alleles on a chromosome is an MHC HAPLOTYPE BCADPDQDR 11 Additional set of variant alleles on second chromosome MHC molecules are CODOMINANTLY expressed Two of each of the six types of MHC molecule are expressed HAPLOTYPE 1 HAPLOTYPE 2 BCADPDQDR 11 Polygeny Co-dominant expression The alleles inherite from both parents are expressed equally The alleles inherite from both parents are expressed equally Linkage disequilibrium and haplotype MHC heplotype The set of MHC alleles present on each chromosome The set of MHC alleles present on each chromosome All heterozygous individuals have two haplotypes (from mother and father) All heterozygous individuals have two haplotypes (from mother and father) The alleles are codominantly expressed The alleles are codominantly expressed Inheritance of MHC haplotypes BCADPDQDR BCADPDQDR BCADPDQDR BCADPDQDR X Parents DP-1,2 DQ-3,4 DR-5,6 B-7,8 C-9,10 A-11,12 DP-9,8 DQ-7,6 DR-5,4 B-3,2 C-1,8 A-9,10 DP-1,8 DQ-3,6 DR-5,4 B-7,2 C-9,8 A-11,10Wrongmethod DP-2,8 DQ-4,6 DR-6,4 B-8,2 C-10,8 A-12,10 DP-2,9 DQ-4,7 DR-6,5 B-8,3 C-10,10 A-12,9 BCADPDQDR BCADPDQDR BCADPDQDR BCADPDQDR BCADPDQDR BCADPDQDR BCADPDQDR BCADPDQDR Children Linkage disequilibrium The phenomenon that certain MHC alleles at different loci are inherited together more frequently than would be predicted by random assortment The phenomenon that certain MHC alleles at different loci are inherited together more frequently than would be predicted by random assortment : A1-B8 A2-B46-Cw3-DR9-DQ9-Dw23 A33-B17-Cw2-DR3-DQ2-Dw3 ( ) A33-B17-Cw2-DR3-DQ2-Dw3 ( ) : A1-B8 A2-B46-Cw3-DR9-DQ9-Dw23 A33-B17-Cw2-DR3-DQ2-Dw3 ( ) A33-B17-Cw2-DR3-DQ2-Dw3 ( ) --- BCADPDQDR 11 Polygeny BCADPDQDR 11 Variant alleles polymorphism Genes in the MHC are tightly LINKED and usually inherited in a group The combination of alleles on a chromosome is an MHC HAPLOTYPE BCADPDQDR 11 Additional set of variant alleles on second chromosome MHC molecules are CODOMINANTLY expressed Two of each of the six types of MHC molecule are expressed HAPLOTYPE 1 HAPLOTYPE 2 BCADPDQDR 11 Polygeny BCADPDQDR 11 Polygeny BCADPDQDR 11 Variant alleles polymorphism Genes in the MHC are tightly LINKED and usually inherited in a group The combination of alleles on a chromosome is an MHC HAPLOTYPE BCADPDQDR 11 Additional set of variant alleles on second chromosome MHC molecules are CODOMINANTLY expressed Two of each of the six types of MHC molecule are expressed Diversity of MHC molecules in the individual HAPLOTYPE 1 HAPLOTYPE 2 Generation and significance of MHC polymorphism Variant MHC molecules protect the population Example: If MHC X was the only type of MHC molecule Population threatened with extinction Survival of individual threatened Pathogen that evades MHC X MHC XX Example: If each individual could make two MHC molecules, MHC X and Y Impact on the individual depends upon genotype Pathogen that evades MHC X MHC XX MHC XY Population survives MHC YY but has sequences that bind to MHC Y YRYRYRYR XY XXXX R XY R YX R YY R YYXRXRXRXR XRYRXRYR From 2 MHC types and 2 variants. 10 different genotypes Variants of each type of MHC molecule increase the resistance of the population from rapidly mutating or newly encountered pathogens without increasing the number of types of MHC molecule Variant MHC molecules protect the population Pathogen that evades MHC X and Y MHC XY MHC XX MHC YY MHC XX R MHC YY R but binds to the variant MHC X R and MHC Y R Chapter 3 peptide-MHC interaction peptide-MHC interaction Molecular basis characteristics Ag presentation Form peptide-MHC complex Form peptide-MHC complex Displaying antigenic peptides for recognition by T cells Displaying antigenic peptides for recognition by T cells Antigen Presentation CD4 + Th MHC restriction T cells respond to self MHC T cells respond to self MHC TCRs can discriminate among TCRs can discriminate among Peptides Peptides Different allelic forms of a given MHC protein Different allelic forms of a given MHC protein MHC restriction Class restriction Class restriction CD8 + T cells generally recognize peptides bound to class MHC protein CD8 + T cells generally recognize peptides bound to class MHC protein Class restriction Class restriction CD4 + T cells generally recognize peptides bound to class MHC protein CD4 + T cells generally recognize peptides bound to class MHC protein T * MHC , MHCI CD4T MHCII CD8T T cell development in thymus See section See section Significance of the MHC role in immune response role in predisposition to disease Role in organ transplantation role in immune response role in predisposition to disease Role in organ transplantation