Transcript HLA

HLA and antigen presentation
Institute of Immunology
University Hospital
Motol
Structure and function of HLA
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history
structure of HLA gens and molecules
function of HLA moleculs
nomenclature of HLA system
HLA association with disease
antigen presentation
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.
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.
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.
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
structure of HLA class I. molecules
• HLA class I. molecules are composed from
 heavy a chain
 b-2 microglobulin
 peptide
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.
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.
Structure of HLA class II. molecules
• Class II molecules consist of two transmembrane polypeptides
and bound peptide.
Structure
of HLA class I. and II. molecules
HLA class I.
HLA class II.
HLA and peptides
• antigenic peptids in the binding sites of HLA molecules
• class I.
• class II.
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HLA genes
chromozom 6
HLA region
D
DP
DQ
HLA class III.
B C
E A GF
DR
• HLA class III. are soluble molecules as complement, TNF, HSP
• HLA DR a chain is not polymorphic
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
B
C
A
B
C
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.
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.
HLA nomenclature
HLA Alleles
There are currently (2015) 14,015 alleles described by the HLA nomenclature
and included in the IMGT/HLA Database.
HLA nomenclature
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.
Immune system
General defense
Innate immunity
Adaptive immunity
TCD4
neutrophil
B
TCD8
Monocyte/macrophage
Dendritic cell
Plasma cell
Immune synapse
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.
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.
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
lysozom
APC
ER, Golgi
CD4
HLA class II.
antigen
TCR
T lymfocyte
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.
APC
ER, Golgi
CD8
HLA class I.
antigen
TCR
– endogenous antigen presentation
T lymfocyte
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
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
CD4+
Exogenous pathway
Steps of the exogenous antigen presentation:
APC
– 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.
endosome
– Invariant chain is actively deleted by HLA DM.
– Invariant chain is replaced by antigen.
Golgi
– Complex of HLA and antigens moves to the surface of the cell.
– Complex HLA-antigen is recognized by CD4 positive
lymfocyte.
ER
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).
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
TAP
• Transport associated protein - TAP is
responsible for the peptide transport from
cytoplasm to ER.
proteazome
• 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
TAP
Antigen presentation pathways
endogenous antigens, HLA class I. exogenous antigens, HLA class II.
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.
B lymfocyte
CD4
T lymfocyte
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
Antibodies
antibody production
B lymfocyte
CD4
plasma cell
cytokines
T lymfocyte
Signal pathways, cell activation
APC
CD3
ion channels
signal pathways
T lymfocyte
protein phosphorylation
protein kinases
Summary antigen presentation pathways
lysozome
APC
APC
ER, Golgi
ER, Golgi
CD8
HLA class I.
antigen
TCR
T lymfocyte
endogenous
cell destruction
CD4
HLA class II.
antigen
TCR
T lymfocyte
exogenous
immune response
B lymfocyte
CD4
HLA class II.
antigen
TCR
T lymfocyte
B lymfocytes
antibody production
Antigen presentation and T lymphocyts
Polarisation of T lymphocytes
Presentation of antigen and infection
Presentation of antigen and autoimmunity
Presentation of antigen and transplantation
Presentation of antigen and tumours
Presentation of antigen and vaccines
Presentation of antigen - summary
Presentation of antigen - summary
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)
Antigen presentation and immune
defense
Antigen presenting cell and lymphocyte
Antigen presenting cell and lymphocyte