Lecture Lecture

Major histocompatibility complexMajor histocompatibility complexMHCMHC

IntroductionIntroduction

Every mammalian species studied to date possesses a tightly linked cluster of genes – the major histocompatibility complex – whose products (MHC antigenes) are associated with self/nonself discrimination.

The MHC copmplex plays a central role in the development of both humoral and cellular immune response.

Basic termsBasic terms

• MHCMHC – – major histocompatibility systemmajor histocompatibility system, system of genes which, system of genes which products determine the discrimination of products determine the discrimination of self and self and nonselfnonself

• major histocompatibility (transplantation) antigenes major histocompatibility (transplantation) antigenes -- products of MHC genesproducts of MHC genes

• HLAHLA – – human leukocyte human leukocyte genes or genes or antigensantigens (human (human MHCMHC))• H-2H-2 – – MHC of miceMHC of mice

• haplotypehaplotype – – a group of MHC genes on single chromosomea group of MHC genes on single chromosome

• alleleallele – – one of the several alternate forms of a gene at a single one of the several alternate forms of a gene at a single

locus that control a particular characteristiclocus that control a particular characteristic

• polymorphismpolymorphism – – the existence of multiple alleles of single genethe existence of multiple alleles of single gene in in population population

Major histocompatibility complexMajor histocompatibility complexMHCMHC

StructurStructuree

StructureStructure of MHC molecules of MHC molecules

MHC class I MHC class IIMHC class I MHC class II

MHC IMHC I and binding of Ag fragments and binding of Ag fragments

Top viewAntigen fragment (green) is trapped by MHCI molecule in endoplasmic reticulum and transported to the surface of the cell.

The Ag fragment spans for 8-10 amino-acid residues. Alfa helices of 1 and 2 domain (red) bind Ag fragment.

StructureStructure MHC I and peptide binding MHC I and peptide binding

SSide viewide view

MHC and TCR MHC and TCR Antigens and superantigensAntigens and superantigens

Antigens are processed by APC cells and presented in the frame of MHCII molecules. Ag fragments are localized in the cleft between 1 and 1 domains of MHCII. APC`s activate just Ag specific clone of T cells.(right side of picture)

Superantigens bind out of MHC cleft and activate many clones of T cells. The response is nonspecific, produce a lot of mediators (interleukines) that can lead to shock reaction.(left side of picture)

Exogenous antigens (Ag) are presented by APC cells.

MHCII is synthesized in endoplasmic reticulum. Transported to Golgi system and released to cytoplasma in primary lysosome.

Ag is endocytosed and transported in early edosome.

After fusion of early endosome and primary lysosome the Ag is degradated to Ag fragments by lysosmal enzymes.

Fragments of Ag are trapped by MHCII molecules and expressed on cell surface where recognized by Th cells.

Antigen processing and presentation MHC II molecules

APCcell

Activation of Th cells MHC II molecules

Th cells recognize Ag fragments by TCR (T cell receptor).

The response of Th cells depend on the affinity between TCR and MHCII+Ag. 1) low affinity (usually self Ag) -> T cells are not activated 2) high affinity (usually foreign Ag) - > T cells accept the interaction as

THE FIRST SIGNAL, but the T cells are still not fully activated.

After delivery of SECOND SIGNAL represented by cytokine IL-1 (produced by macrophages) Th cells became ACTIVATED and provide HELP for :

1) Tc cells via IL-2 ( Tc became cytolytic)

2) B cells via IL-4, IL-5 (proliferation, diferentiation, class switching)

Activation of Th cells MHC I molecules

Endogenous antigenes (foreign as well as self) are presented by all nucleated cells.

MHCII molecules are synthesized in endoplasmic reticulum. Endogenous Ag is cleaved in cytoplasm by proteasome and Ag fragments are transported to endoplasmic reticulum via TAP transporters.

Ag fragments are then trapped by MHCII molecules and transportedto surface of cell membrane, where recognized by Tc cells.

Activation of Tc cells MHC I molecules

Tc cells recognize Ag fragments by TCR (T cell receptor).

The response of Tc cells depend on the affinity between TCR and MHCI+Ag. 1) low affinity (usually self Ag) -> T cells are not activated 2) high affinity (usually foreign Ag) - > T cells accept the interaction as

THE FIRST SIGNAL, but the T cells are still not fully activated.

After delivery of SECOND SIGNAL represented by cytokine IL-2 (produced by Th cells) Tc cells became ACTIVATED - cytolytic and lyse cells which present the Ag which was recognized during the first signal delivery.

Major histocompatibility complexMajor histocompatibility complexMHCMHC

GeneticsGenetics

GeneticsGenetics

MHC genes are:

• very polymorphic

• inherited according Mendelian rules

• expressed codominantly on the cells

The MHC complex

Simplified organization of MHC complexSimplified organization of MHC complex

Complex HLAMHC class

II III I

Region DP DQ DR C4, C2, BF B C A

Gene products

DP

DQ

DR

Complement

TNF TNF HLA-B HLA-C HLA-A

Major histocompatibility complexMajor histocompatibility complexMHCMHC

FunctionFunctionss

TransplantationTransplantation

Biological roles of MHC moleculesBiological roles of MHC molecules

MHCmolecules

Transplantation

Legal medicine

Autoimmunity

Susceptibility to infection

T cell maturation

Graft versus host reactionGraft versus host reactionGvHRGvHR

Common manifestations (figure 4) of GVH reaction are diarrhea, erythema, weight loss, malaise, fever, joint pains, etc. and ultimately death.