HISTORICAL BACKGROUND

G. SNELL gave term histocompatibility antigen and

histocompatibility genes.
PETER GORER demonstrated in mice alloantigen
responsible for tumor graft rejection.
G.SNELL identified MHC alloantigens using a large no. of
congenic pairs of inbred mouse strains.
In humans MHC antigens were found by J. DAUSSET in
1950 .
BARUJ BENACERRAF demonstrated that MHC genes
could control the ability of an animal to mount an
immune response to a specific epitope and got the
Nobel Prize in 1980
 MHC
Cluster of genes on human chromosome 6 or mouse
chromosome 17 that encode a set of membrane
glycoproteins called the MHC molecules which
present the appropriate peptides to the T cells. MHC
also encodes proteins involved in antigen processing
and other aspects of host defence.
 MAJOR HISTOCOMPATIBILITY COMPLEX
The genes responsible for causing a grafted tissue to
be percieved as similar to one, s own tissue or as
foreign are MHC genes.
These genes were discovered as a result of breeding of
congenic mouse strains.
 MHC CONTD…….

• a tightly linked cluster of genes.

• roles in intercellular recognition & discrimination between

self & nonself.

• the rejection of foreign tissue is result of an i.r. to cell

surface molecules called histocompatibility antigen (HC).

• implicated in the susceptibility to disease & in the

development of autoimmunity.
MHC
HLA genes in humans and H-2 genes in mouse
Polygenic : >200 genes
Polymorphic ; multiple variants
MHC genes are codominant
GENOMIC ORGANISATION OF MHC
In human beings, MHC located on short arm of
chromosome-6 and region is called HLA region.
Beta2 microglobulin located on chromosome-15.
In mice, MHC located on chromosome-17 and genes
are called H-2 genes.
Beta 2 microglobulin on chromosome 2
GENOMIC ORGANISATION OF HUMAN MHC
Human MHC occupies a large segment of DNA,
extending up to 7×106 base pairs
Class I MHC genes : encode glycoproteins expressed
on the surface of nearly all nucleated cells -----
peptide - Tc

Class II MHC genes : encode glycoproteins expressed

primarily on antigen-presenting cells ( M, DCs, and
B cells) ------peptide - TH

Class III MHC genes : encode secreted proteins e.g.

serum proteins, complement components, tumor
necrosis factors )
MHC CLASS 1 GENES
In human 3 main class 1 genes
HLA-A
HLA-B
HLA-C
In mouse class 1 genes are
H2-K
H2-D
H2-L
The genes for β-microglobulin are located on a different
chromosome.
MHC CLASS 1 GENES
gene products are expressed on fibroblasts and
intestinal epithelial cells in stress conditions and
recognized by NK and CD8 cells and activate these
cells to kill MIC expressing targets
MHC Class II genes
In humans:
HLA-DP
HLA-DQ
HLA-DR
In mice:
Immune response genes
I-A & I-E.
the code for Immune associated surface Ag i.e. Ia
molecules.
MHC Class II genes
Encoding several antigen processing genes: HLA-
DMα, HLA-DOα and DOβ
 Proteasome components: form peptides from
proteins
LMP-2 & 7, TAP-1 & 2 (transporter antigen
processing)
These transport peptides from cytosol to E.R.
 Many pseudogenes
MHC Class III genes
In humans: Encoding complement proteins C4A and
C4B, C2 and FACTOR B, TUMOUR NECROSIS
FACTORS α & β
In mice: Secretory or serum proteins
MHC POLYMORPHISM
Multiple variants of each gene with in the population
as a whole. Three properties of MHC molecules are
affected by MHC polymorphism
The range of peptides bound
The conformation of the bound peptide
The direct interaction of the MHC molecule with the
T cell receptor
Why Polymorphism and Polygenism in MHC?

Polymorphism and polygenism in MHC make it

impossible for a pathogen to alter its antigenic
epitopes so that the epitopes cannot be presented by
a majority of the individuals in a population.
Most individuals have six MHC class I proteins (and
at least 6 MHC class II) so if one MHC protein cannot
present a pathogen’s antigens, another MHC protein
probably can.
MHC polymorphism is determined only in the
germline
Alleles for MHC genes are co-dominant. Each MHC
gene product is expressed on the cell surface of an
individual nucleated cell.
Most polymorphic residues of Class I are in the alpha
1 and alpha 2 domains
Most polymorphic residues of Class II are in the alpha
1 and beta 1 domains
MHC genes

*Also Co-dominance
MHC Restriction
MHC CLASS 1 AND 2 MOLECULES
Peptides from the cytosol are bound to MHC class 1
molecules and recognized by CD8 T cells. These
molecules are expressed on all nucleated cells. While
peptides generated in intracellular vesicles are bound
to MHC class 2 molecules and recognized by CD4 T
cells. These molecules are present on professional
antigen presenting cells.
General Properties of MHC Molecules
Each MHC molecule consists of an extracellular
peptidebinding cleft, followed by immunoglobulin
(Ig)–like domains and transmembrane and
cytoplasmic domains.
The polymorphic amino acid residues of MHC
molecules are located in and adjacent to the
peptide-binding cleft.
The non-polymorphic Ig-like domains of MHC
molecules contain binding sites for the T cell
molecules CD4 and CD8.
The peptides that bind to MHC molecules share
structural features that promote this interaction.
Each class I or class II MHC molecule has a single
peptide-binding cleft that binds one peptide at a
time, but each MHC molecule can bind many
different peptides.
MHC molecules acquire their peptide cargo
during their biosynthesis and assembly inside
cells.
The MHC molecules of an individual do not
discriminate between foreign peptides (e.g., those
derived from microbial proteins) and peptides
derived from the proteins of that individual (self
antigens).
Endogenous or Cytosolic pathway of Antigen
Processing and Presentation
Exogenous or Endocytic pathway of Antigen
processing and presentation