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Major

Histocompatibility
Proteins (MHC)

Shebina Babu
D3 Biotech
The major histocompatibility complex (MHC) is a
set of cell surface proteins essential for acquired
immune system to recognize foreign molecules .

The main functions of MHC molecule is :


to bind to peptide fragments derived fr0m pathogens .
to display them on the cell surface for recognition by
the appropriate T-cells.
to mediate cell-cell interactions [interactions of
leukocytes (WBCs), which are immune cells, with other
leukocytes or with body cells.]
to determine compatibility of donors for organ
transplant, as well as one's susceptibility to an
autoimmune disease.
The MHC in humans, is also called the human
leukocyte antigen (HLA).
MHC molecules are inherited in a gene complex
called Major Histocompatibility complex.
The absolute need for antigens to be presented
bound to MHC molecule is called MHC
restriction.
All mammals posses a MHC in their genome.
a. in humans the MHC is located on the short arm
of chromosome 6
b. in mice it is found on chromosome 17
. the human MHC contains about 3.5
megabases, which is 2 to 3 times larger than
mouse MHC.
The MHC contains 3 classes of genes .
Class I genes code for MHC molecules
found on the surface of most nucleated
cells.
Class II genes codes for a different set
of polymorphic MHC molecules found on
the surface of macrophages, dendritic
cells, and B cells.
Class III genes code for a mixture of
proteins with wide variety of functions
that are not directly linked to antigen
presenting. Some of these code for
complement proteins.
MHC CLASS I PROTEINS
Some antigens originate within the cell itself
- endogenous Ag.
These after fragmentation are bound to MHC
class I molecules and transported to the cell
surface.
Ag bound to MHC class I triggers a response
by a population of lymphocytes called
cytotoxic T cells.
The class I gene can be divided into those
that are highly polymorphic, called class Ia
genes,
and those that show very little
MHC CLASS Ia PROTEIN
Structure

All the class Ia molecules consists of

a single peptide chain of 45kDa

called the that is noncovalently

linked to a much smaller chain called


2-microglobulin and bound to the cell

surface. The chain contains 3 extracellular

domains 1,2 and 3,each about 100

amino acids long and containing a single intrachain disulphide


bond, as well as a transmembrane domain, and a cytoplasmic
domain. The chain consists of a single extracellular domain.
Gene arrangement
Each mammal species studied has two or three MHC
class Ia loci. For example, in humans there are three
class Ia called A,B, and C. The class Ia loci in the mouse
H-2 complex are called K and D.
Polymorphism
In human populations, as many as 23 chain alleles
can be found at the A loci ,49 chain at B and 8 chain
alleles at C.
This polymorphism is a result of variations in the
amino acids sequence of the 1 and 2 domains.
About half of the 182 amino acid in the 1 and 2
domains are variable.
The 3 domain as well as the transmembrane and
cytoplasmic domains are highly conserved and show
little sequence variation.
The polymorphism of the 1 and 2 domains occurs as a
Function
a.One function of the T cell mediated
immune response is the identification and
destruction of abnormal cells such as
those infected by viruses.
Cytotoxic T cells must respond to
fragmented viral proteins expressed
on the surface of infected cells.
They are first bound to the Ag binding
groove of the MHC class Ia
molecules on the target cell.
Cytotoxic T cells recognize this
virus protein-class Ia molecule complex.
The 3 domain attaches the receptor-like structure to the
cell membrane, and the 2 microglobulin component
probably stabilizes the structure.
b. MHC class Ia molecules also bind peptides
obtained from intracellular sources.
Newly synthesized peptides are marked by
attachment to ubiquitin(U), degraded by
proteasomes, and their fragments transported to the
newly forming MHC class I molecule where they are
inserted in the Ag-binding groove.
The complexes are then transported to the cell
surface for presentation to Ag-sensitive cells.
MHC CLASS Ib PROTEINS
The nonpolymorphic MHC class Ib molecules
have a restricted tissue distribution; some
maybe secreted and some are not encoded by
genes located within the MHC.
STRUCTURE AND GENE ARRANGEMENT
In humans there are six class Ib loci : HLA-
E,F,G,H, J and X.
The last three are pseudogenes.
HLA-E and X are located between HLA-A and C
and expressed on a variety of cells and skin
cells. A second family of class Ib- molecules
called CD1 is found on another chromosome.
The class Ib gene loci in mice can be divided
These proteins each consists of a membrane bound
chain of 44kDa, associated with 2
microglobulin.
Their extracellular conformation is similar to class
Ia.

FUNCTIONS

As a result of their lack of polymorphism,


class Ib molecules can bind to only limited
range of peptides.

It is now believed that they can act as


receptors for specific ,commonly
encountered microbial antigens.
MHC CLASS II PROTEINS
The human class II region (called HLA-D) is
1.1 megabases in size and is located on the
centromeric side of the classI and classIII
regions on chromosome 6.

Found on professional Ag presenting cells (B


cells,dentritic cells,macrophages) or they may
be induced(as on the T cell,keratinocytes and
vascular endothelial cells).

The number of class II molecules on the cell


surface is enhanced in rapidly dividing cells
and in cells treated with interferon.
STRUCTURE
MHC class II are glycoproteins, each consisting
of the noncovalently
linked polypeptide chains called and .
The chains are 31 to 34kDa, and the
chains are 25 to 29kDa.
Each chain consists of :
2 extracellular domains
A connecting peptide
A trasmembrane domain and
A cytoplasmic domain.
A third chain, a or invariant chain( also
called CD74) of 32 kDa, is associated with
intracellular classII molecules.
GENE ARRANGEMENT
Within the HLA-D region are five loci called DN,
DO, DP, DQ and DR as well as the genes for
proteins involved in transporting Ag fragments
across the endoplasmic reticulum, located
btwn the DP and DQ gene loci.
Within each locus, the genes for chains are
designated
GENE LOCUS A
No.and
Of A the
No.genes
Of B for chains are
PSUEDOGENES(dont
GENES GENES form protein products)
called B.
DN 1 - No protein product

DO - 1 No protein product

DP 2 2 DPA2,DPB2

DR 1 2 DRB2

DQ 2 3 DQB2,DQA2
f
POLYMORPHISM
Class II molecules show great polymorphism(their amino acid
sequence shows great variability. These sequence variations
are restricted to the 1 and 1 domains.
Within these domains, the polymorphic amino acids are
concentrated in three to four discrete hypervariable regions.
The outermost domains of each MHC class II chain (1 and 1)
fold together to form an open ended groove. This groove
functions as an Ag-binding site.
The hypervariabile regions are located almost exclusively in
the walls of the groove, and they determine the shape of the
groove.
A -pleated sheet composed of eight antiparallel strands
forms the floor of the groove, and the two -helices form its
walls.
In humans, DOB and DRA are the least polymorphic, while the
DRB genes and DQB1 are most polymorphic. This MHC class II
polymorphism results from multiple point mutations and gene
conversions.
FUNCTION
The presentation of exogenous antigen is the prime
function.

Although all macrophages can phagocytise foreign


particles, only those that express MHC class II
molecules can process this material in such a way that it
can stimulate an immune response.

These molecules can also bind fragments of the


ingested antigen and present them to Ag-recognizing
cells .

These Ag-recognizing cells are subpopulation of


lymphocytes called helper T cell . Helper T cells can only
recognize a foreign antigen and respond to it if
Steps involved
Ag is phagocytised and taken into phagosomes.

Phagosomes fuse with granules containing acidic


proteases.
Ingested peptides are broken down by lysosomal
enzymes into fragments abt 10 -20 amino acids long.
The endosomes containing the antigenic peptides
then fuse with other endosomes carrying newly
synthesized MHC class II molecules.
This reaches cell surface, they fuse with cell
membrane in such a way that they are recognised by
receptors on the T cell.
MHC CLASS III PROTEINS
The remaining genes located within the MHC can be grouped as
class III genes.
They code for protein with a great variety of functions. Several of
these genes code for proteins that belong to the complement
system.
In addition, there are other loci that code for enzyme 21-
hydroxylase A and B ,tumour necrosis factor(TNF and ) and
heat shock protein 70 (HSP70).
All is classified as MHC class III loci.

In mice , a gene locus called S codes two proteins collectively


called as SS.
Humans also possess 4 genes for complement components in

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