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IMMUNOLOGY
Major Histocompatibility
Complex (MHC) and its encoding
molecules
Weilin Chen, Ph. D.
Institute of Immunology, ZJU
MHC
1.
Introduction
2.
Structure of MHC genes and products
3.
Polymorphism of MHC
4.
Interactions of MHC molecules with antigenic
peptides
5.
HLA and clinical medicine
6.
Biological function of MHC molecules
MHC
Introduction
1. Histocompatibility
The ability to accept grafts between individuals.
2. Histocompatibility antigen
The Ags primarily responsible for rejection of genetically different
tissues are known as histocompatibility Ags.
3. Histocompatibility antigen system
4. Major histocompatibility antigen system
5. Minor histocompatibility antigen system
MHC
6. Major histocompatibility complex,MHC
 A cluster of genes (complex) on chromosome 6 in
humans, encoding cell surface molecules that are
polymorphic and that code for antigens causing
rapid graft rejection between members of a
single species that differ at these loci.
 Several classes of protein such as MHC class I and
II proteins are encoded in this region.
 Human: Human leukocyte antigens (HLA)
 Mouse: H-2
MHC
Organization and Structure of MHC Genes
and Products
1. Organization of MHC genes
2. Products of MHC class I and MHC
class II genes---HLA molecules
3. Other immune function related genes
1. Organization of MHC genes
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MHC
2. Products of MHC class I and class II
genes---HLA molecules
1) HLA class I molecules
Genes: A, B, C
Distribution: every nucleated cell
Structure: α chain (45kD)
β2m (12kD)
peptide-binding cleft: α1+α2
CD8 binding: α3
Function: recognize and present
endogenous and cross-present
exogenous Ags to CD8+ T cells
MHC
2) HLA class II molecules
Genes: DR, DQ, DP
Distribution: APC (B, DC, MΦ)
thymic epithelial cells, activated T cells
Structure: α chain (35kD)
β chain (28kD)
peptide-binding cleft: α1+β1
CD4 binding: β2
Function: recognize and present the
exogenous Ags to CD4 T cells
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Location of MHC Class I and Class II molecules in tissues
MHC
3. Other immune function related genes
1) Antigen presenting function related genes
LMP (low molecular weight polypeptide): LMP2/7
Function: processes endogenous Ag
TAP (transporter associated with Ag processing):
TAP1, TAP2
Function: transports endogenous Ag peptides
HLA-DM: participates in the exogenous pathway
HLA-DO: negative regulation of DM
tapasin (TAP associated protein): participates in the
endogenous pathways
MHC
2. Serum complement encoded genes
MHC class III
3. Non-classical class I genes (HLA Ib)
HLA-E, HLA-G: inhibit NK cell activity
4. Inflammation related genes
 TNF gene family: TNF, LTA, LTB
 Transcription factor gene family: I-κBL,
ZNF173
 MIC family: MIC A, MIC B (ligand for KAR)
 Heat shock protein gene family: HSP70
MHC
Other immune function related genes
Ag processing-related
genes
Complemen Inflammati
t encoding on-related
genes
genes
Non-classical
MHC I genes
MHC
Polymorphism of MHC
1. Polymorphism
The phenomenon of having multiple stable
forms of one gene in the population
 HLA 8016 (HLA-A 2013; HLA-B 2605 ; HLA-DRB
1260)
 HLA-A*0103 HLA-DRB1*1102
 Expression of MHC alleles is co-dominant
2. Linkage disequilibrium and haplotype
A2-B46-Cw3-DR9-DQ9-Dw23
Ref:
http://hla.alleles.org/
HLA Nomenclature
MHC
MHC
3. Production of MHC Polymorphism
The significance of MHC polymorphism:
 Almost all of the polymorphism among MHC alleles
involves amino acid residues located in and around
the peptide-binding groove. As a result, each allelic
form has its own unique peptide-binding properties.
 Affects the ability to make immune responses
(e.g. resistance or susceptibility to infectious diseases).
 Ensures survival of the population as a whole when
they encounter any new pathogens by presenting new
microbial epitopes.
MHC
Interactions of MHC molecules with antigenic
peptides
1. Molecular basis
(1) Antigen-binding cleft
class I Molecules: 1/2
closed at both ends
8~10 amino acids
class II Molecules: 1/1
open at both ends
11~15 amino acids
(2) Anchor site and anchor residue
MHC
MHC I
MHC II
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MHC
Molecular mechanism
 anchor site
 anchor residue
 consensus motif
MHC
2. Characteristics of peptide-MHC binding
(1) Specificity: special anchor residues
The important point is that peptide binding
by a given MHC protein is selective but less
specific than antigen binding by a TCR or a
BCR.
(2) Flexibility: a series of different antigenic
peptides with the same consensus binding
motif can be presented by a given MHC
molecule.
Biological function of HLA
1.
Participates in the adaptive immune response
serving as antigen presenting molecules
* T cells recognize both the antigenic peptide
and MHC molecules by TCR (double
recognition)
Separate antigenpresenting
pathways are
utilized for
endogenous
(green) and
exogenous (red)
antigens.
* MHC molecules can present both
autoantigens and MHC molecules
themselves. Such that MHC molecules
participate in autoimmunity,in the
response to non-self MHC molecules as
well as in the differentiation of T cells in
the thymus.
* MHC polymorphism is a crucial determinant
of disease susceptibility in different
individuals
* MHC contributes to the genetic heterogeneity
of the population
2. Participates in the innate immunity
serving as regulatory molecules
1) Classical MHC class III genes encode
complement, hereby participating in
complement reactions and in the
pathogenesis of some immune diseases.
2) Non-classical HLA class I molecules
(HLA-E, G) regulate the activity of NK
cells.
3) Inflammation related genes initiate and
control inflammation. They also play a
role in stress responses (such as HSP).
MHC
HLA and clinical medicine
1. HLA and transplantation
HLA typing; cross-match
2. Abnormal expression of HLA
Tumor: class I molecule↓
Autoimmune diseases: class II molecule↑
3. HLA and disease susceptibility
Ankylosing spondylitis: B27
4. Adverse drug reaction:
carbamazepine : HLA-B*15:02 (SJS)
allopurinol: HLA-B*58:01
5. HLA and forensic medicine
MHC
Paternity Testing:
Wife: A2, A11; B27, Bw44
Child 1: A2, A1; Bw44, B15, Cw3
Child 2: A2, Aw24; Bw44, Bw54; Cw3
Husband: A1, A3; B15, -; Cw3
Another man: A2, Aw24; B7, Bw54; Cw3