Transcript Major Histocompatibility Antigens

MAJOR
HISTOCOMPATABILITY
COMPLEX
Dr.T.V.Rao MD
Dr.T.V.Rao MD
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MHC - The Major Histocompatibility Complex
1) Originally identified in mice as blood cell antigens
by R.A. Gorer and G.D. Snell in 1930s, and defined
on the basis of tissue graft rejection - 1980 Nobel
prize awarded to Snell.
2) Work by Rolf Zinkernagel and Peter Doherty in the
1970s revealed that it is the complex of MHC
molecule plus antigen that is recognized by T cells
(MHC restriction of T cell responses) - 1996 Nobel
Prize
3) Two classes of MHC molecule: Class I (single MHC
a chain + b2-microglobulin) and Class II (a chain
plus b chain) - more Ig-superfamily
members (Ig-C 2
Dr.T.V.Rao MD
domains)
Major Histocompatibility complex
(MHC)
• The Major Histocompatibility
complex (MHC) is a large genomic
region or gene family found in most
vertebrates. It is the most gene-dense
region of the mammalian genome and
plays an important role in the immune
system, autoimmunity, and
reproductive success.
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Major Histocompatibility Complex
Definition
• A group of genes that code for cellsurface Histocompatibility antigens
and are the principal determinants of
tissue type and transplant
compatibility. They are the most
diverse genes in humans and are
used to determine if a sample of DNA
comes from a specific person.
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MHC
• Genes Of MHC Organized In 3 Classes
– Class I MHC genes
• Glycoproteins expressed on all nucleated cells
• Major function to present processed Ags to TC
– Class II MHC genes
• Glycoproteins expressed on M, B-cells, DCs
• Major function to present processed Ags to TH
– Class III MHC genes
• Products that include secreted proteins that have immune
functions. Ex. Complement system, inflammatory
molecules
Basis of MHC system
• In man and mouse, as in most species, each
class of MHC is represented by more than one
locus( polygeny), in man these are called HLA
for Human Leucocyte Antigen. The class I loci
are HLA-A,-B and -C and the class II loci HLADR, -DQ and -DP. All the MHC genes map
within a single region of the chromosome (hence
the term Complex); the physical map of the MHC
of man and mouse has been determined by
cloning, mapping and sequencing.
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Class I, II and III MHC
• Class I MHC Genes Found In Regions A, B and
C In Humans (K and D In Mice)
• Class II MHC Genes Found In Regions DR, DP
and DQ (IA and IE In Mice)
• Class I and Class II MHC Share Structural
Features
– Both involved in APC
• Class III MHC Have No Structural Similarity To
Class I and II
– Ex. TNF, heat shock proteins, complement
components
Composition of Class I
Molecules
• Class I molecules are composed of two
polypeptide chains; one encoded by the BCA
region and another (ß2-microglobulin) that is
encoded elsewhere. The MHC-encoded
polypeptide is about 350 amino acids long and
glycosylated, giving a total molecular weight of
about 45 kDa. This polypeptide folds into three
separate domains called alpha-1, alpha-2 and
alpha-3. ß2-microglobulin is a 12 kDa
polypeptide that is non-covalently associated
with the alpha-3 domain.
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Class II molecules
• MHC (major Histocompatability
complex) Class II molecules are
found only on a few specialized
cell types, including
macrophages, dendritic cells and
B cells, all of which are
professional antigen-presenting
cells (APCs).
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Humans are very
Diversified MHC Plays a Great Role
The loci which specify MHC’s are
polymorphic.
Many alleles may exist at a locus:
HLA A locus has ~60 alleles
HLA B locus
~110 alleles
HLA C locus
~40 alleles
The high level of allelism creates diversity
within a species (thus restricting allografting)
but does not produce diversity within an
individual
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What is polygenecity?
• Humans have DP, DQ, and DR “regions”
specifying a and b chains of MHC-II.
• Why are these called “regions”?
MHC Molecules Control the
Immune response
• The Major Histocompatibility Complex
(MHC) is a set of molecules displayed on
cell surfaces that are responsible for
lymphocyte recognition and "antigen
presentation". The MHC molecules control
the immune response through recognition
of "self" and "non-self" and, consequently,
serve as targets in transplantation
rejection
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Peptide Binding to MHC Molecules: Class I vs. II
Class I
Class II
• Generated by proteasome (cytosol)
• Generated in endosomes/lysosomes
• Transported to ER by TAP1/2
• Bind in specialized vessicles (MIIC)
• Restricted length, 8-9 residues
• Any length, extend from MHC
• Binding energy from N, C termini
• Binding energy from backbone
• “Anchor” residues fill specific pockets
• “Anchor” residues fill specific pockets
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MHC- I
MHC-II
MHC-I
Heavy chain
(alpha) and
“microglobulin”
(beta two)
Heavy is 45
kilodaltons, has
three domains +
a
transmembrane
component (40
aa) + a cytoplasmic tail (30
aa)
The three alpha
domains are
called: a1, a2, &
a3
a1 and a2 interact to
present
processed Ag
Process Ag is
optimally a
nonomer
Microglobulin (12 kDa) associates non-covalently with a3
Microglobulin and a3 are part of immunoglobulin
superfamily
Microglobulin is the only member of the superfamily that
does not have a component linking it to a membrane
MHC-II
An alpha and beta chain, 33 kDA and
28 kDa, respecitvely.
Chains are non-covalently associated.
Each chain has two domains.
a1-b1 interact to present processed Ag
Processed Ag is optimally 13-18 aa
a2 & b2 are part of immunoglobulin
super family
The Major Histocompatibility Complex
1) MHC Class I and Class II genes are encoded in a large
(>4 Mb, >200 genes) tightly linked gene cluster: the
MHC
2) The MHC is similarly organized in mice (Ch17) and
humans (Ch6) - syntenic
3) Known in humans as HLA (human leukocyte antigen)
genes; in mouse as H-2 (histocompatibility group 2)
genes
4) Genes are highly polymorphic (many alleles)
5) Class I: HLA-A, -B, -C (human); H-2K, -2D, -2L
(mouse)
6) Class II: HLA-DP, -DQ, -DR (human), I-A, I-E (mouse)
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Human
MHC class I:
HLA-A, -B, -C
MHC class II:
HLA-DR, -DP, -DQ
Mouse
MHC class I:
H2-K, -D, -L
MHC class II
H2-A, -E (I-A, I-E)
b2-microglobulin is located on a different
chromosome.
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MHC is represented …
• In man and mouse, as in most species, each
class of MHC is represented by more than one
locus(polygeny), in man these are called HLA for
Human Leucocyte Antigen. The class I loci are
HLA-A,-B and -C and the class II loci HLA-DR, DQ and -DP. All the MHC genes map within a
single region of the chromosome (hence the
term Complex); the physical map of the MHC
of man and mouse has been determined by
cloning, mapping and sequencing.
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Class I and II MHC
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MHC- I
&
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MHC-II
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Class I And II Specificity
• Several Hundred Allelic Variants Have Been
Identified In Humans
• However, up to 6 MHC I And 12 MHC II Molecules
Are Expressed In An Individual
• Enormous Number Of Peptides Needs To Be
Presented Using These MHC Molecules
• To Achieve This Task MHC Molecules Are Not Very
Specific For Peptides (Unlike TCR and BCR)
• Promiscuous Binding Occurs
– A peptide can bind a number of MHC
– An MHC molecule can bind numerous peptides
Class I And II Diversity And
Polymorphism
• MHC Is One Of The Most Polymorphic
Complexes Known
• Alleles Can Differ Up To 20 a/a
• Class I Alleles In Humans: 240 A, 470 B, 110
C
• Class II Alleles In Humans: HLA-DR 350 b, 2
a!
• HLA-DR
– b genes vary from 2-9 in different individuals!!!,
– 1 a gene (a can combine with all b products
increasing number of APC molecules)
MHC I and II belong to
Immunoglobulin Supergene Family
• The Class I and Class
II MHC molecules
belong to a group of
molecules known as
the Immunoglobulin
Supergene Family,
which includes
immunoglobulin's, Tcell receptors, CD4,
CD8, and others
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MHC location on Chromosome 6
• The major
Histocompatibility
complex is encoded by
several genes located on
human chromosome 6.
Class I molecules are
encoded by the BCA
region while class II
molecules are encoded
by the D region. A region
between these two on
chromosome 6 encodes
class III molecules,
including some
complement components.
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MHC Expression
• Expression Is Regulated By Many Cytokines
– IFNa, IFNb, IFN and TNF Increase MHC
expression
• Transcription Factors That Increase MHC gene
Expression
– CIITA (Trans activator), RFX (Trans activator)
• Some Viruses Decrease MHC Expression
– CMV, HBV, Ad12
• Reduction Of MHC May Allow For Immune
System Evasion
MHC system important in
Rejection of Transplants
• Gene products encoded in the Major
Histocompatibility Complex (MHC)
were first identified as being important
in rejection of transplanted
tissues. Furthermore, genes in the
MHC were found to be highly
polymorphic (i.e. in the population
there were many different allelic
forms of the genes)
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Class I MHC proteins
• Class I MHC proteins (found on all nucleated cell
surfaces) present antigens to cytotoxic T lymphocytes
(CTLs) . Most CTLs possess both T-cell receptors (TCR)
and CD8 molecules On their surfaces. These TCRs are
able to recognize peptides when they are expressed in
complexes with MHC Class I molecules. For the TCR to
bind a peptide-MHC complex two conditions must be
met. Firstly, the TCR must have a structure which allows
it to bind the peptide-MHC complex. Secondly, the
accessory molecule CD8, must bind to the alpha-3
domain of the MHC Class I molecule. Due to genetic
recombination events each CTL expresses a unique
TCR which only binds a specific MHC-peptide complex
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Class I MHC molecules
• Class I MHC molecules
are composed of two
polypeptide chains, a
long α chain and a short
β chain called β2microglobulin (figure
2). The α chain has four
regions. First, a
cytoplasmic region,
containing sites for
phosphorylation and
binding to cytoskeletal
elements
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Class II MHC molecules
• Class II MHC molecules
are composed of two
polypeptide chains an α
and a β chain of
approximately equal
length (Figure 6). Both
chains have four regions:
first, a cytoplasmic region
containing sites for
phosphorylation and
binding to cytoskeletal
elements;
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MHC II are Complex in
Organization
• Within the MHC there are
5 loci that encode class II
molecules, each of which
contains a gene for an α
chain and at least one
gene for a β chain. The
loci are designated as
HLA-DP, HLA –DQ, HLADR, HLA-DM, and HLADO. Among these, HLADP, HLA –DQ, and HLADR are the most
important and are most
polymorphic..
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MHC is highly polymorphic
• The MHC is highly polymorphic. There are a
large number of genetic variants (alleles) at
each genetic locus. Crucially many of these
alleles are represented at significant frequency
(> 1%) in the population, and in addition the
alleles generally differ from one another by
many (up to 30) amino acid substitutions. For
example in humans there are more than 200
alleles described at some MHC loci. Such a
remarkable degree of polymorphism implies a
selective pressure to establish and maintain it.
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MHC Polymorphism
1) MHC Class I and Class II molecules have many alleles
(point mutations, gene conversion, gene recombination)
2) Diversity ensures that a wide range of peptides can be
presented within the population (even if a much more
limited set is presented by any individual)
3) For Class II, both a and b chains are polymorphic (except
DRa in humans and Ea in mice), adding more diversity
1)Collection of Class I + Class II
alleles on one chromosome is called
the haplotype
4) MHC molecules are expressed
co-dominantly:
alleles from both
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chromosomes are expressed in each cell
MHC Polymorphism
1) MHC Class I and Class II molecules have
many alleles
2) Diversity ensures that a wide range of
peptides can be presented within the
population (even if a much more limited
set is presented by any individual)
3) For Class II, both a and b chains are
polymorphic (except DRa in humans and
Ea in mice), adding more diversity
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Inheritance Of HLA Haplotypes
MHC Polymorphism
4)Collection of Class I +
Class II alleles on one
chromosome is called
the haplotype
5)MHC molecules are
expressed codominantly: alleles
from both chromosomes
are expressed in each
cell
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Biological role of the MHC
• The products of the MHC
play a fundamental role in
regulating immune
responses. T cells must
recognise antigen as a
complex with MHC
molecules. This requires
antigen to be processed
by unfolding and
proteolytic digestion
before it complexes with
the MHC molecule
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Biological role of the MHC
• Once formed the complex
of antigenic peptide and
MHC are generally very
stable (half life ~ 24hrs).
Thus the biological role of
MHC proteins is to bind
small peptides and to
"present" these at the cell
surface for the inspection
of T cell antigen
receptors.
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MHC-Linked Diseases
• Defects in MHC gene expression
lead to immunodeficiencies (MHC
molecules are required for both T
cell development and activation)
• Some MHC alleles are associated
with susceptibility or resistance to
autoimmune diseases
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MHC-Linked Immunodeficiencies
Bare Lymphocyte Syndromes lead to
loss of MHC molecule expression:
• Defects in TAP genes prevent MHC Class I
protein surface expression (even though
MHC proteins are normal), so no CD8+ T
cells - surprisingly mild immunodeficiency
(respiratory and skin infections)
• Defects in TF’s controlling Class II gene
expression (CIITA, RFXANK, RFX5,
RFXAP) block CD4+ T cell development result in SCID (severe
combined
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immunodeficiency)
• Programme Created by
Dr.T.V.Rao MD for Medical
Students in the Developing
World
• Email
• [email protected]
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