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MHC class I-like ligands for the activating
receptor NKG2D
human NKG2D-ligands
Classical MHC I
mouse NKG2D-ligands
human MICA, B
a1
a2
ULBP-human RAE-1-like
RAE-1, H60
a3
b2m
a1
a2
a1
a2
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MHC class I related chain (MIC) ligands for
human NKG2D

• polymorphic
• MIC non-conventional MHC molecule
• Expression absent from healthy
  tissue,overexpressed on tumors and in the gut
  epithelium
• A soluble form of MICA is found in the serum of
  cancer patients
• Expression induced by heat shock, viral
  infection and bacteria

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Lymphomas expressing mouse homologues of MIC
molecules (RAE-1) are rejected
Lymphoma cells RAE-1
Lymphoma cells
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Genetic terminology
Genomes are partitioned into chromosomes (23
pairs of chromosomes in humans) Within species
variation at a gene locusalleles The
constellation of alleles of a single chomosome is
a haplotype Most individuals are heterozygous at
MHC loci
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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
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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.
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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
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Allelic variation occurs at specific sites within
MHC molecules
Allelic variability is clustered at specific
sites within domains
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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.
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MHC restriction
The antigen specific T cell receptor recognizes a
complex of antigenic peptide and MHC.
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History MHC restriction
Rosenthal et Shevach 1974, JEM, 1381194
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History MHC restriction
Zinkernagel and Dohety 1975, JEM, 141502
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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
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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

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MHC-dependent mate preferences in humans ??
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Cheetah were bred from limited breeding stock
limited polymorphism. Disadvantage for survival?
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MHC and transplantation
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Mating of inbred mouse strains with different MHC
haplotypes
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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.
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Skin transplantion between between different
mouse strains with same or different MHC haplotype
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T cells (CD4 and CD8 T cells) can transfer
allograft rejection (1950. Mitchison)
Nude mice (have no T cells) even accept xenografts
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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.
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Minor H antigens
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2 different ways of graft recognition
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Initiation of graft rejection Dynamics of graft
rejection
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Hyper acute graft rejection
Preexisting antibody against donor graft antigens
can cause hyperacute graft rejection
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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).
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Effect of antigen matching on the survival of
kidney grafts
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Tissues successfully transplanted
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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
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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