major histocompatibility

1. Major Histocompatibility Complex

2. Major Histocompatibility Complex
• The Major Histocompatibility Complex (MHC) is a set of
molecules displayed on cell surfaces that are responsible for
lymphocyte recognition and "antigen presentation".

3. • The MHC molecules control the immune
response through recognition of "self" and
"non-self" and, consequently, serve as targets
in transplantation rejection. In humans, MHC
is also called human leukocyte antigen (HLA).
Major Histocompatibility Complex

4. The major histocompatibility complex is encoded by
several genes located on the short arm of human
chromosome 6.
Major Histocompatibility Gene
complex:

5. Major Histocompatibility Gene
complex:
Class I MHC molecules Contains three loci A, B
and C, each of which codes for α chain
polypeptides of class I MHC antigenic surface
molecules.
Class II MHC molecules encoded by DP, DQ,
DR regions.

6. 3-Class III region
• It is not actually a part of the HLA complex, but is
located within the HLA region, because its
components are either related to the functions of
HLA antigens or are under similar control
mechanisms to the HLA genes.
• Class III region encodes for certain complement
components (C2, C4, factor B,) and 2 cytokines
TNF-α and β. They have no role in graft rejection.

7.  A person usually inherits two copies of each gene
locus so carries total of six Class I loci(E.g. 2 HLA –
A, 2 HLA –B, 2 HLA –C) and six class loci II (E.g.
2HLA- DR, 2HLA- DP, 2HLA- DQ)
 Multiple of each locus may persist in human
population.
 There are at least 151 HLA –A alleles, 301 HLA- B
alleles and 282 HLA- DRβ alleles.
 Diversity of this type is called
Allelic polymorphism and the MHC genes are the
most polymorphic gene.
Inheritance of Major Histocompatibility
Genes

9. The alleles are “Codominantly expressed”
Each set of allele is referred to as
Haplotype. An individual inherits one
haplotype from the mother and another
haplotype from the father.
The alleles are “Codominantly expressed”
that is both maternal and paternal gene
products are expressed in the same cell.
Inheritance of Major Histocompatibility Genes

10.  MHC polymorphism benefits humanity ?
Because it increases the likelihood that at least
some individuals will be able to present antigens
from any new pathogens , thus helping to
ensure the survival of the whole population.
 MHC is also known as HLA as because they are
found in high concentration on lymphocytes &
other WBCs.
 Peptide antigens associated with class I MHC
molecules are recognized by CD8+ cytotoxic T
cells.
Inheritance of Major Histocompatibility Genes

11. Regulation of Major Histocompatibility
complex (MHC) expression
 Cytokines : IFN α,β,γ and TNF increases the
expression of class I MHC on cells
IL-4 increases expression of class II molecules by
resting B cell
MHC expression is decreased in some viral
diseases like CMV, HBV, Adenovirus and in tumer
cell.

12. • Although the decrease in MHC class I expression
decrease CD8+T cells response it may also act as
a trigger of NK cells response to virus infected
cells and tumor cells. MHC class I are negative
regulators of NK cells activity i.e. MHC class I
expressed on normal cells interact with killer
inhibitory receptor (KIR) expressed on the surface
of NK cells so preventing NK cells from killing the
host cells. If the cell is MHC-I deficient, the KIR-
MHC complex is not formed and the cell is a
target for killing with NK cells.

13. A- Class I-MHC Molecules:
Class I MHC molecules contain two
separate polypeptide chains
a) Heavy (44-47 KDa) alpha chain
b) Light (12 KDa) beta chain
known as β2-microglobulin.
Both α chain and β2-microglobulin
are members of the Ig superfamily.
Structure of MHC Molecules:

14. 1- Alpha (α) chain:
• The carboxyl end of α chain
resides inside the cell while
the amino end projects on
the surface of cell .
• α chain is coded by the
MHC genes and has three
globular domains α1, α2
and α3.
• The alloantigenic sites that
carry determinants specific
to each individual are found
in the α1 and α2 domains.

16.  The α1 and α2 domains bind T cell receptor (TCR) of
CD8 T lymphocytes.
 α1 and α2 domains show marked variability
(polymorphism). The greatest variability in amino acids
occurs in the α1 and α2 sequences that line the wall
and floor of the peptide binding groove (hyper variable
region). α3 domain is constant .
 The importance of the highly conserved region of α3 is
that CD8 molecules present on CD8 T lymphocytes
binds to this region.

17. 2- Beta chain (β2-microglobulin):
It is encoded by a gene on
another chromosome away from
MHC genes (on chromosome 15).
It is important for transport
and expression of MHC-I on the
cell surface.
 Individuals with defective β2
microglobulin gene do not
express any class I MHC
and hence they have a deficiency
of cytotoxic T cells.

18. B- Class II Molecules:
MHC class II molecules comprise
two non-identical and non-
covalently bound polypeptide
chains (α and β).
1- α and β chains:
• These two chains have amino
ends on the surface, a short
transmembrane stretch and
intracytoplasmic carboxyl ends.
• Both α chain (34 kDa) and β
chain (28 kDa) are MHC-
encoded by the D region.

19. • Each polypeptide chain folds
into two separate domains;
alpha-1 and alpha-2 for the
alpha polypeptide, and
beta-1 and beta-2 for the
beta polypeptide.
• With the exception of the
α1 domain, all domains are
stabilized by disulfide
bridges.

20. • α1 and β1show marked
polymorphism while α2
and β2 are largely non-
polymorphic.
• During antigen
presentation, CD4
molecule of Helper T
lymphocyte binds to β2
domain of the class II MHC
molecules.

21. Similarities and differences between MHC class
I and II:
A- Similarities:
1- functions:
They bind peptides and present them at the
surface to T cell receptors.
Are strong transplantation antigens.
MHC molecules bind only one peptide at a
time, and all peptides that bind to a particular
MHC molecule share the same structural
motifs.

22. Similarities and differences between
MHC class I and II:
2- Structure: both have
Two polypeptide chains.
A transmembrane region and a cytoplasmic
region.
A single peptide binding groove.
A polymorphic region (which includes the peptide
binding region) and a constant region.
3- Both show genetic polymorphism with multiple
alleles in the population.

23. MHC I MHC II
Nomenclature HLA- A, B, C HLA-DP, DQ, DR
Found on all nucleated cells dendritic cells,
macrophages, B cells and
activated T cells
Recognized by CD8 TC (CTLs) CD4 TH cells
Peptides that are bound Endogenously synthesized in
cytosol
Exogenously processed in
vesicles
Bind peptides of 8-9 amino acids of 12-25 amino acids
Functions Presentation of antigens to
TC cells leading to
elimination of abnormal or
infected host cells.
Presentation of antigen to
TH cells which secrete
cytokines.
β2 micro-globulin Yes No
Coded for on chromosome 6 but light
chain β2 microglobulin is on
chromosome 15
Entirely on chromosome 6.
B- Differences:

24. Variability of MHC antigens or (HLA):
MHC antigens differ from one individual to another. These
differences are genetically determined. These differences in
MHC molecules structure arise from 2 sources:
1- polygenecity:
A heterozygous human inherits one paternal and one
maternal haplotype, each containing three Class-I (B, C and A)
and three Class II (DP, DQ and DR) loci.
Each individual inherits a maximum of two alleles for each
locus. The maximum number of class I MHC gene products
expressed in an individual is six and that for class II MHC
products rarely exceed six. Thus, as each chromosome is
found twice (diploid) in each individual, a normal tissue type
of an individual will involve 12 HLA antigens.

25. 2- Polymorphism:
It means that multiple stable forms of each MHC
gene (multiple alleles) exist in population.
Although MHC molecules are diverse within the
population, each cell in a particular person
expresses the same set of HLA class I and class II
molecules.

26. Antigen Processing and Presentation
Types of antigens
a) Endogenous antigens are generated within a
cell (e.g., viral proteins in any infected cell,
tumor antigens)
b) Exogenous antigens (inhaled, ingested, or
injected) are taken up by antigen-presenting
cells (APCs) by endocytosis.

27. Antigen Processing and Presentation
Intracellular peptides for MHC class I
presentation are made by proteases and the
proteasome in the cytosol, then transported
into the endoplasmic reticulum via TAP
(Transporter associated with Antigen
Processing) to be further processed.
They are then assembled together with MHC
I molecules and travel to the cell surface ready
for presentation.

28. a- Presentation of endogenous antigens in MHC-I
pathway:
Endogenous antigens are processed in the cytoplasm.
They are degraded by proteasomes into fragments
(peptides) within the cell.
Class I histocompatibility molecules are synthesized
by ribosomes on the rough endoplasmic reticulum
(RER) and assembled within its lumen then move
through the Golgi apparatus to the cell surface.
Antigen Processing and Presentation

30. MCH Class II Molecules
• The route of processing for exogenous antigens
for MHC class II presentation begins with
endocytosis of the antigen. Once inside the cell,
they are encased within endosomes that acidify
and activate proteases, to degrade the antigen.
• MHC class II molecules are transported
into endocytic vesicles where they bind peptide
antigen, and then travel to the cell surface.

32. Endogenous (cytosolic) Exogenous
(vesicular)
Types of cells in which antigen
is processed then presented
All nucleated cells Dendritic cells, Macrophages
and B cells
Source of protein antigen Mainly endogenously
synthesized proteins in the
cytosol e.g. viruses.
Extracellular proteins or
microbes internalized in
vesicular compartment
Site of processing Cytoplasm Vesicles
Enzymes responsible for peptide
generation
Cytosolic proteasomes Endosomal and lysosomal
proteases
Site of peptide loading of MHC Endoplasmic reticulum (ER) Specialized vesicular
compartment
Peptides bind to MHC-I MHC-II
Peptide/MHC complex is
presented to
CD8 cytotoxic T cells CD4 helper T cells
Outcome Killing of presenting cells by
CTLS
Secretion of cytokines by TH
cells activating macrophages
and other cells.

34. Significance of MHC
1-Organ transplantation and graft rejection.
2-MHC is essential for antigen presentation: TC
recognizes antigens only in association of MHC-I
molecules and TH recognize antigens only in
association of MHC-II molecules.
3-Paternity testing and forensic investigations.

35. 4-Disease association: certain HLA types are associated
with some autoimmune diseases. E.g. HLA-B27 is
associated with ankylosing spondylitis, Reiter's disease
and post gonococcal arthritis. DR2 is associated with
multiple sclerosis, B8 with myasthenia gravis, DR4 with
rheumatoid arthritis, and DR5 with Hashimoto's
thyroiditis.
Significance of MHC