Transcript Folie 1 - German Cancer Research Center

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
•
polymorphic
•
MIC = non-conventional MHC molecule
•
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
•
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
Genetic terminology
Genomes are partitioned into
chromosomes (23 pairs of
chromosomes in humans)
Within species variation at a gene
locus=alleles
The constellation of alleles of a
single chomosome is a haplotype
Most individuals are heterozygous
at MHC loci
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
Rosenthal et Shevach
1974, JEM, 138:1194
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
MHC-dependent mate preferences in humans ??
Cheetah were bred from limited breeding stock:
limited polymorphism. Disadvantage for survival?
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