Download MHC ( Major Histocompatibility Complex)

MHC
( Major Histocompatibility Complex)
I. Concepts
II. Organization of MHC
III. genetic characteristics of MHC
IV . MHC molecules
V. Interaction of antigenic peptides with MHC
molecules
VI. Biologic activities of MHC
Part I. Some concepts
1.Histocompatibility Ag
Antigens which cause immune response
to the graft and determine the survival of
the graft.
2.MHS(Major histocompatibility antigen
system )
A group of complex histocompatibility
antigens which cause rapid and strong
immunoreaction to the graft .
3.MHC (Major histocompatibility
complex)
A cluster of genes which encode for
major histocompatibility antigens
and relate to immune response.
4.HLA (human leucocyte antigen)
The major histocompatibility antigens of
human which are associated with
histocompatibility and immune response.
5.HLA complex
The MHC of human, a cluster of the genes
which encode for HLA and relate to
histocompatibility and immune response.
6.H-2 complex
The MHC of mice
Part II.Organization of HLA complex
Located on chromosome 6.
● Class I gene region
1. classical HLA I genes-------HLA-A,B,C gene loci
2. non-classical HLA I genes----HLA-E,F,G
3. MHC I chain-related genes
●
Class II gene region
1. classical HLA II genes---HLA-DP,DQ,DR
subregion
(2 or more than 2 gene loci in each subregion)
2. genes associated with antigen processing
●
Class III gene region
complement genes-----C4,C2,B
inflammation-associated genes----TNF,HSP70
Located on chromosome 6.
● Class I gene region
1. classical HLA I genes-------HLA-A,B,C
gene loci
2. non-classical HLA I genes----HLAE,F,G
3. MHC I chain-related genes
●
Class II gene region
1. classical HLA II genes---HLA-
DP,DQ,DR subregion
(2 or more than 2 gene loci in each
subregion)
2. genes associated with antigen
processing
HLA-DM gene
TAP gene（transporter associated with
antigen processing)
PSMB gene (Proteasome subunit, beta
type）
HLA-DOA and HLA-DOB genes
●
Class III gene region
complement genes-----C4,C2,B
inflammation-associated genes---TNF,HSP70
III. Genetic characteristics of MHC
1. Polymorphism:
Multiple alleles
In a population, there are multiple alleles at a gene
locus of MHC
Codominance
The two alleles at a gene locus of MHC in the two
homogenous chromosomes are expressed together.
.
2. Haplotype
A gene combination which results
from gene loci linked in a chromosome.
3. Linkage disequilibrium
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,that is ,the distribution of
haplotypes is not random in a
population
Diversity -----MHC molecules are
diverse.
Diversity is generated by natural
selection and show life-force.
Part IV. MHC molecules
I) Molecular structure
II) Distribution
I. Molecular Structure of HLA
1. HLA class I molecules
1) two separate polypeptide
chains
 MHC-encoded
alpha (or
heavy) chain;
 non-MHC-encoded
beta
chain (beta2 microglobulin)
2) Only alpha chain spans
the membrane
3)The molecule has four domains
1 domain,  2 domain
interact to form a peptide-binding
region ( A peptide 8-10 amino
acids long sits in the groove.)
3 domain ,
combining site of CD8
 2 microglobulin domain
refered to as immunoglobulin-like
region to maintain their proper
conformation.
2.Class II HLA
1) two chains,  and . both
are MHC-encoded
2)both  and  chain span
the membrane.
3) four domains
 1 and  1
form the peptide-binding
region
 2 and  2
form the immunoglobulin-like
region.  2 : Combining site of
CD4
II) Distribution of HLA molecules
1.class I molecules
In human, all nucleate cells carry the
class I antigens in variant amounts
2.class II molecules
Activated Tcells,
Professional antigen-presenting
cells (macrophages, dentritic cells
and B cells),
Thymus epithelial cells et al.
Part V. Interaction of HLA molecules
and antigen peptides
1.
2.
3.
Combination of antigen peptide and
antigen-binding groove
Molecular basis of the interaction of
HLA molecules and antigen peptides
Characteristics of MHC moleculesantigen peptides interaction
1. Combination of antigen peptide
and antigen binding groove
1
MHC-I 分子
 螺旋
COOH
（衔接 3）
肽槽
 螺旋
NH2
2
NH2
1
COOH（衔接 2）
 螺旋
MHC-II 分子
肽槽
COOH
（衔接 2）
 螺旋
1
NH2
Class I MHC molecule
A peptide 8-10 amino acids long sits in the groove.
The greatest variability in amino acids occurs in
the 1 and  2 sequences
 Class II MHC molecule
A peptide 13-17 amino acids long sits in the
groove.

2.Molecular basis of the interaction of HLA
molecules and antigen peptides
Anchor sites
binding sites of an antigen peptide bound with
antigen-binding grooves of MHC molecules
anchor residues
amino acids in the
anchor sites bind
to antigen- binding
grooves of
MHC molecules.
NH2
C00H
抗原肽
凹槽
锚定位(锚定残基)
MHC-II分子
Anchor sites : places of the anchor residues
3. Characteristics of MHC
molecules/anigen peptides interaction
relative specificity
(1) Specificity
Certain MHC molecule
recognizes corresponding
consensus motif
(2) Flexibility
Amino acids “x” and anchor
residue are variable
Different MHC molecules can
recognize similar consensus
Part VI. Biologic activities of HLA
1. induce the differentiation of T cell to
form T cell repertoire
2. present 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
Application of HLA in medicine
1.HLA in transplantation
2.some diseases are associated with HLA
genotypes