Dr. ihsan edan abdulkareem alsaimary
PROFESSOR IN MEDICAL MICROBIOLOGY AND MOLECULAR IMMUNOLOGY
ihsanalsaimary@gmail.com
mobile : 009647801410838
university of basrah - college of medicine - basrah -IRAQ
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Hla and antigen presentation dr. ihsan alsaimary
1. HLA and antigen presentation
prof.dr.ihsan edan alsaimary
department of microbiology – college of
medicine – university of basrah
2. Structure and function of HLA
• history
• structure of HLA gens and molecules
• function of HLA moleculs
• nomenclature of HLA system
• HLA association with disease
• antigen presentation
3. HLA - MHC
• HLA molecules are responsible for the compatibility of
the tissues of genetically different individuals
• combination of HLA molecules is unique in each
individual
• monozygotic twins have the same histocompatibility
molecules on their cells
• HLA molecules are responsible for the rejection of transplant
• HLA molecules present antigens and provoke immune reaction
leading to the transplant rejection and destruction
• histocompatibility molecules are called histocompatibility
antigens or transplantation antigens.
4. HLA -
immune system development
• Histocompatibility molecules are glycoproteins
expressed at the surface of all vertebrate cells.
• HLA molecules represent the latest stage of the
development of the immune system.
5. structure of HLA molecules
• Two classes of HLA molecules are recognized and
designed HLA class I. and HLA class II.
• HLA molecules of both classes are glycoproteins,
heterodimers, composed from two chains. At least one
of the chains is polymorphic.
• Structure of HLA molecules of both classes enables
antigen binding and contact with T cell receptors.
6. HLA class I. molecules
Class I molecules consist of three parts
a transmembrane protein, called the heavy chain. The outermost
domains contain two segments of polymorphic alpha helix that form
two ridges with a groove between them called a1and a2, a3 is
nonpolymorphic domain close to the membrane..
a molecule of beta-2 microglobulin (ß2m), which is attached
noncovalently to the heavy chain
peptide bound to the groove formed by a1and a2 domaines
7. structure of HLA class I. molecules
• HLA class I. molecules are composed from
heavy a chain
b-2 microglobulin
peptide
8. HLA A,B,C
• Humans synthesize three different types of class I. molecules
designated HLA-A, HLA-B, and HLA-C.
• These differ only in their heavy chain, all sharing the same type of
beta-2 microglobulin.
• HLA class I. molecules are expressed on all nucleated cells of the
body.
• HLA class I. molecules are not expressed on red blood cells and
only minor level of expression is detected on the cells of central
nervous system.
• The genes encoding the different heavy chains are clustered on
chromosome 6 in the major histocompatibility complex.
9. HLA class II. molecules
• Class II molecules consist of two transmembrane polypeptides:
an alpha chain and a beta chain. Both chains are polymorphic.
• The alpha and beta chains are encoded by clusters of loci in the
region of chromosome 6 designated HLA-D.
• HLA class II. molecules form 3 types, designed HLA DR, DP and
DQ.
• Class II molecules are not as widely expressed in the body as
the class I molecules are. However, cells where inflammation is
occurring express class II strongly and provide a powerful
stimulus to the immune system.
10. Structure of HLA class II. molecules
• Class II molecules consist of two transmembrane polypeptides
and bound peptide.
11. HLA class I. HLA class II.
Structure
of HLA class I. and II. molecules
12. HLA and peptides
• antigenic peptids in the binding sites of HLA molecules
• class I.
• class II.
•
13. HLA genes
• HLA class III. are soluble molecules as complement, TNF, HSP
• HLA DR a chain is not polymorphic
HLA region
D HLA class III. B C E A G F
DP DQ DR
chromozom 6
14. HLA haplotypes
• Haplotype is combination of allelic forms of HLA molecules on
one chromosome.
• We inherit 3 types of heavy chains for HLA class I. molecules
from each parent .
• Everybody expresses 6 different types of HLA class I. molecules
unless honmozygous status for some of the types was inherited.
A B C A B C
A B C A B C
A
A
B
B
C
C
15. HLA polymorfism
• Genes for HLA are the most polymorhic structures from all
known systems.
• The diversity of alleles in the population makes possible
thousands of different combinations. In a study of 1000 blood
and organ donors in San Francisco that were typed for HLA-A
and HLA-B,
Over half the group had a combination that was
unique.
Another 111 donors had a set of these molecules that
they shared with only one other person in the group.
The most frequent phenotype (HLA-A1, HLA-A3,
HLA-B7, and HLA-B8) was found in 11 donors.
16. HLA typing
The MHC of humans is now completely
sequenced! A consortium of laboratories
reports in the 28 October 1999 issue of
Nature that they have determined the
sequence of 3,673,800 nucleotides on
chromosome 6 that encode the genes of
the MHC as well as many other genes
involved in immune function.
17. HLA nomenclature
HLA Alleles
Assigned July 2012
There are currently 8159 HLA alleles described by the HLA nomenclature and
included in the IMGT/HLA Database.
19. HLA and antigen presentation
• Although histocompatibility molecules were discovered because
of the crucial role they play in graft rejection, clearly evolution did
not give vertebrates these molecules exclusively for that function.
• The main function of HLA molecules is the process called
antigen presentation to T lymphocytes.
20. HLA and antigens
• Antigens presented to the immune system come from
different sources. The main division of the antigens
recognizes extracellular antigens and intracellular
antigens.
• The nature of extracellular and intrcellular antigens
differs markedly and both induce different type of
immune reaction.
• Intracellular antigens are presented in connection
with HLA class I.
• Extracellular antigens are presented in connection
with HLA class II.
21. Antigen presentation
• Antigens are molecules able to induce immune response.
• Antigens are mostly proteins, glycoproteins or polysaccharides.
• Extracellular antigens enter the body from the environment. They
are inhaled or ingested macromolecules or molecules that are
introduced beneath the skin .
Intracellular antigens are antigens that are generated within the
cells of the body; these would include proteins encoded by the
genes of viruses that have infected a cell or aberrant proteins
that are encoded by mutant genes such as mutated genes in
cancer cells.
22. Antigen presenting cells and
T lymphocytes
• The recognition of antigen by T cells
is necessary for induction of the
immune response.
• The nature of the outcome of the
immune response is directed
according to the nature of presented
antigen.
– exogenic antigen presentation
HLA class II.
antigen
TCR
CD4
T lymfocyte
APC
lysozom
ER, Golgi
23. Antigen presenting cells and
T lymphocytes
• The recognition of antigen by T cells
is necessary for induction of the
immune response.
• The nature of the outcome of the
immune response is directed
according to the nature of presented
antigen.
– endogenous antigen presentation
HLA class I.
antigen
TCR
CD8
T lymfocyte
APC
ER, Golgi
24. Exogenous antigens
• Exogenous antigens (inhaled, ingested, or injected) are taken up
by "professional" antigen-presenting cells
• These include:
• phagocytic cells like macrophages and dendritic cells
• B lymphocytes which are responsible
for producing antibodies against the antigen.
• professional antigen-presenting cells
• All these cells expressed HLA class II. molecules
25. Exogenous antigens and cells
Antigen presenting cells
engulf the antigen by endocytosis
degrade it into fragments (e.g. break an
antigenic protein into short peptides)
display these peptides at the surface of the cell
nestled within
a class II. histocompatibility molecule
here they may be recognized by CD4+ T cells
26. Exogenous pathway
Steps of the exogenous antigen presentation:
– The two chains of the class II molecule are inserted into the membrane of
the RER.
– They bind (in their groove) one molecule of invariant chain.
– This trimolecular complex is transported through
the Golgi apparatus and into vesicles called lysosomes.
– Invariant chain is actively deleted by HLA DM.
– Invariant chain is replaced by antigen.
– Complex of HLA and antigens moves to the surface of the cell.
– Complex HLA-antigen is recognized by CD4 positive
lymfocyte.
CD4+
APC
ER
Golgi
endosome
27. Endogenous antigens
Antigens that are generated within a cell are
degraded into fragments (e.g., peptides) within the cell in
proteasome
selected antigens are transported to ER with active action of
TAP (transport associated protein)
stable complex of HLA class I. and antigen is formed in ER,
moves to Golgi
displayed at the surface
Here they may be recognized by CD8+ T cells.
Most CD8+ T cells are cytotoxic.
They have the machinery to destroy the infected cell (often
before it is able to release a fresh crop of viruses to spread the
infection).
28. Endogenous pathway
• HLA antigens class I. are expressed on all
nucleated cells
• There are three subunits in each class I
histocompatibility molecule:
the transmembrane polypeptide - heavy chain
the antigenic peptide
beta-2 microglobulin
complex on the cell surface meets CD8+ T
lymphocyte
29. TAP
• Transport associated protein - TAP is
responsible for the peptide transport from
cytoplasm to ER.
• Proteins are degraded to peptide in
proteasome.
• The peptides are picked up by TAP proteins
and transported from the cytosol into the RER
where they assemble with
– the transmembrane polypeptide and beta-2
microglobulin.
– this trimolecular complex then moves through the
Golgi apparatus and is inserted in the plasma
membrane
proteazome
TAP
31. B lymfocytes
• B lymphocytes process antigen
by the class II pathway.
However, antigen processing by
B cells differs from that of
phagocytic cells like
macrophages in crucial ways. CD4
T lymfocyte
B lymfocyte
32. BCR
B cells engulf antigen by receptor-mediated
endocytosis
The affinity of B cells for an epitope on an
antigen may be so high that the B cell can
process the antigen when it is present in body
fluids in concentrations thousands of times
smaller than a macrophage would need
The remaining steps of antigen processing occur by
the same class II pathway
The B cell grows into a clone of plasma cells under
the influence of cytokines produces by CD4+
lymohocyte
The antibodies are secreted into the surroundings
B lymfocyte
35. Summary -
antigen presentation pathways
CD4
T lymfocyte
B lymfocyte
HLA class I.
antigen
TCR
CD8
T lymfocyte
APC
ER, Golgi
HLA class II.
antigen
TCR
CD4
T lymfocyte
APC
lysozome
ER, Golgi
HLA class II.
antigen
TCR
endogenous exogenous B lymfocytes
cell destruction immune response antibody production
46. defective ribosomal products (DRiPs)
mature proteins (retirees)
ER aminopeptidases (ERAP)
Peptides that fail to bind to MHC
class I molecules are removed by the
translocon SEC61 and enter the
cytoplasm
Making sense of mass destruction: quantitating MHC class I antigen prese
Jonathan W. Yewdell, Eric Reits & Jacques Neefjes
Nature Reviews Immunology 3, 952-961 (December 2003)
Presentation of antigen - summary
