Transcript 2. Class Ⅱ HLA molecules

Chapter 5 Major Histocompatibility Complex
 PartⅠ Several important concepts
 PartⅡ Composition of HLA complex
 PartⅢ Molecular structure and distribution of HLA
 PartⅣ Interaction of MHC molecules and antigen
peptide
 PartⅤ Biological functions of MHC
 PartⅥ 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 which
cause rapid and strong immunoreaction to the graft.
• mHS(Minor histocompatibility antigen system)：
A group of complex histocompatibility antigens which
cause slow and weak immunoreaction to the graft.
• MHC (Major histocompatibility complex)：
A large cluster of linked genes located in some
chromosome 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 encode
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 III
Class II
Class I
第六对
染色体
Class II
DP DQ DR
RING
Class III
C4B C4A Bf C2
DP
DM
B2 A2 B1 A1
A B
Class I
HSP TNF
LMP2 LMP7
TAP1 TAP2
B
C
E
DQ
B2 A2 B3 B1 A1
A
F
G
DR
B*
A
Ⅰ. ClassⅠgene region
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

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
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
Classical HLA classⅡ genes---HLA-DP,DQ,DR
Genes associated with antigen processing
Ⅲ. Class Ⅲ gene region
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
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.
Ⅱ. Class Ⅱ gene region
1. Classical class Ⅱ genes----HLA-DP,DQ,DR
Participate in exogenous antigen presenting and
immune regulation.
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 presenting
HLA-DM----Processing and presenting of
exogenous Ag
HLA-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 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 domain
 1 and 2 domains: Interact to form a peptide-binding
region which is a groove(cleft) having a "floor"of 8 betapleated strands and two "walls" with alpha-helices.
( Containing a peptide of 8-11 aa in the groove)
 3 domain: Binding to CD8 on Tc cells
 2 microglobulin domain: To maintain proper
conformation 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 betapleated 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 cells
Trans-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
PartⅣ Interaction between MHC molecule and
antigenic peptide
Class I MHC molecule antigenic peptide complex
Class II MHC moleculeantigenic peptide complex
Ⅰ. Molecular basis of interaction between MHC
molecule and antigenic peptide
Interaction between MHC and antigen
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).
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 antigenpresenting cell(APC) or target cell need
restriction by MHC molecules.
Interaction of Th(CD4+T) cell and antigenpresenting cell (APC) is restricted by class Ⅱ
molecules.
Interaction of Tc(CD8+T) cell and antigenpresenting cell (APC) or target cell is
restricted by class Ⅰ molecules.
CD8+T cell(Tc)
CD4+T cell(Th)
T cell
Receptor
T cell
Receptor
Peptide
CD4
MHC
Class II
Peptide
CD8
MHC
Class I
Antigen Presenting
Cell
Antigen Presenting
Cell
PartⅤ 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
PartⅥ Application of HLA in medicine
HLA and transplantation
MLR
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.
Some diseases are associated with HLA
genotypes
HLA and forensic medicine:
Paternity testing
Criminal investigation