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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