MHC and its functions

Review:Class I/peptide TCR/CD8 cytotoxic functionClass II/peptide TCR/CD4 Helper function

TH1 MacrophagesTH2 B cells

Strong selective pressure for pathogens to escape presentation by MHC.

It is extremely difficult for the pathogens to evade MHC molecules and immune surveillance. Why?

MHC is polygenic. Several different MHC class I and II genes.

MHC is highly polymorphic. Multiple variants of the gene within the population.

MHC complex on the genomeChromosome 6 extends over 7 centimorgansMHC I a and MHC II a and b all in the same locus.2 microglobulin and the invariant chain genes are not in this locus.In humans MHC are known as HLA antigens and in mouse as H-2.Class I A, B, C.Class II DR, DP, DQ.HAL-DR has an extra gene whose product can pair with the DR . 4 pairs of Class II molecules.

TAP- peptide transporterLMP- proteasome sub unitTapasain- that binds to TAP and empty MHC molecules.All in the MHC locus.IFN , and produced early as an innate immune response.They all increase the expression of the above genes.HLA-DM catalyzes peptide binding to MHC class II.MHC class II and related genes regulated by IFMHC class II transactivator (CIITA).

MHC locus very important.Several genes that have vital functions inImmune response also are located here.

Complement 2, 4 and factor BTNF, lymphotoxin.

Specialized class I molecules act as ligand for activation and inhibition of NK cells.MICA and MICB- induced due to cellular stress such as Heat shock. They act as ligands for receptors expressed on NK, T cells and some CD8 positive cells. Induce killing of MIC expressing targets.NKG2D- activationDAP10HLA-G expressed on fetal placental cells that recognizes ILT-2 receptor on NK cells and inhibits killing. Similar with HLA-E.

MHC molecules are highly polymorphic.

MHC highly polymorphic.More than 200 alleles that occur in high frequency.

Most individuals heterozygous at MHC locus.

MHC haplotype.

Expression codominant.

Codominance

Allelic variation in peptide binding cleft:

MHC Class I

Allelic variation in peptide binding cleft:MHC class II

MHC restriction first demonstrated by Peter Doherty and Rolf Zinkernagel from studies of virus specific toxic cells.Virus specific cytotoxic T cells generated in say MHC(a) type individual can not recognize and kill the same virus infected cells from an individual having MHC(b).

Corecognition of peptide and MHC molecule by TCR is known as MHC restriction.

The rapid and very potent cell-mediated immune response to the transplanted tissue results from a large number of T cells that are specifically reactive to non-self.

MLR- mixed lymphocyte reaction.

Transplant rejection

Super antigens

Recognized by T cells without being processed.Fragmentation usually destroys the ability of super antigens to trigger T cells.

MHC class II

V especially CDR1, CDR2 and HV4 regions.20-50 V segments

2-20% of T cells are activated.

Advantages of MHC polymorphism

Extends the range of antigens to which the immune system can respond.Papua New Guinea- some pockets of populations have mainly MHC-A11 alleles.EBV virus isolated from these individuals have mutations in a dominant peptide that is presented by MHC-A11. T cells no longer recognize.

Infection: all individuals due to MHC polymorphism will not succumb to the same extent to the disease.

Polymorphism

Gene conversion.

Point mutations.

Genetic processes that result in polymorphisms

CD1 molecules are MHC class I like molecules encoded outside MHC locus.

It has chain associated with 2-microglobulin.

Behaves like a MHC class II molecule.Targeted to vesicles.

They can present antigens derived from breakdown of glycolipids.

Summary

MHC locus- many of the genes encoding proteins related to antigen presentation.

Extensive polymorphism

MHC restriction

Transplant rejection