11 22 33  m 11 22 33 11 22 11 22 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

MHC class I related chain (MIC): ligands for human NKG2D 11 22 33 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

Lymphomas expressing mouse homologues of MIC molecules (RAE-1) are rejected Lymphoma cells +RAE-1

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 (IA  )x 100 (IEa) x 100 (IEb) x 100 (D)=10 12 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 V  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