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The MHC complex genetics, function and disease
association
Lecturer Adelheid Cerwenka, PhD, D080, Innate
Immunity Sources Janeway Immunobiology, 5th
edition Kuby Immunology, 4th edition Klein/Hore
jsiImmunology 2nd edition
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Only complementary surfaces fit together
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MHC-structure
Major Histocompatibility Complex (MHC) linked
cluster of genes, which products play a role in
intercellular recognition between self and
nonself. The MHC is a region of multiple loci
that play major roles in determining, whether
transplanted tissue is accepted as self
(histocompatible) or rejected as foreign
(histoincompatible)
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The concept of Histocompatibility
A skin-graft transplanted from A donor to a
genetically identical recipient is accepted, to a
genetically disparate recipient is rejected
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Nomenclature

• MHC Major Histocombitibiliy Complex
• Minor Histocompatibility Antigens proteins,
  which are cell surface expressed and their
  peptides are loaded into MHC molecules
• MHC is a generic name
• HLA Human Leucocyte Antigen, eg SLA Swine
  Leucocyte Antigen
• Mouse MHC has an historical name H2 (H-2)
  stands for histocompatibility 2

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Table of contents

• Introduction
• Structure of MHC I and II molecules
• Genetic organisation of the MHC
• Polymorphisms of MHC alleles
• MHC and disease

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Communication of cells in the body
1.) Cell cell contact via cell surface
receptors cell surface proteins have been
classified as CDs (cluster of differentiation)
CD2
T cell
DC
MHC
TCR
CD28
B7
2.) Cell to cell contact via soluble mediators
such as cytokines (interleukins-IL) or chemokines
(CCR, CXCR)
IFN-g
T cell
DC
MHC
TCR
CD28
B7
IL-12
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Host defense
Against intracellular infection by mycobacteria
Against intracellular infection by viruses
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MHC class I molecules present antigen derived
from proteins in the cytosol
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MHC class II molecules present antigen
originating in intracellular vesicles
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MHC molecules on the cell surface display peptide
fragments
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Structure of MHC class I
Computer graphic representation and ribbon
diagramms of of the human MHC class I
molecule HLA-A2. Heterodimer a chain (43 kDa)
polymorphic b2-microglobin (12 kDa)
non-polymorphic, non-covalently bound a1 and a2
peptide binding, cleft formed by single
structure a3 transmembrane
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Structure of MHC class II
Computer graphic representation and ribbon
diagramms of of the human MHC class II molecule,
HLA-DRI Heterodimer, 2 transmembrane chains a
chain (34 kDa) b-chain (29 kDa) b1 and a1
peptide binding, not joined by covalent bond A2
and b2 transmembrane Peptide binding groove is
the MHC class II molecules is open at both ends
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Peptide binding sites and binding sites for CD4
or CD8 on MHC class I and MHC class II
b chain (white)
a- Chain (white)
a chain (purple)
b2- Microglobuline (purple)
Base of b2 domain (green)
Base of a3 domain (green)
The binding sites for CD4 and CD8 on MHC class II
molecules or MHC class I lie in the
immunoglobulin domain, nearest to the membrane
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Peptides bind to MHC I molecules through
structurally related anchor molecules
Free amino and carboxy termini are stabilizing
contacts Peptides eluted from two different MHC
class I molecules are shown. Anchor residues in
green Not identical but related eg F and Y
are both aromatic amino acids V, L and I are
large hydrophobic amino acids MHC class I
without peptide instable
Pockets in the MHC molecules are lined by
polymorphic amino acids.
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Peptides that bind MHC class II are variable in
length and anchor residues lie at various
distances from the ends of the peptide
Peptides that bind to mouse MHC II Ak allele, or
human MHC II HLA-DR3 Peptides that bind to MHC
class II are at least 13-17 AA long, Ends of
peptides are not conserved. Ends do not bind,
binding pockets more permissive Blue negatively
charged residue D, aspartic acid, E glutamic
acid, green hydrophobic residues
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The expression of MHC molecules differs between
tissues
MHC class I Expressed on all nucleated
cells MHC class II Expressed on surface of
APCs (antigen presenting cells) Viruses can
infect all types of cells Plasmodia
(malaria) live in red blood cells
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Regulation of MHC class I expression
Expression of MHC class I regulated by sequences
upstream of the coding part. MHC enhancer
segment enhancer A, IRE interferon response
element, enhancer B MHC class I expression can be
regulated by Interferon (IFN-g). IFN-g also
induces the key components of the intracellular
machinery that enables peptides to be loaded
onto MHC class I molecules
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T cells bearing a gd T cell receptor

• gd T cells are not restricted by classical MHC
  molecules
• They may be specialized to bind certain types of
  ligands (heatshock proteins, mycobacterial lipid
  antigens) directly or presented by non-classical
  MHC molecules.

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Conclusion Structure of MHC molecules

• MHC class I and II molecules have different
  structure, different distribution on cells in the
  body, and different function
• Peptides, that bind to MHC class I or II are
  derived of different compartments and are of
  different length
• The expression of MHC class I molecules can be
  regulated by interferon-g.

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Genetic organisation of MHC
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MHC diversity
MHC is polygenic means that it contains several
different MHC class I and class II genes
MHC is polymorphic (polymany Morphicshape,
structure) means that there are multiple
variants of a gene within a population as a whole
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Genetic organisation of the MHC
Human chromosome 6
Mouse chromosome 17
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Detailed map of the human MHC
MHC class IB genes Non-classical MHC
Molecules Non-conventional MHC Class I
molecules
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Function of non-conventional MHC molecules

• Ligands of inhibitory (HLA-G) or activating (MIC)
  Natural Killer cell receptors
• Presentation of non-conventional peptides to ??
  Cells In mice, the H-2M locus encodes a
  nonconventional MHC class I molecule that present
  peptides that have a formylated methionin (eg
  also found in prokaryotic organisms such as
  mycobacterium tuberculosis, listeria, Salmonella)
• Presentation of lipid antigens (CD1)

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MHC class I receptors on human Natural killer
cells
ReceptorsLigands effect KIR
receptors (Killer immunoglobulin
receptors)HLA-C mostly

inhib. NKG2A/CD94..HLA-E
mostly

inhib. NKG2D.MIC activ.
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MHC class I-like ligands for the activating
receptor NKG2D
human NKG2D-ligands
Classical MHC I
mouse NKG2D-ligands
human MICA, B
a1
a2
ULBP-human RAE-1-like
RAE-1, H60
a3
b2m
a1
a2
a1
a2
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MHC class I related chain (MIC) ligands for
human NKG2D

• polymorphic
• MIC non-conventional MHC molecule
• Expression absent from healthy
  tissue,overexpressed on tumors and in the gut
  epithelium
• A soluble form of MICA is found in the serum of
  cancer patients
• Expression induced by heat shock, viral
  infection and bacteria

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Lymphomas expressing mouse homologues of MIC
molecules (RAE-1) are rejected
Lymphoma cells RAE-1
Lymphoma cells
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Polymorphism of MHC genes
The figures are the numbers of alleles currently
officially assigned by the WHO 100 different
class I or class II alleles in mice H-2 complex
theoretical diversity is 100 (K) x 100 (IAa)x
100 (IEa) x 100 (IEb) x 100 (D)1012 Linkage
disequilibrium occurs in human
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Expression of MHC alleles is co dominant
4 possible combinations of haplotypes are found
in the offspring, there being one chance in four
that an individual will share both haplotypes
with a sibling.
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Diversity of MHC molecules expressed by an
individual
Polygeny the presence of several different
related genes With similar function ensures that
each individual produces a number of different
MHC molecules
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Allelic variation occurs at specific sites within
MHC molecules
Allelic variability is clustered at specific
sites within domains
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Gene conversion and new alleles
Sequences can be transferred from one gene to a
similar but different gene by a process know as
gene conversion. This can occur by a misalignment
of two paired homologous chromosomes When there
are many copies of similar genes arrayed in
tandem. Polymorphisms have been actively
selected during evolution.
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MHC restriction
The antigen specific T cell receptor recognizes a
complex of antigenic peptide and MHC.
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History MHC restriction
Zinkernagel and Dohety 1975, JEM, 141502
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Many T cells respond to superantigens
Superantigens (produced by bacteria and viruses)
can bind independently to MHC class II molecules
and TCR, binding to the Vb domain of the
TCR. Stapphylococcal enterotoxins (SE) cause food
poisoning and toxic shock syndrome
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Conclusion Polymorphism of MHC

• Extensive polymorphism can extend the range of
  antigens to which the immune system can respond.
• It is an advantage for the survival of the
  species
• It has evolved to outflank evasive strategies of
  pathogens.
• Pathogens are clever they can evade detection or
  can suppress host responses.
• Exposure to select for expression of particular
  MHC alleles strong association of HLA-B53 with
  recovery from malaria
• Why not more MHC loci? For maintenance of
  self-tolerance

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Cheetah were bred from limited breeding stock
limited polymorphism. Disadvantage for survival?
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MHC-dependent mate preferences in humans ??
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MHC and transplantation
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Mating of inbred mouse strains with different MHC
haplotypes
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Various MHC molecules expressed on antigen
presenting cells of a heterozygous H-2 k/d mouse
Diversity generated by these mechanisms
presumably increases the number of antigenic
peptides that can be presented and thus is
advantageous to the organism.
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Skin transplantion between between different
mouse strains with same or different MHC haplotype
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T cells (CD4 and CD8 T cells) can transfer
allograft rejection (1950. Mitchison)
Nude mice (have no T cells) even accept xenografts
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Even complete matching does not ensure graft
survival
1.) HLA typing not precise, complex
polymorphisms, only siblings inherit the same
haplotypes 2.) Minor histocompatibility antigens
exist, peptides from polymorphic proteins
presented by the MHC molecules on the
graft. Although MHC genotype can be matched,
polymorphism in any other gene can graft
rejection.
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Minor H antigens
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2 different ways of graft recognition
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Initiation of graft rejection Dynamics of graft
rejection
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Hyper acute graft rejection
Preexisting antibody against donor graft antigens
can cause hyperacute graft rejection
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Mixed lymphocyte reaction
Allogeneic bone marrow transplantion often graft
versus host disease (rashes, diarrhea,
pneumonitis). Also because of minor H anitgen
difference with siblings. Tests with MLR (mixed
lymphocyte reaction).
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Effect of antigen matching on the survival of
kidney grafts
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Tissues successfully transplanted
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Pregnancy The fetus is an allograft that is
tolerated repeatedly.
Fetus carries parental MHC and minor H antigens
that differ from the mother. Trophoblast and
immunosuppressive cytokines (low MHC class I)
protects fetus
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Conclusion MHC and transplantation

• Most transplants need generalized
  immunosuppression (toxic)
• MHC matching often not sufficient for graft
  survival (minor H antigens)
• Tolerance to fetus is the key for a species to
  survive

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MHC and disease association

• Autoimmune disease
• Viral disease
• Neurologic disorders
• Allergic reactions

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MHC genes and Pathogen defence
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Population studies show association of
susceptibility to IDDM with HLA genotype
Affected siblings share 2 HLA haplotypes much
more frequently than expected
Certain HLA genotype are frequently found in
diabetic patients DR3/4 tight linkage to DQb,
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Position of the DQb chain affects susceptibility
to insulin-dependent diabetes mellitus
AA 57 forms a salt bridge Across the peptide
binding cleft of DQ Possible explanation 1.)
Allelic variants of MHC molecules differ in
ability to present the autoantigenic peptides
to autoreactive T cells 2.) Shaping of the T
cell repertoire
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Significant associations of HLA Alleles with
increased risk for various diseases

• Both inherited and environmental factors play a
  role in the induction of autoimmune disease
• Inbred mice show uniform susceptibility to
  autoimmune disease
• But also other independly segregating disease
  susceptibility loci have been defined
• Also amount of self antigen transcribed in the
  thymus plays a role

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In the fight against viruses and tumors high MHC
I expression on target cellsgood or bad ??
NK cell
NK cell
Lysis
No lysis
CD8 cell
CD8 cell
No Lysis
Lysis
Tumor cell little MHC I
Tumor cell lots of MHC I