MHC

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The major histocompatibility complex (MHC) (also called human leukocyte
antigens, HLAs) is the mechanism by which the immune system is able to
differentiate between self and nonself cells.
The MHC is a collection of glycoproteins (proteins with a carbohydrate) that exist
on the plasma membranes of nearly all body cells. The proteins of a single
individual are unique, originating from 20 genes, with more than 50 variations per
gene between individuals. Thus, it is extremely unlikely that two people, except for
identical twins, will possess cells with the same set of MHC molecules.
Major histocompatibility complex (MHC) is the cluster of gene arranged within a
long continuous stretch of DNA on chromosome number 6 in Human which
encodes MHC molecules.
The term ‘histo’ stands for tissue and ‘compatibility’ refers to ‘getting along or
agreeable’. On the other hand, the term ‘complex’ refers to the ‘genes that are
localized to a large genetic region containing multiple loci’. These genes code for
antigens which involve in the determination of the compatibility of the transplanted
tissue. The compatible tissues will be accepted by the immune system while the
histo-incompatible ones are rejected. The rejection of foreign tissue leads to an
immune response to cell surface molecules. The concept was first identified by
Peter Gorer and George Snell. The main function of MHC molecules is to bring
antigen to the cell surface for recognition by T cells.
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MHC molecule is a cell surface glycoprotein receptor present in APCs and acts
as antigen presenting structure It plays vital role in immune recognition,
including interaction between T cells and other cell types.
In Human MHC is known as Human Leucocyte antigen (HLA) complex and the
genes of MHC are recognized in three classes, consequently there are three
types of MHC molecules.

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Types of MHC:
Class I MHC
Class II MHC
Class III MHC

MHC class-I:
Class-I MHC gene encodes glycoprotein molecule which expressed on the surface
of all nucleated cells and platelets.
MHC-I molecule contains a 45KDa α-chain associated non-covalentely with a
12KDa β2 microglobulin molecule.
Association of α-chain and β2 microglobulin is required for expression of class-I
MHC molecule on cell membrane.
α-chain of MHC-I:
The α-chain is a transmembrane glycoprotein encoded by polymorphic gene within
A, B and C region of Human HLA complex
The α-chain is anchored in the plasma membrane by its hydrophobic trans-
membrane segment and hydrophilic cytoplasmic tail.
α-chain is made up of 3 domains (α1,α2 and α3). Each domain containing
approximately 90 aminoacids, a transmsmbrane domain of about 25 hydrophobic
aminoacids followed by short stretch of charged (hydrophilic) aminoacids of
cytoplasmic tails of 3o aminoacids.
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α1 and α2 domains interacts to form a deep groove on the top which is a peptide
binding clift. It can binds antigen of 8-10 animoacids long.
α3 and β2 are organized into β-pleated sheets, each formed by antiparallel β-strand
of aminoacids, this structure is known as immunoglobulin fold. Because of this
structure α-chain and β2 microglobulin are classified as member of
immunoglobulin super-family receptor.

β2 microglobulin of MHC-I:
β2 microglobulin is a protein encoded by a highly conserved gene located on
different chromosome
β2 microglobulin is similar in size and organization to α3 domain.
Β2 microglobulin does not contain transmembrane region and is non-covalently
linked with α-chain.
Functions of MHC class I:
Major function of MHC-I is to bind peptide antigens and present to CD8+ T cells
(T helper cells)
CD8 T cells are specific for MHC-I antigen
MHC-I binds endogenous antigen and present to T helper cells.
MHC-I molecules are found on surface of all nucleated cells.

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MHC class-II:
•Class-II MHC is the glycoprotein molecule expressed primarily on antigen
presenting cells such as macrophages, dendritic cells and B-cells.
•MHC-II molecules contains two different polypeptide chains, 1 33 KDa α-chain and
28KDa β-chain which are associated by non-covalent interactions.
α-chain and β-chain of MHC-II:
•α-chain and β-chain of MHC-II is a membrane bound glycoprotein that contains
external domains, atransmembrane segment and acytoplasmic tail.
•α-chain and β-chain are made up of two domains (α1 and α2) and (β1 and β2)
respectively.
•The peptide biding cleft is a open ended groove formed between α-chain and β-
chain at proximal end. The cleft can bind antigenic peptide of 13-18 aminoacids
long.
Functions of MHC class II:
•Major function of MHC-II is to bind peptide antigen and present to CD4 T cells.
•MHC-II are found on surface of Antigen presenting cells (APCs).
•CD4+T-cells are specific for MHC-II
•Activates B cells for antibody production
•MHC-II plays a significant role in graft versus host response and in mixed
lymphocyte reaction (MLR) because the immune response gene is identical to MHC-
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MHC class-III:
MHc-III are diverse group of molecules that serves a wide variety of functions
in immune system.
MHC-III are not a marker on cell surface.
Functions of MHC class-III:
Involved in complement activation
Involved in inflammation caused by cytokines, tumor necrosis factors etc

HLA complex
MHC MHC I MHC II MHC III
class
Regio A B C DP DQ DR C4, C3,
n BF
Gene HLA- HLA- HLA- TNF
produ A B C -α
DQ, DR, C’
cts DP, αβ TNF
αβ αβ Protein
-β
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Functions of Major Histocompatibility Complex
Antigen Processing and Presentation
Nucleated cell normally present peptides, mostly self peptides derived from
protein turnover and defective ribosomal products. Also, during viral infection,
intracellular microorganism infection, or cancerous transformation, such
proteins degraded inside the cell by proteasomes are also loaded onto MHC
class I molecules and displayed on the cell surface.

Transplant Rejection
During transplant of an organ or stem cells, MHC molecules themselves act
as antigens and can provoke immune response in the recipient causing transplant
rejection. Since, the MHC variation in the human population is high and no two
individuals except identical twins express the same MHC molecules, they can
mediate transplant rejection.

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Gene Regulation of MHC Expression:
Regulation of MHC genes has not been studied much. Understanding of complete
genomic map of the MHC complex hopefully will accelerate the identification and
coding, and regulatory sequences. Transcriptional regulation of the MHC is
mediated by both positive and negative elements e.g. MHC II trans-activator (cll
TA) and transcription factor (RFX) binds to promoter region of Class II MHC
gene.
ny error in these transcription factor causes a type of disease in lymphocytes.
Expression of MHC molecules is also regulated by many kinds of cytokines.
Interferons and tumour necrosis factor increases the expression of Class I
molecules on cells. Interferon-gamma induces the expression of cIITA.
Expression of MHC decreases after infection by certain viruses e.g. hepatitis B
virus, and adenovirus 12, cytomegalovirus, etc. Adenovirus 12 causes a decrease
in transcription of the transporter genes (TAP1 and TAP2). When these genes are
blocked, class I molecules foil to assemble with β2-micro-globulin.
Decreased level of Class I molecules promotes viral infection. Expression of Class
II molecules by B cells is down-regulated by INF-gamma. Corticosteroids and
rostaglandins decrease the expression of Class II molecules.

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Antigen Presentation and Processing
The T cells can recognize the foreign antigen when the antigen is attached to the
MHC molecules as an MHC peptide complex. The formation of the MHC-
peptide complex requires the degradation of protein antigen by several steps. The
degradation process is known as antigen processing. These degraded proteins are
then attached to the MHC molecules inside the cell and then the MHC molecules
transported to the membrane to present the antigen with the T cell.
Antigen Presentation Pathway: Class I MHC molecules (Cytosolic pathway)
Class I MHC molecules involve in presenting intracellular or endogenous
pathogens or antigens. Intracellular pathogens refer to those organisms which
live and replicates inside the host cell. An example of this type of pathogen is a
virus.
Under normal condition the MHC class I molecules forms a complex with the
self-peptides or self-antigens. While, in case of any viral infection, the MHC
class I molecules present the peptide derived from the virus which is then further
recognized by T cells.
Cell components such as a nucleus, endoplasmic reticulum and Golgi apparatus
play an important role in antigen processing and presentation.
When a virus infected a normal cell, the viral DNA moves inside the cell and
produce viral proteins with the help of the host cell mechanisms. The viral
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The cytoplasm also contains a cylindrical protein complex called the proteasome. The
main function of the proteosome is to degrade the unwanted or damaged protein into
smaller peptides. At the time of viral infection, the viral proteins interacted with the
proteosomes present in the cytoplasm. The processing took place in the cytosol and as
a result, the proteins are degraded into smaller peptides (8-15 amino acid long).
In the next step, these fragmented peptides are transported into the endoplasmic
reticulum. The transport took place due to a peptide delivery system called the
transporter associated with antigen processing (TAP). TAP is made up of two domains
or subunits called TAP 1 and TAP 2.
Inside the endoplasmic reticulum the α and β chains of MHC class I molecules are
synthesized and by the help of a group of chaperone proteins, the MHC class I
molecule is formed and moves towards the TAP. As a result, the peptides bind at the
peptide-binding site of the class I MHC molecule inside the endoplasmic reticulum
and forms the MHC class I-peptide complex.
In the next step, the MHC class I- peptide complex moves to the surface of the Golgi
apparatus and by the help of secretory vesicle, it moves towards the surface of the
plasma membrane.
Once the MHC class I-peptide complex reaches the cell surface, the T cell receptors
recognize the antigen peptide complex. Moreover, the co-receptor CD8 of the T cell
attaches with the α3 domain of the MHC class I molecule. Hence, the antigen is
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Antigen Presentation Pathway: Class I MHC molecules (Cytosolic pathway)

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Antigen Presentation Pathway: Class II MHC molecules (Endocytic Pathway
MHC class II molecules are responsible for presenting exogenous or extracellular
pathogen or antigen. The extracellular pathogen refers to the organisms which can
grow and reproduce outside of the host cell. Bacteria, exotoxins, parasites are
examples of extracellular antigens. These antigens are taken up by the cell by
endocytosis or phagocytosis.
Only the antigen-presenting cells involved in antigen processing and presentation by
MHC class II molecules. These cells include B cells, macrophages, and dendritic
cells. The pathway took place only after the engulfment of the antigen by the
antigen-presenting cells.
Inside the cell, the antigen carries a covering called an endosome. The endosome is
fused with the lysosome present in the cytoplasm and forms endolysosomes. As a
result, the foreign protein is degraded by the proteolytic enzyme present inside the
lysosome and small peptides are formed.
The class II MHC molecules are synthesized and formed in the endoplasmic
reticulum. The α and β chain of the molecule is also associated with the invariant
chain. This association helps to restrict the binding of self-antigen with the class II
MHC molecule. The invariant chain- MHC complex is then transported from the
endoplasmic reticulum to the Golgi apparatus and from the Golgi apparatus to
another vesicle. Inside the vesicle, the invariant chain is digested and only a small
fragment (Class II-associated Downloaded
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the molecule.
In the next step, the vesicle containing the MHC class II molecule is then fused
with the vesicle containing fragmented peptides. The fragmented peptide is then
bound with the MHC class II molecule by displacing the CLIP. This newly
formed MHC class II-peptide complex is then transported to the surface of the
cell.
Once at the cell surface, the antigen is presented to the T cells. The T cell
recognizes the peptide bound with the MHC class II molecule by the help of the
T cell receptor and the CD4 co-receptor binds with the β2 domain of the class II
MHC molecule.

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Summary
MHC molecules enable T-lymphocytes to recognize epitopes and discriminate self
from non-self.
T-cell receptors (TCRs) of T-lymphocytes can only recognize epitopes - typically
short chains of amino acids called peptides - after they are bound to MHC molecules.
MHC-I presents epitopes to T8-lymphocytes; MHC-II presents epitopes to T4-
lymphocytes.
MHC-I molecules are designed to enable the body to recognize infected cells and
tumor cells and destroy them with cytotoxic T-lymphocytes or CTLs. (CTLs are
effector defense cells derived from naïve T8-lymphocytes.)
MHC-I molecules are made by all nucleated cells in the body; bind peptide epitopes
typically from endogenous antigens; present MHC-I/peptide complexes to naive T8-
lymphocytes and cytotoxic T-lymphocytes possessing a complementary-shaped T-cell
receptor or TCR.
Through the process of cross-presentation, some antigen-presenting dendritic cells can
cross-present epitopes of exogenous antigens to MHC-I molecules for eventual
presentation to naive T8-lymphocytes.
Endogenous antigens are proteins found within the cytosol of human cells and include
viral proteins produced during viral replication, proteins produced by intracellular
bacteria, proteins that have escaped into the cytosol from the phagosome of
phagocytes such as antigen-presenting
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During the replication of viruses and intracellular bacteria within their host cell, as
well as during the replication of tumor cells, viral, bacterial, or tumor proteins are
degraded into a variety of peptide epitopes by cylindrical organelles called
proteasomes. The resulting peptide epitopes are then attached to MHC-I molecules
that are then transported to the surface of that cell.
Exogenous antigens are antigens that enter from outside the body such as bacteria,
fungi, protozoa, and free viruses.
MHC-II molecules are made by antigen-presenting cells or APCs, such as dendritic
cells, macrophages, and B-lymphocytes; bind peptide epitopes typically from
exogenous antigens; and present MHC-II/peptide complexes to naive T4-
lymphocytes or effector T4-lymphocytes that have a complementary shaped T-cell
receptor or TCR.
Through the process of cross-presentation, some antigen-presenting dendritic cells
can cross-present epitopes of endogenous antigens to MHC-II molecules for
eventual presentation to naive T4-lymphocytes.
Exogenous antigens enter antigen-presenting macrophages, dendritic cells, and B-
lymphocytes through phagocytosis, and are engulfed and placed in a phagosome
where protein antigens from the microbe are degraded by proteases into a series of
peptides. These peptides are then attached to MHC-II molecules that are then put on
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