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 组织相容性 Histocompatibility 组织相容性 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 Ⅰ loci Class Ⅰ loci Class Ⅱ loci Class Ⅱ loci Class Ⅲ loci Class Ⅲ 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 11 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. 44 55 33 3 extra DR  genes in some individuals can allow 3 extra HLA-DR molecules

Class Ⅰ loci Include HLA-A, -B and – C loci Include HLA-A, -B and – C loci Highly polymophic Highly polymophic Encode classical class Ⅰ molecules expressed on the surface of nearly all nucleated cells Encode classical class Ⅰ molecules expressed on the surface of nearly all nucleated cells

Class Ⅱ loci Include HLA-DP, -DQ and – DR loci Include HLA-DP, -DQ and – DR loci Encode classical class Ⅱ molecules expressed mainly on APC (macrophages, dendritic cells, B cells) Encode classical class Ⅱ molecules expressed mainly on APC (macrophages, dendritic cells, B cells)

MHC molecules About class Ⅰ and class Ⅱ 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 Ⅰ molecules α-chain: polymorphic α-chain: polymorphic β 2 - microgrobuline: nonpolymorphic β 2 - microgrobuline: nonpolymorphic 4 domains 4 domains 3 formed from α-chain (α 1, α 2, α 3 ) 3 formed from α-chain (α 1, α 2, α 3 ) 1 formed from β 2 - microgrobuline 1 formed from β 2 - microgrobuline

Structure of class Ⅰ molecules Only the α-chain spans the plasma membrane 12 Peptide-binding site: α 1 -chain and α 2 - chain

11 33 22 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 2m2m  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 Ⅰ 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 Ⅱ molecules 2 12 β-β 1 β 2 2 α-chains (α 1 -chain and α 2 -chain ) and 2 β-chains (β 1 -chain and β 2 - chain ) Both chains are similar in size Both chains anchored in the surface membrane 1 β 1 Peptide-binding site: α 1 -chain and β 1 -chain

22 11 and a  -chain of 29kDa MHC-encoded,  -chain of 34kDa 22 11 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 Ⅱ 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 11 Polygeny  BCADPDQDR 11 Polygeny  BCADPDQDR 11 Polygeny  BCADPDQDR 11 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 11 Polygeny  BCADPDQDR 11 Polygeny  BCADPDQDR 11 Polygeny  BCADPDQDR 11 Polygeny

 BCADPDQDR 11 Polygeny  BCADPDQDR 11 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 11 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 11 Polygeny

Co-dominant expression The alleles inherite from both parents are expressed equally The alleles inherite from both parents are expressed equally

共显性遗传

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 北欧白人具特征性的单元型 : A1-B8 汉族人特征性的单元型： 汉族人特征性的单元型： A2-B46-Cw3-DR9-DQ9-Dw23 （南方人） A33-B17-Cw2-DR3-DQ2-Dw3 ( 北方人 ) A33-B17-Cw2-DR3-DQ2-Dw3 ( 北方人 )

北欧白人具特征性的单元型 : A1-B8 汉族人特征性的单元型： 汉族人特征性的单元型： A2-B46-Cw3-DR9-DQ9-Dw23 （南方人） A33-B17-Cw2-DR3-DQ2-Dw3 ( 北方人 ) A33-B17-Cw2-DR3-DQ2-Dw3 ( 北方人 ) --- 两个或两个以上基因座位上的某些等位 基因 同时出现于同一染色体上的几率高于 随机出现的频率，此现象称为连锁不平衡

 BCADPDQDR 11 Polygeny  BCADPDQDR 11 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 11 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 11 Polygeny

 BCADPDQDR 11 Polygeny  BCADPDQDR 11 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 11 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 细胞 外源性抗原加工、处理和呈递示意图

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 Ⅰ restriction Class Ⅰ restriction CD8 + T cells generally recognize peptides bound to class Ⅰ MHC protein CD8 + T cells generally recognize peptides bound to class Ⅰ MHC protein Class Ⅱ restriction Class Ⅱ restriction CD4 + T cells generally recognize peptides bound to class Ⅱ MHC protein CD4 + T cells generally recognize peptides bound to class Ⅱ MHC protein

参与 T 细胞限制性识别 * MHC 制约相互作用的细胞类型, 即 MHCI 类分子将抗原肽提呈给 CD4T 细胞， MHCII 类分子将抗原肽提呈给 CD8T 细胞。

T cell development in thymus See section Ⅱ See section Ⅱ

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