MHC(主要组织相容性复合体)

Significance of MHC Polymorphism
• to be able to present any microbial peptide antigen to ensure survival of the population as a whole；
• Genetic control of immune responses (Ir gene)；
LMP-2 and LMP-7 code a polypeptide, which is a portion of the proteasome.
TAP-1 and TAP-2 code transporter in antigen processing，TAP.
HLA class-Ⅲ genes
CLASS II: 3 types HLA-DP, HLA-DQ, HLA-DR (sometimes called class IIa genes)
Human MHC－HLA gene
• Three gene region: HLA-I, HLA-II, HLA-III gene regions • HLA-I: encode HLA-I molecules
H-2 system: mouse’s MHC antigen ,the gene of it is located on chromosome 17.
Concepts
• Major histocompatibility antigen (MHC molecules)
• Major histocompatibility complex (MHC,gene)
participate in antigen presentation
• HLA-II: encode HLA-II molecules
• HLA-III: encode HLA-III molecules (not important in antigen presenting procedure). • HLA-I gene region: A, B, C gene loci • HLA-II gene region: DP, DQ, DR gene loci.
MHC Polymorphism
MHC genes are highly polymorphic, meaning that there are many different alleles present among the different individuals in the population and the MHC is one of the most polymorphic genetic systems known in higher vertebrates. Determined not only by Multiple genes ,but the genetic features of MHC.
Class II
DP DQ DR
Class III
C4B C4A B1 C2 HSP TNF B C
Class I
A E F MIC G H
encode various secreted proteins that have immune functions, include: * components of the complement system (C4、Bf、C2) ; * molecules involved in inflammation (TNF、HSP70 etc.).
Classical HLA class-I genes
Class II
DP DQ DR
Class III
C4B C4A B1 C2 HSP TNF B C
Class I
A E F MIC G H
The class I gene complex contains three major loci:B, C and A and other undefined minor loci . Each major locus codes for a polypeptide: the alpha-chain and associates with beta-2 microglobulin and is expressed on nucleated cell surface, present endogenous antigens The class I antigens are polymorphic. 2 1
Outline of Lecture
• Discovery & concepts of MHC
• Structure & properties of MHC Genes
• Structure & properties of MHC Molecules
• Peptide-MHC Interaction
• HLA (human leukocyte antigen)
• HLA gene
Other discovery
• 1960 – 1970，Benacerraf and McDevitt found immune response genes(Ir) existing in MHC • There is MHC restriction in CTL killing virus-infected target cells. • The main function is antigen presentation to T cells ,initiating immune response.
• Major histocompatibility complex (MHC) is a series of gene clusters tightly interlocked which encode the major histocompatibility antigens.
• .
HLA (human leukocyte antigen): human’s MHC antigen, the gene of it is located on chromosome 6.
• Significance：difficult to find organ donor,
Alloantibodies
Alloantigens These Ags are the products of
polymorphic genes that distingush foreign tissues from self Tissues. human leukocyte antigens, HLAs (Human MHC antigen)
Outline of Lecture
• Discovery & concepts of MHC
• Structure & properties of MHC Genes
• Structure & properties of MHC Molecules
• MHC polymorphism
• Peptide-MHC Interaction
• Functions of MHC Molecules
• HLA & clinic medicine
Rejection response
1930-1940 Gorer Snell
Ags which can induce rejection responses
in transplantation in mice are called
histocompatibility antigens (H-2 Ag).
The genes encode H-2 Ags are called
histocompatibility genes (H-2 gene).
Discovery of Human MHC (HLA)
1950s: Jean Dausset, Jan van Rood Blood transfusion, Kidney transplantation Circulating Abs react with Ags on the WBC or donor organs. Alloantisera
• Personal identification；
Genetic features of MHC
• • • • Haplotype Multiple alleles Codominant expression Linkage Disequilibrium
Haplotype inheritance
3 2m
Class II
Classical HLA class-II genes
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 The class II antigens are also polymorphic,mainly expressed on professional APC, present exogenous antigens. 1 1 The DR locus may contain more than one 2 2 (up to 4) functional beta-chain genes.
nonclassical HLA class-II genes
RING DP DM LMP2 LMP7 DQ DR
B2 A2 B1 A1
A B
TAP1
TAP2
B2 A2 B3 B1 A1
B*
A
DMA and DMB gene loci code a chain and chain respectively，which play an important role in the assembling of MHC II.
• Functions of MHC Molecules
• HLA & clinic medicine
Байду номын сангаас
Gene maps of human and mouse MHC
HLA gene
• 3600kb; • Short arm of chromosome 6; • >100 locus; • Organized into regions encoding three classes of molecules.
Simplified map of the HLA region

DP

DM LMP/TAP DQ

1
DR
3 4 5

B C
A
MHC Class II
Class III MHC Class I
CLASS I: 3 types HLA-A, HLA-B, HLA-C (sometimes called class Ia genes)
• MHC haplotype：The set of MHC alleles present
on each chromosome
• Inheritance of HLA haplotypes ：
human MHC loci are closely linked and
usually inherited as a haplotype.
Dr. Jean Dausset
• Major histocompatibility antigen (MHC molecules)
are molecules which can induce intensively and rapidly transplantation rejection between two homogeneous variants.