Chapter 9 Major Histocompatibility Complex (MHC)

Chapter 9

Major Histocompatibility Complex

(MHC)

Contents

Part Ⅰ 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

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.

• MHS(Major histocompatibility antigen system )： A group of complex histocompatibility antigens whic

h cause rapid and strong immunoreaction to the graft.

• mHS(Minor histocompatibility antigen system)： A group of complex histocompatibility antigens whic

h cause slow and weak immunoreaction to the graft.

• MHC (Major histocompatibility complex)： A large cluster of linked genes located in some chr

omosome of human or other mammals encode for MHS and relate to allograft rejection, immune response, immune regulation and cell-cell recognition.

• 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 enco

de for HLA and relate to allograft rejection

immune response, immune regulation and cell-cell recognition.

H-2 complex: The MHC of mouse

(chromsome 17)

PartⅡ Composition of HLA complex

HLA complex is located on chromosome 6

and divided into three regions

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

Class II Class III

Class I第六对 染色体

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

Ⅰ. Class Ⅰ gene region

1. Classical HLA class Ⅰ genes

------HLA-A,B,C Participate in endogenous antigen presenting and

immune regulation.

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.

1. Classical class Ⅱ genes----HLA-DP,DQ,DR

Participate in exogenous antigen presenting and immune regulation.

Ⅱ. Class gene regionⅡ

2. Genes associated with antigen processing

(1) 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）

(2) The genes associated with exogenous

antigen-processing and presentingHLA-DM----Processing and presenting of exo

genous AgHLA-DO----Inhibit the function of HLA-DM

Ⅲ. Class Ⅲ gene region

1. Encoded genes of complement

------C4B,C4A,Bf,C2

2. TNF genes family

3. Heat-shock protein(HSP) genes family

PartⅢ Genetic characteristics of HLA

Haplotype inheritancePolymorphismLinkage disequilibrium

1. Haplotype inheritance

Haplotype GenotypePhenotype

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.

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.

PartⅣ Molecular structure and distribution of HLA molecules

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

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

(4) Function of each domain1 and 2 domains: Interact to form a peptide-binding r

egion 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)

3 domain: Binding to CD8 on Tc cells2 microglobulin domain: To maintain proper con

formation of class Ⅰ HLA molecules. Trans-membrane region: Anchoring class Ⅰ HLA

molecules Intra-membrane region: Transmitting the signal

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

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

(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)

2 and 2 domain : Form the immunoglobulin-like region.

2 domain can bind to CD4 on Th cellsTrans-membrane region: Anchoring class Ⅱ HLA molecules

Intra-membrane region: Transmitting the signal

β α

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

PartⅤ Interaction between MHC molecule and antigenic peptide

Class II MHC molecule-antigenic peptide complex

Class I MHC molecule -antigenic peptide complex

Ⅰ. Molecular basis of interaction between

MHC molecule and antigenic peptide

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.

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 similar anchor sites and anchor residues

(consensus motif)

Interaction between MHC and antigen

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

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.

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.

CD4+T cell(Th) CD8+T cell(Tc)

T cellReceptor

Peptide

MHCClass II

T cellReceptor

Peptide

MHCClass I

Antigen PresentingCell

Antigen PresentingCell

CD4 CD8

PartⅥ Biological functions of MHC

1.Induce the differentiation and maturation of T cell to form functional T cell repertoire

2.Present antigen to initiate immune response

1. Induce the differentiation of T cell to form T cell repertoire

2. Present antigen to initiate immune response

Endogenous antigen: antigens synthesized within cells

Exogenous antigen: antigens comes outside the cell

Endogenous Ag is presented to CD8+ T cell by MHC class Ⅰ molecule

Exogenous Ag is presented to CD4+ T cell by MHC class Ⅱ molecule

CD8+T cell

CD4+T cell

PartⅦ Application of HLA in medicine

HLA and transplantation

Mixed lymphocyte reaction to determine identity of class II HLA antigens between a potential donor and recipient. Lymphocytes from the donor are irradiated or treated with mitomycin C. If the class II antigens on the two cell populations are different, the recipient cells will divide rapidly and take up large quantities of radioactive nucleotides into the newly synthesized nuclear DNA. The amount of radioactive nucleotide uptake is roughly proportionate to the MHC class II differences between the donor and recipient lymphocytes.

MLR

Some diseases are associated with HLA genotypes

HLA and forensic medicine:

Paternity testing

Criminal investigation