11 22 33 m 11 22 33 11 22 11 22 Classical MHC I human MICA, B ULBP-human RAE-1- like human...
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Transcript of 11 22 33 m 11 22 33 11 22 11 22 Classical MHC I human MICA, B ULBP-human RAE-1- like human...
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Classical MHC I
human MICA, B
ULBP-human RAE-1-like
human NKG2D-ligands mouse NKG2D-ligands
RAE-1, H60
MHC class I-like ligands for the activating receptor NKG2D
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MHC class I related chain (MIC): ligands for human NKG2D
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• 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
Lymphoma cells+RAE-1
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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
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Polymorphism of MHC genes
The figures are the numbers of alleles currently officially assigned by the WHO100 different class I or class II alleles in mice H-2 complex: theoretical diversity is:100 (K) x 100 (IA)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 genesWith 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 Shevach1974, JEM, 138:1194
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History: MHC restriction
Zinkernagel and Dohety1975, JEM, 141:502
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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 V 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 haplotypes2.) 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