MHCDr Alok Tripathi

Department of Biotechnologyaquaimmuno@yahoo.co.in

09795894495

Gorer & Snell(‘30s) were working on blood group:

And stated that

•mice in an arbitrarily-designated blood group II (of I,II, III, and IV) was somehow involved in tissue rejection – •when skin from mice of blood-group II was transplanted to other blood-group II mice, the skin was accepted; however, if blood-group II skin was transplanted to blood-group III mice, the skin was rejected.

They reported that

•there must be something on the tissue that allowed the tissue to be recognized as foreign by an animal of a different genetic background.

Consequently, Snell re-named this genetic region - the genes responsible for the

expression of these tissue characteristics –

In humans, the MHC is called the Human Lymphocyte Antigen (HLA) Complex.

Many years later, these genes were found to encode species-specific,

And, that these proteins, while very similar among all species, were

different enough to be recognized as foreign

What these MHC Molecules Mean to Immune Recognition?

What wonder MHC iS?

The MHC molecules are highly polymorphic within a species and among species.

•i.e. while the MHC molecules of a given MHC Class are structurally very similar to one another, there is a wide degree of variation in amino-acid sequence among them

Effector   Cells   in   Adaptive   Immunity

  EffectorT   Cell

PathogenLocation

AntigenPresentatio

n

Target   Cell

Action

CellularImmunity

Tc CD8cytotoxic Cytoplasm Infected cell

MHC IInfected cellapoptosis

Th1 CD4inflammatory

Macrophagevesicles

Macrophage MHC II

Macrophage activation to kill pathogen

Polymorphism in MHC

The estimated extent of polymorphism is approximately 100 different alleles for each of the MHC Class I and Class II molecules, e.g., H-2K, H-2D, H-2L, IA,

and IE, in both the human and the mouse.

Complex

HLA

MHC class

II III I

Region DP DQ DR C4 C2 BF B CA

Gene products

DPαβ

DQαβ

DRαβ

C′ protein

s

TNF-αTNF-β

HLA-B

HLA-C

HLA-C

Polymorphism in MHC contd..

In a given outbred species, each individual within that species is very likely to have a different set of alleles

expressed.

Consequently, it is for this reason that transplants of human organs from one individual to another is so difficult – • difficult to find an exact match of tissue

with respect to the structure of the MHC molecules present on the tissue.

And Also , It is the recognition by an animal's immune system of these very molecules that allows the animal to

recognize cells as "self" or as "foreign."

the loci constituting the MHC are highly polymorphic(i.e. many alternative forms of

the gene, or alleles), exist at each locus among the

population.

one haplot

ype from the

father.

one haplotype from

the mother

and

An individual inherits

Schematic diagram of class I MHCgenes, mRNA transcripts, and protein molecules.

Schematic diagram of class II MHCgenes, mRNA transcripts, and protein molecules.

Peptide binding by class I and class II MHC molecules

Class I molecules Class II molecules

Peptide-binding domain

ἃ1/ἃ2 ἃ1/β2

Nature of peptide-binding cleft

Closed at both ends Open at both ends

General size of bound peptides

8–10 amino acids 13–18 amino acids

Peptide motifs involved in binding to MHC molecule

Anchor residues at both ends of peptide; generally hydrophobic carboxyl-terminal anchor

Anchor residues distributed along the length of the peptide

Nature of bound peptide

Extended structure in which both endsinteract with MHC cleft but middlearches up away from MHC molecule

Extended structure that is held at a constant elevation above the floor of MHC cleft

MHC-I Structure

Representations of the 3D structure of the external domains of a human class I MHC molecule based on x-ray crystallographic analysis.-Side view in which the strands

are depicted as thick arrows and the helices as spiral ribbons. Disulfide bonds

are shown as two interconnected spheres. The 1 and 2 domains interact to form the

peptide-binding cleft. Note the immunoglobulin- fold structure of the 3

domain and 2-microglobulin

Antigen-binding cleft of dimeric class II DR1 molecule in (a) top view and (b) side view. This molecule crystallized as a dimer of the heterodimer. The crystallized dimer is shown with one DR1 molecule in red and the other DR1 molecule in blue. The bound peptides are yellow. The two

peptide-binding clefts in the dimeric molecule face in opposite directions.