MAJOR

HISTOCOMPATABILITY
COMPLEX

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 MHC - The Major Histocompatibility Complex

• 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.
• 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
• Two classes of MHC molecule: Class I (single
MHC

plus + 2-microglobulin)
 chain)
chain and Class
- more Ig-superfamily II ( chain
members (Ig-C 2
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 cell-
surface 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 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, 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
HLA A Blocus ~110 alleles
locushas ~60
HLA
allelesC 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  and  chains of MHC-II.
• Why are these called “regions”?
 MHC MoleculesControl
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 cyto-
plasmic tail (30
aa)

The three alpha

domains are
called: 1, 2, &
3
1 and 2 interact to MHC-II
present
processed Ag An alpha and beta chain, 33 kDA and
Process Ag is 28 kDa, respecitvely.
optimally a
nonomer Chains are non-covalently associated.
Each chain has two domains.
Microglobulin (12 kDa) associates non-covalently with 3 1-1 interact to present processed Ag
Microglobulin and 3 are part of immunoglobulin Processed Ag is optimally 13-18 aa
superfamily

Microglobulin is the only member of the superfamily that 2 & 2 are part of immunoglobulin
does not have a component linking it to a membrane super family
 The Major Histocompatibility Complex
• MHC Class I and Class II genes are encoded in a large
(>4 Mb, >200 genes) tightly linked gene cluster: the
MHC
• The MHC is similarly organized in mice (Ch17) and
humans (Ch6) - syntenic
• Known in humans as HLA (human leukocyte antigen)
genes; in mouse as H-2 (histocompatibility group 2)
genes
• Genes are highly polymorphic (many alleles)
• Class I: HLA-A, -B, -C (human); H-2K, -2D, -2L
(mouse)
• 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)
2-microglobulin is located on a different chromosome 16
 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 & 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 , 2
!
• HLA-DR
 genes vary from 2-9 in different individuals!!!,
– 1  gene ( can combine with all 
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, T-
cell 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
– IFN, IFN, 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
ofproducts
• Gene Transplants
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 β2-
microglobulin (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, HLA-
DR, HLA-DM, and HLA-
DO. Among these, HLA-
DP, HLA –DQ, and HLA-
DR 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

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 MHC Polymorphism
• MHC Class I and Class II molecules have
many alleles
• 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)
• For Class II, both  and  chains are
polymorphic (except DR in humans and
E 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 co-
dominantly: 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
immunodeficiency) 40