HLA and antigen presentation

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HLA and antigen presentation

• Institute of Immunology
• University Hospital
• Motol

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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

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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.

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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.

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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.

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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

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structure of HLA class I. molecules

• HLA class I. molecules are composed from
• heavy a chain
• b-2 microglobulin
• peptide

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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.

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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.

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Structure of HLA class II. molecules

• Class II molecules consist of two transmembrane
  polypeptides and bound peptide.

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Structure of HLA class I. and II. molecules

• HLA class I. HLA class II.

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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 HLA class III. B C E A G F
DP DQ DR

• HLA class III. are soluble molecules as
  complement, TNF, HSP
• HLA DR a chain is not polymorphic

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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
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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.

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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.

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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.
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HLA nomenclature
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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.

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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.

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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.

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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

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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

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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

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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

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Exogenous pathway
CD4

• 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.

APC
endosome
Golgi
ER
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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).

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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

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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
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Antigen presentation pathways
exogenous antigens, HLA class II.
endogenous antigens, HLA class I.
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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.

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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

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Antibodies

• antibody production

cytokines
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Signal pathways, cell activation
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Summary -antigen presentation pathways
endogenous exogenous B lymfocytes
cell destruction immune response
antibody production
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Antigen presentation and T lymphocyts
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Polarisation of T lymphocytes
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Polarisation of T lymphocytes
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Presentation of antigen and transplantation
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Presentation of antigen and infection
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Presentation of antigen and autoimmunity
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Presentation of antigen and tumours
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Presentation of antigen and vaccines
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Presentation of antigen - summary
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Presentation of antigen - summary
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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 presentation Jonathan W.
Yewdell, Eric Reits Jacques Neefjes Nature
Reviews Immunology 3, 952-961 (December 2003)
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Prezentace antigenu v obrane organismu
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Antigen presenting cell and lymphocyte
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Antigen presenting cell and lymphocyte