Chapter 9 Major Histocompatibility Complex (MHC)

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Chapter 9Major Histocompatibility Complex(MHC)
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Contents

• Part? Several important concepts
• Part? Composition of HLA complex
• Part? Genetic characteristics of HLA
• Part? Molecular structure and distribution of HLA
• Part? Interaction of MHC molecules and antigen
  peptide
• Part? Biological functions of MHC
• Part? Application of HLA in medicine

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Part? Several important concepts

• Transplantation antigen(Histocompatibility
  antigen) Antigens which cause immune response to
  the graft and determine the survival of the
  graft.They are alloantigen which is specific for
  each individual.

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• MHS(Major histocompatibility antigen system )
• A group of complex histocompatibility antigens
  which cause rapid and strong immunoreaction to
  the graft.
• mHS(Minor histocompatibility antigen system)
• A group of complex histocompatibility antigens
  which cause slow and weak immunoreaction to the
  graft.

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• MHC (Major histocompatibility complex)
• A large cluster of linked genes located in
  some chromosome of human or other mammals encode
  for MHS and relate to allograft rejection, immune
  response, immune regulation and cell-cell
  recognition.

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• HLA (Human leucocyte antigen)
• The MHS of human which is associated with
  allograft rejection, immune response, immune
  regulation and cell-cell recognition.
• HLA complex
• The MHC of human,a cluster of the genes which
  encode for HLA and relate to allograft rejection
• immune response, immune regulation and
  cell-cell recognition.

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• H-2 complex The MHC of mouse
• (chromsome 17)

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Part? Composition of HLA complex

• HLA complex is located on chromosome 6
• and divided into three regions

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• ?. Class?gene region
• Classical HLA class?genes-------HLA-A,B,C
• Non-classical HLA class?genes-----HLA-E,F,G
• MHC class? chain related genes
• ?. Class ? gene region
• Classical HLA class? genes---HLA-DP,DQ,DR
• Genes associated with antigen processing
• ?. Class ? gene region
• Complement genes-----C4,C2,Bf
• Inflammation-associated genes----TNF,HSP70

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?. Class ? gene region

• Classical HLA class ? genes
• ------HLA-A,B,C
• Participate in endogenous antigen presenting
  and immune regulation.

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• 2. Non-classical HLA class? genes
• ----HLA-E,F,G
• Participate in immune regulation
• Associated with maternal-fetal immune tolerance.
• 3. MHC class?chain-related genes(MIC)
• MICA,MICB,MICC,MICD,MICE
• Associated with cytotoxicity effect of NK cell.

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?. Class ? gene region

• 1. Classical class ? genes----HLA-DP,DQ,DR
• Participate in exogenous antigen presenting
  and immune regulation.

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• 2. Genes associated with antigen processing
• The genes associated with endogenous
• antigen-processing and presenting
• TAP(Transporter associated with antigen
  processing,?????????)
• LMP(Large multifunctional proteasome,?????????)or
  ( low molecular weight polypeptide ??????)

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• (2) The genes associated with exogenous
• antigen-processing and presenting
• HLA-DM----Processing and presenting of exogenous
  Ag
• HLA-DO----Inhibit the function of HLA-DM

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?. Class ? gene region

• 1. Encoded genes of complement
• ------C4B,C4A,Bf,C2

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• 2. TNF genes family
• 3. Heat-shock protein(HSP) genes family

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Part? Genetic characteristics of HLA

• Haplotype inheritance
• Polymorphism
• Linkage disequilibrium

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1. Haplotype inheritance

• Haplotype
• Genotype
• Phenotype

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2. Polymorphism

• Polymorphism means there are multiple alleles
  at a gene locus of MHC in a population so that an
  individual may have variant allele.
• ------multiple allele
• ------codominance The two alleles at a gene
  locus of MHC in the two homogenous chromosomes
  are expressed together.

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3. Linkage disequilibrium

• The distribution of haplotypes is not random in a
  population.
• The probability in which two or more than two
  alleles present together in one chromosome is
  greater than the probability in which they
  present randomly.

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Part? Molecular structure and distribution of
HLA molecules
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?. Molecular Structure of HLA molecules

• 1. Class ? HLA molecules
• (1)Class ? HLA molecules contain two separate
  polypeptide chains
• HLA-encoded alpha (or heavy) chain
• Non-HLA-encoded beta chain (beta2
  microglobulin,ß2m)---15 chromosome
• (2) Only alpha chain is trans-membrane

HLA
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• (3) Class ? HLA molecules have four regions
• Peptide binding region----a1, a2
• IgSF region----a3, ß2m
• Trans-membrane region
• Cytoplasmic region

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• (4) Function of each domain
• ?1 and ?2 domains Interact to form a
  peptide-binding region which is a groove(cleft)
  having a "floor"of 8 beta-pleated strands and two
  "walls" with alpha-helices.
• ( Containing a peptide of 8-11 aa in the
  groove)

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• ?3 domain Binding to CD8 on Tc cells
• ?2 microglobulin domain To maintain proper
  conformation of class ? HLA molecules.
• Trans-membrane region Anchoring class ? HLA
  molecules
• Intra-membrane region Transmitting the signal

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• 2. Class ? HLA molecules
• (1) Class ? HLA molecules consist of a
  non-covalent complex of two chains ? and ?.
• (2) Both ? and ? chain span the membrane.
• (3) Both ? and ? chain are HLA-encoded

HLA
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• (4) Class ? HLA molecules have four regions
• Peptide binding region----a1, ß1
• IgSF region----a2, ß2
• Trans-membrane region
• Cytoplasmic region

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• (5) Function of each domain
• a1 and ?1 Interact to form the peptide-binding
  region which is a groove having a "floor" of 8
  beta-pleated strands and two "walls" with
  alpha-helices.
• (Containing a peptide of 10-30aa in the
  groove)

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• ? 2 and ? 2 domain Form the immunoglobulin-like
  region.
• ? 2 domain can bind to CD4 on Th cells
• Trans-membrane region Anchoring class ? HLA
  molecules
• Intra-membrane region Transmitting the signal

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ß
a
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?. Distribution of HLA molecules

• 1.Class ? HLA molecule
• Expressed on nucleate cells
• 2.Class ? HLA molecule
• Expressed on professional antigen-presenting
  cell(macrophage, dentritic cell and B cell),
  activated T cell, thymus epithelial cell et al.
• 3.sHLA

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Part? Interaction between MHC molecule and
antigenic peptide
Class II MHC molecule-antigenic peptide complex
Class I MHC molecule -antigenic peptide complex
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?. Molecular basis of interaction between MHC
molecule and antigenic peptide

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Interaction between MHC and antigen

• Anchor sites Two or more sites on antigenic
  peptide bind to groove or pocket of MHC
  molecules.
• Anchor residues The amino acid residues on
  anchor sites of antigenic peptide.

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Interaction between MHC and antigen

• Certain MHC molecule binds the corresponding
  anchor residue of antigenic peptides.
• Antigenic peptides which can combine with
• the same kind of MHC molecule have same or
  similar anchor sites and anchor residues
• (consensus motif)

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?. Characteristics of interaction

• Relative specificity
• (1) Specificity
• Certain MHC molecule recognizes corresponding
  consensus motif
• (2) Flexibility
• Amino acids x and anchor residues are variable
• Different MHC molecules can recognize similar
  consensus motif

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• MHC restriction
• T cell only recognize antigenic peptide
  combining with MHC molecules.
• That is to say, interaction of T cell and
  antigen-presenting cell(APC) or target cell need
  restriction by MHC molecules.

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• Interaction of Th(CD4T) cell and
  antigen-presenting cell (APC) is restricted by
  class ? molecules.
• Interaction of Tc(CD8T) cell and
  antigen-presenting cell (APC) or target cell is
  restricted by class ? molecules.

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Part? Biological functions of MHC

• 1.Induce the differentiation and maturation of T
  cell to form functional T cell repertoire
• 2.Present antigen to initiate immune response

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1. Induce the differentiation of T cell to form
T cell repertoire
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2. Present antigen to initiate immune response

• Endogenous antigen antigens synthesized within
  cells
• Exogenous antigen antigens comes outside the
  cell
• Endogenous Ag is presented to CD8 T cell by MHC
  class ? molecule
• Exogenous Ag is presented to CD4 T cell by MHC
  class ? molecule

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CD8T cell
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CD4T cell
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Part? Application of HLA in medicine

• HLA and transplantation

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MLR
Mixed lymphocyte reaction to determine identity
of class II HLA antigens between a potential
donor and recipient. Lymphocytes from the donor
are irradiated or treated with mitomycin C. If
the class II antigens on the two cell populations
are different, the recipient cells will divide
rapidly and take up large quantities of
radioactive nucleotides into the newly
synthesized nuclear DNA. The amount of
radioactive nucleotide uptake is roughly
proportionate to the MHC class II differences
between the donor and recipient lymphocytes.
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• Some diseases are associated with HLA genotypes
  

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• HLA and forensic medicine
• Paternity testing
• Criminal investigation