Transcript Folie 1 - German Cancer Research Center

The MHC complex: genetics, function and disease
association
Lecturer: Adelheid Cerwenka, PhD, D080, Innate Immunity
Sources: Janeway: Immunobiology, 5th edition
Kuby: Immunology, 4th edition
Klein/Horejsi:Immunology 2nd edition
Only complementary surfaces fit together
MHC-structure
Major Histocompatibility Complex (MHC):
linked cluster of genes, which products play a role in
intercellular recognition between self and nonself.
The MHC is a region of multiple loci that play
major roles in determining, whether transplanted
tissue is accepted as self (histocompatible)
or rejected as foreign (histoincompatible)
The concept of Histocompatibility
A skin-graft transplanted from A donor to a genetically identical recipient is accepted, to
a genetically disparate recipient is rejected
Nomenclature
• MHC = Major Histocombitibiliy Complex
• Minor Histocompatibility Antigens: proteins, which
are cell surface expressed and their peptides are
loaded into MHC molecules
• MHC is a generic name
• HLA = Human Leucocyte Antigen, eg SLA = Swine
Leucocyte Antigen
• Mouse: MHC has an historical name = H2 (H-2)
stands for histocompatibility 2
Table of contents
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Introduction
Structure of MHC I and II molecules
Genetic organisation of the MHC
Polymorphisms of MHC alleles
MHC and disease
Communication of cells in the body
1.) Cell cell contact via cell surface receptors:
cell surface proteins have been classified as CDs
(=cluster of differentiation)
CD2
T cell
DC
MHC
TCR
CD28
B7
2.) Cell to cell contact via soluble mediators such as
cytokines (interleukins-IL) or chemokines (CCR, CXCR)
IFN-g
T cell
MHC
TCR
CD28
IL-12
B7
DC
Host defense
Against intracellular infection by viruses
Against intracellular infection by mycobacteria
MHC class I molecules present antigen derived from
proteins in the cytosol
MHC class II molecules present antigen originating
in intracellular vesicles
MHC molecules on the cell surface display peptide
fragments
Structure of MHC class I
Computer graphic representation
and ribbon diagramms of
of the human MHC class I molecule
HLA-A2.
Heterodimer:
a chain (43 kDa): polymorphic
b2-microglobin (12 kDa): nonpolymorphic, non-covalently bound
a1 and a2: peptide binding, cleft
formed by single structure
a3: transmembrane
Structure of MHC class II
Computer graphic representation
and ribbon diagramms of
of the human MHC class II molecule,
HLA-DRI
Heterodimer, 2 transmembrane chains:
a chain (34 kDa)
b-chain (29 kDa)
b1 and a1: peptide binding, not joined
by covalent bond
A2 and b2 : transmembrane
Peptide binding groove is the MHC
class II molecules is open at both ends
Peptide binding sites and binding sites for CD4 or
CD8 on MHC class I and MHC class II
b chain (white)
a chain
(purple)
Base of
b2 domain
(green)
aChain (white)
b2Microglobuline
(purple)
Base
of a3 domain
(green)
The binding sites for CD4 and CD8 on MHC class II molecules or MHC class I
lie in the immunoglobulin domain, nearest to the membrane
Peptides bind to MHC I molecules through
structurally related anchor molecules
Free amino and carboxy
termini are stabilizing contacts
Peptides eluted from two
different MHC class I
molecules are shown.
Anchor residues in green:
Not identical but related:
eg: F and Y are both aromatic
amino acids
V, L and I are large
hydrophobic amino acids
MHC class I without peptide
instable
Pockets in the MHC molecules are lined by polymorphic amino acids.
Peptides that bind MHC class II are variable in
length and anchor residues lie at various distances
from the ends of the peptide
Peptides that bind to mouse MHC II Ak allele, or human MHC II HLA-DR3
Peptides that bind to MHC class II are at least 13-17 AA long,
Ends of peptides are not conserved. Ends do not bind, binding pockets more permissive
Blue: negatively charged residue D, aspartic acid, E glutamic acid,
green: hydrophobic residues
The expression of MHC molecules differs between
tissues
MHC class I:
Expressed on all nucleated cells
MHC class II:
Expressed on surface of APCs
(antigen presenting cells)
Viruses can infect all types of cells
Plasmodia (malaria)
live in red blood cells
Regulation of MHC class I expression
Expression of MHC class I regulated by sequences upstream of the coding part.
MHC enhancer segment: enhancer A, IRE interferon response element, enhancer B
MHC class I expression can be regulated by Interferon (IFN-g).
IFN-g also induces the key components of the intracellular machinery that
enables peptides to be loaded onto MHC class I molecules
T cells bearing a gd T cell receptor
 gd T cells are not restricted by classical
MHC molecules
• They may be specialized to bind certain
types of ligands (heatshock proteins,
mycobacterial lipid antigens) directly or
presented by non-classical MHC
molecules.
Conclusion: Structure of MHC molecules
• MHC class I and II molecules have
different structure, different distribution on
cells in the body, and different function
• Peptides, that bind to MHC class I or II are
derived of different compartments and are
of different length
• The expression of MHC class I molecules
can be regulated by interferon-g.
Genetic organisation of MHC
MHC diversity
MHC is polygenic
means that it contains
several different MHC class I
and class II genes
MHC is polymorphic
(poly=many
Morphic=shape, structure):
means that there are
multiple variants of a gene within
a population as a whole
Genetic organisation of the MHC
Human chromosome 6
Mouse chromosome 17
Detailed map of the human MHC
MHC class IB genes
=Non-classical MHC
Molecules
=Non-conventional MH
Class I molecules
Function of non-conventional MHC molecules
• Ligands of inhibitory (HLA-G) or activating (MIC) Natural
Killer cell receptors
• Presentation of non-conventional peptides to ?? Cells: In mice,
the H-2M locus encodes a nonconventional MHC class I
molecule that present peptides that have a formylated
methionin (eg also found in prokaryotic organisms such as
mycobacterium tuberculosis, listeria, Salmonella)
• Presentation of lipid antigens (CD1)
MHC class I receptors on human Natural killer cells
Receptors……………………………Ligands
KIR receptors
(Killer immunoglobulin receptors)…HLA-C
NKG2A/CD94………………………..HLA-E
NKG2D……………………………….MIC
effect
mostly
inhib.
mostly
inhib.
activ.
MHC class I-like ligands for the activating receptor
NKG2D
Classical MHC I
human NKG2D-ligands
mouse NKG2D-ligands
human MICA, B
a1
a2
a1
a2
ULBP-human RAE-1-
a3 b2m
a3 b2m
RAE-1, H60
like
a1
a2
a1
a2
MHC class I related chain (MIC): ligands for
human NKG2D
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polymorphic
•
MIC = non-conventional MHC molecule
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a3 on
Expression absent from healthy tissue,overexpressed
tumors and in the gut epithelium
a1 a2
• A soluble form of MICA is found in the serum of cancer
patients
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Expression induced by heat shock, viral infection and
bacteria
Lymphomas expressing mouse homologues
of MIC molecules (RAE-1) are rejected
Lymphoma cells
+RAE-1
Lymphoma cells
Polymorphism of MHC genes
The figures are the numbers of alleles currently officially assigned by the WHO
100 different class I or class II alleles in mice H-2 complex: theoretical diversity is:
100 (K) x 100 (IAa)x 100 (IEa) x 100 (IEb) x 100 (D)=1012
Linkage disequilibrium occurs in human
Expression of MHC alleles is co dominant
4 possible
combinations of
haplotypes are found
in the offspring, there
being one chance in
four that an individual
will share both
haplotypes with a
sibling.
Diversity of MHC molecules expressed by an
individual
Polygeny the presence of
several different related genes
With similar function ensures that
each individual produces a number
of different MHC molecules
Allelic variation occurs at specific sites within MHC
molecules
Allelic variability is clustered at specific sites within domains
Gene conversion and new alleles
Sequences can be transferred from one
gene to a similar but different gene by a
process know as gene conversion.
This can occur by a misalignment of
two paired homologous chromosomes
When there are many copies of similar genes
arrayed in tandem.
Polymorphisms have been actively
selected during evolution.
MHC restriction
The antigen specific T cell receptor recognizes a complex of antigenic peptide and
MHC.
History: MHC restriction
Zinkernagel and Dohety
1975, JEM, 141:502
Many T cells respond to superantigens
Superantigens (produced by bacteria and viruses) can bind independently to
MHC class II molecules and TCR, binding to the Vb domain of the TCR.
Stapphylococcal enterotoxins (SE) cause food poisoning and toxic shock syndrome
Conclusion: Polymorphism of MHC
• Extensive polymorphism can extend the range of antigens to
which the immune system can respond.
• It is an advantage for the survival of the species
• It has evolved to outflank evasive strategies of pathogens.
• Pathogens are clever: they can evade detection or can suppress
host responses.
• Exposure to select for expression of particular MHC alleles:
strong association of HLA-B53 with recovery from malaria
• Why not more MHC loci? For maintenance of self-tolerance
Cheetah were bred from limited breeding stock:
limited polymorphism. Disadvantage for survival?
MHC-dependent mate preferences in humans ??
MHC and transplantation
Mating of inbred mouse strains with different MHC
haplotypes
Various MHC molecules expressed on antigen
presenting cells of a heterozygous H-2 k/d mouse
Diversity generated by these mechanisms presumably increases the number
of antigenic peptides that can be presented and thus is advantageous
to the organism.
Skin transplantion between between different mouse
strains with same or different MHC haplotype
T cells (CD4 and CD8 T cells) can transfer allograft
rejection (1950. Mitchison)
Nude mice (have no T cells) even accept xenografts
Even complete matching does not ensure graft
survival
1.) HLA typing not precise, complex polymorphisms, only siblings inherit
the same haplotypes
2.) Minor histocompatibility antigens exist, peptides from polymorphic proteins
presented by the MHC molecules on the graft.
Although MHC genotype can be matched, polymorphism in any other gene
can graft rejection.
Minor H antigens
2 different ways of graft recognition
Initiation of graft rejection: Dynamics of graft
rejection
Hyper acute graft rejection
Preexisting antibody against donor graft antigens can cause
hyperacute graft rejection
Mixed lymphocyte reaction
Allogeneic bone marrow transplantion: often graft versus host disease
(rashes, diarrhea, pneumonitis).
Also because of minor H anitgen difference with siblings.
Tests with MLR (mixed lymphocyte reaction).
Effect of antigen matching on the survival of kidney
grafts
Tissues successfully transplanted
Pregnancy: The fetus is an allograft that is tolerated
repeatedly.
Fetus carries parental MHC and minor H antigens that differ from the mother.
Trophoblast and immunosuppressive cytokines (low MHC class I) protects fetus
Conclusion: MHC and transplantation
• Most transplants need generalized
immunosuppression (toxic)
• MHC matching often not sufficient for graft
survival (minor H antigens)
• Tolerance to fetus is the key for a species
to survive
MHC and disease association
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Autoimmune disease
Viral disease
Neurologic disorders
Allergic reactions
MHC genes and Pathogen defence
Population studies show association of susceptibility
to IDDM with HLA genotype
Affected siblings share 2 HLA haplotypes
much more frequently than expected
Certain HLA genotype are
frequently found in diabetic patients
DR3/4 tight linkage to DQb,
Position of the DQb chain affects susceptibility to
insulin-dependent diabetes mellitus
AA 57 forms a salt bridge
Across the peptide
binding cleft of DQ
Possible explanation:
1.) Allelic variants of MHC
molecules differ in ability
to present the
autoantigenic peptides to
autoreactive T cells
2.) Shaping of the
T cell repertoire
Significant associations of HLA Alleles with
increased risk for various diseases
• Both inherited and environmental factors play a role in
the induction of autoimmune disease
• Inbred mice show uniform susceptibility to autoimmune
disease
• But also other independly segregating disease
susceptibility loci have been defined
• Also amount of self antigen transcribed in the thymus
plays a role
In the fight against viruses and tumors: high MHC I
expression on target cells:
good or bad ??
NK cell
NK cell
Lysis
No lysis
CD8 cell
CD8 cell
Lysis
Tumor cell: lots of MHC I
No Lysis
Tumor cell: little MHC I