Major Histocompatibility Complex

1,Concepts

2,Organization of MHC

3,Genetic Characteristics of MHC

4,MHC Molecules

5,Interaction of Antigenic Peptides with MHC Molecules

6,Biologic Activities of MHC

7,MHC and Disease Susceptibility

"for their discoveries concerning genetically determined structures on the cell surface that regulate immunological reactions" 1980

H2HLAIr gene

"for their discoveries concerning the specificity of the cell mediated immune defence"

1996

MHC restriction

1,Concepts

(1)Histocompatibility (transplantation) antigens: Antigens on tissues and cells that determine their rejection when the organ is grafted between two genetically different individuals.

(2)Major histocompatibility (MHC) antigens: Histocompatibility antigens that cause a very strong immune response and are most important in rejection.

(3)MHC (Major histocompatibility complex) A cluster of genes which encode for major histocompatibility antigens. MHC molecules may present antigen peptide on APC for being recognized by TCR on T cell, thereby initiating adaptive immune response.

(4)HLA (human leucocyte antigen)The major histocompatibility antigens of human which are associated with histocompatibility and immune responses(first detected on leukocytes).

(5)HLA complexThe MHC of human, a cluster of genes which encode for HLA and relate to histocompatibility and immune responses.

(6)H-2 complex The MHC of mice

Antigens are expressed on cellsThree regions : HLA-I

HLA-II

HLA-III Antigens are proteins in serum and other body fluids (e.g.C4, C2, factor B, TNF). Antigens of class III gene products have no role in graft rejection.

2,Organization of MHC

The MHC, located on chromosome 66 of humans, is now

known to contain nearly 100 genes and the complete DNA

sequence is sequenced.

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 Ichromosome 6

Class II Class III Class I

DP DQ DR C4B C4A B1 C2 HSP TNF B C A E F MIC G H

Genomic map of MHC genes of human

(1) Region I of HLA genes

Class II Class III Class I

DP DQ DR C4B C4A B1 C2 HSP TNF B C A E F MIC G H

The class I gene complex contains：

Each major locus codes for a polypeptide: the alpha-chain. It associates with beta-2 microglobulin (beta-chain) and is expressed on the cell surface.

a2

a3

a1

b2m

①classical HLA I genes-------HLA-A,B,C gene locinon-classical HLA I genes----HLA-E,F,G②MHC I chain-related genes③

(2 ) Region II of HLA genesClass II

RING DP DM LMP2 LMP7 DQ DR

B2 A2 B1 A1 A B TAP1 TAP2 B2 A2 B3 B1 A1 B* A

The class II gene complex contains at least three loci, DP, DQ and DR

Each of these loci codes for  one alpha- and one beta-chain polypeptide which associate together to form the class II antigens

1

1

Genes associated with antigen processing： HLA-DM, TAP, LMP2/7

(3)MHC genes, mRNA transcripts, and protein molecules

3,Genetic Characteristics of MHC

(1)Polymorphism Multiple alleles In a population, there are multiple alleles at a gene locus of MHC CodominanceThe two alleles at a gene locus of MHC in the two homogenous chromosomes are expressed together.

Class I

B C A E F MIC G H

Father

Class I

B C A E F MIC G H

mother

MHC class I Genotype A1, A6, B5, B7,C3,C9

MotherFather

A1 A6B5

B7

C9C3

A1 A2

B8 B35

A2 A10

B40 B16×

a b c d

A2

B35

A2

B40

A1

B8

A10

B16

A1

B8

A2

B35

A2

B40

A10

B16

a d b d c b c a

1 2 3 4

Father Mother

(2)Haplotype A gene combination which results from closely linked gene lociin a chromosome.

(3)Linkage disequilibrium linkage disequilibrium is the difference between the frequency observed for a particular combination of alleles and that expected from the frequencies of the individual alleles. The expected frequency for the combination may be calculated by multiplying the frequencies of the two alleles.

DRB1*0301

B6B8

A B

DRB5

B8 B3

DRB4

C

B2 B11

DRB7 DRB1*0301DRB6

9% 12%

9% 12%=0.0108=1%7%

Schematic diagrams of a class I and a class II MHC molecule showing the external domains, transmembrane segment, and cytoplasmic tail.

4,MHC Molecules

(a) Peptide-binding region

Groove: 1+ 2

MHC-I

a2

a3

a1

b2m

Peptide-binding region

Transmembrane region

immunoglobulin-like region

(1)MHC-I

Figure 3-20

8-12 residues

8-12 residues

The a1 and a2 domains as viewed from top, showing the peptide-binding cleft consisting of a base of antiparallel β strands and sides of helices. This cleft in Class I molecules can accommodate peptides containing 8-12 residues.

(b) Immunoglobulin-like region 3 + β2-microglubulin 3 is bound by CD8, a molecule expressed on cytolytic T cell that recognizes class I MHC molecule. β2-microglubulin is essential for maintaining MHC I structure.

(c) Transmembrane region for molecule stability

(d) Cytoplasmic region for signal transduction

TCR

HLA- I

3

2 1

2m

CD 8 Antigenic peptide

(a) peptide-binding region groove : 1+ 1

MHC- IIMHC- II

b1

b2

a1

a2

Peptide-binding region

Transmembrane region

immunoglobulin-like region

(2) MHC-II

Figure 3-21

12-17 residues

(c,d) Transmembrane and cytoplasmic regions have proposed functions similar to their counterparts in class I MHC.

( b) Immunoglobulin-like region

2+ 2 Ig-like domains

2 is bound by the CD4 molecule expressed on helper T cells.

CD4

TCR

HLA- II

1

1

TCR

HLA- II

Antigenic peptide

2

1

2

1

MHC-I MHC-II

Peptide chain

MW（kDa）

Molecular Formula

Extracellular region

Peptide binding region

CD4/CD8 biding site

HLA coding gene

Cellular distribution Nearly all nucleated cells

Macrophage,DC, thymic epithelial cell, B cell and activated cell

The composition and structure of MHC-I and MHC-II of human

2m

2m （）

m

A、B、C DR、DP、DQ

5,Interaction of Antigenic Peptides with MHC Molecules

(1)Combination of antigen peptide and antigen-binding groove

(2)Molecular basis of the interaction of HLA molecules and antigen peptides

(3)Characteristics of MHC molecules-antigen peptides interaction

Figure 3-22(1)Combination of antigen peptide and antigen-binding groove

Space-filling model of human class

I molecule HLA-A2 (white) with

peptide (brown) from HIV reverse

transcriptase in the binding groove.

b2-microglobulin is shown in blue.

Peptides in the groove of Class I MHC molecule

A peptide 8-12 amino acids long sits in the groove.

The greatest variability in amino acids occurs in the 1 and 2 sequences.

Space-filling model of human class II molecule HLA-DR1 with the peptide. A chain shown in white and another chain in blue. The peptide (brown) in the binding groove is from influenza hemagglutinin.

Peptides in the groove of Class II MHC molecule

A peptide 12-17 amino acids long sits in the groove.

NH2 Antigenic peptide

pockets Anchor residue

MHC-II molecule MHC-II molecule

C00H

Antigenic peptide binding to MHC molecule The N-and C- terminals of the antigenic peptide are out of the cleft , anchor residues in the middle inlay into pockets of the cleft for maintenance of the binding between the antigenic peptides and MHC molecule.

(2)Molecular basis of the interaction of HLA molecules and antigen peptides

Anchor sites Binding sites of an antigen peptide that bind to antigen-binding grooves of MHC molecules.

Anchor residues Amino acids in the anchor sites that bind to antigen- binding grooves of MHC molecules.

Examples of anchor residues (blue) in nonameric peptides eluted from two class I MHC molecules. Anchor residues that interact with the class I MHC molecule tend to be hydrophobic amino acids.

Amino acids “x”

Conformation of MHC I peptides bound to class I MHC molecules.

conformational difference in bound peptides of different lengths.

(3)Characteristics of MHC molecules-antigen peptides interaction

1) Specificity Certain MHC molecule recognizes the corresponding consensus motif.

2) Flexibility Amino acids “x” and anchor residue are variable; Different MHC molecules can recognize similar sequences.

6,Biologic Activities of MHC

(1)Inducing the differentiation of T cells

(2)Presenting antigens to initiate immune response 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

Disease Associated Alleles

Frequency in Relative RiskPatients Control

Ankylosing spondylitis B27 90 9 90

Reiter's disease (syndrome) B27 79 9 37.0

Acute anterior uveitisB27 52 9 10.4

Psoriasis vulgaris Cw6 87 33 13.3

Dermatitis herpetiformis DR3 85 26 15.4

Celiac Disease DR3 79 26 10.8

Insulin-dependent diabetes mellitus DR3/4 91 57 7.9

7,MHC and Disease SusceptibilitySome diseases are associated with HLA genotypes

Ankylosing spondylitis (B27)

1,Master the concept of MHC

2,Know the gene locus of HLA-I and HLA-II complex

3,Know the cellular distribution of HLA molecules

4,Master the molecule structure of HLA-I and HLA-II

5,Master biologic activities of MHC molecule

Learning Objectives