Major Histocompatibility Complex

MHC
• Major Histocompatibility Complex

– Cluster of genes found in all mammals

– Its products play role in discriminating self/non-
self
– Participant in both humoral and cell-mediated
immunity

• MHC Act As Antigen Presenting Structures

 MHC

• In Human MHC is Found On Chromosome 6

– Referred to as HLA complex

• In Mice MHC is Found On Chromosome 17

– Referred to as H-2 complex
 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 MΦ, 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
 Simplified map of the HLA region

DP DM LMP/TAP DQ DR B C A
β α α β βα β β3 β4 β5 α
1

MHC Class MHC

II Class Class I
III
Polygeny
CLASS I: 3 types HLA-A, HLA-B, HLA-C (sometimes called class Ia
genes)
CLASS II: 3 types HLA-DP, HLA-DQ , HLA-DR.
 Class I, II and III MHC
• 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
 Class I MHC Molecule
• Comprised of 2 molecules
– α chain (45 kDa), transmembrane
– β2-microglobulin (12 kDa)
– Non-covalently associated with each other
• Association Of α Chain and β2 Is Required For Surface
Expression
• α Chain Made Up Of 3 Domains (α1, α2 and α3)
• β2-microglobulin Similar To α3
• α1 And α2 Form Peptide Binding Cleft
– Fits peptide of about 8-10 a/a long
• α3 Highly Conserved Among MHC I Molecules
– Interacts with CD8 (T C) molecule
 Class II MHC Molecule
• Comprised of α and β chains
– α chain and β chain associate non-covalently
• α and β chains Made Up Of Domains
– α1 and α2 (α chain)
– β1 and β2 (β chain)
• α1and β1 Form Antigen Binding Cleft
• α and β Heterodimer Has Been Shown To
Dimerize
• CD4 Molecule Binds α2/β2 domains
 MHC molecules

MHC class I MHC class II

Peptide

Peptide
binding
groove

Cell
Membrane
 Cleft geometry

MHC class I

MHC class II

Peptide is held in the cleft by non-covalent forces

 Cleft geometry

α-chain α-chain

Peptide β-chain
Peptide
β2-
M

MHC class I accommodate MHC class II accommodate

peptides of 8-10 amino acids peptides of >13 amino acids
 Class I And II Specificity
• Several Hundred Allelic Variants Have Been
Identified In Humans
• 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
 MHC-binding peptides
Each human usually expresses:
3 types of MHC class I (A, B, C) and
3 types of MHC class II (DR, DP,DQ)

The number of different T cell antigen receptors is estimated to be

1,000,000,000,000,000
Each of which may potentially recognise a different peptide antigen

How can 6 invariant molecules have the capacity to

bind to 1,000,000,000,000,000 different peptides?
 A flexible binding site?
A binding site that is flexible enough to bind any
peptide?

NO because: at the cell surface, such a binding site would be

unable to
1. allow a high enough binding affinity to form a
trimolecular complex with the T cell antigen receptor
2. prevent exchange of the peptide with others in the
extracellular milieu
 A flexible binding site?
A binding site that is flexible at an early, intracellular stage of
maturation Formed by folding the MHC molecules around the
peptide.

Venus fly trap

Floppy Compact

Allows a single type of MHC molecule to

• bind many different peptides
• bind peptides with high affinity
• form stable complexes at the cell surface
• Export only molecules that have captured a peptide to the cell surface
 Class I MHC Peptides
• Peptides Presented Through MHC I Are
Endogenous Proteins
• Peptide Features
– size 8-10 a/a, preferably 9
• Peptides Bind MHC Due To Presence Of
Specific a/a Found At The Ends Of Peptide.
Ex. Glycine
 Peptide antigen binding to MHC class I molecules

• Peptides bound to a
particular type of MHC I N T Y Q R T R L V C
molecule have conserved S Y F P E I H I
patterns of amino acids K Y Q A V T T L
S Y I P S A K I
• Tethering amino acids need
not be identical but must be R G Y V Y Q Q L
related S I I N F E K L
A P G N Y P A L
• Y & F are aromatic
V, L & I are hydrophobic
Different types of MHC molecule bind peptides with different
patterns of conserved amino acids
 Class II MHC Peptides

• Peptides Presented through MHC II Are

Exogenous
• Peptides Are Presented To TH
• Peptides Are 13-18 a/a Long
• Binding Is Due To Central 13 a/a
• Longer Peptides Can Still Bind MHC II
– Like A long hot dog
 Peptide antigen binding to MHC class II molecules
Negatively
charged Hydrophobic
I S N Q L T L D S N T K Y F H K
I P D N L F K S D G R I K Y T L N
A T K Y G N M T E D H V N H L L Q N A
G K F A I R P Y K K S N P I I R T V
V F L L L L A Y K V P E T S L S
T F D Y I A S G F R Q G G A S Q
P P E V T V L T N S P V Y L R E P N V
Y G Y T S Y Y F S W A E L
T G H G A R T S T Y P T T D Y

• Anchor residues are not localised at the N and C termini

• Motifs are less clear than in class I-binding peptides
• Pockets are more permissive
How can 6 invariant molecules have the capacity to
bind to 1,000,000,000,000,000 different peptides
with high affinity?

• Adopt a flexible “floppy” conformation until a

peptide binds
• Fold around the peptide to increase stability of the
complex
• Tether the peptide using a small number of anchor
residues
• Allow different sequences between anchors and
different lengths of peptide
MHC molecules are targets for immune evasion by
pathogens

• Without T cells there is no effective immune response

• Ag–specific T cells are activated by peptide/MHC
complexes
• There is therefore strong selective pressure for pathogens
to mutate genes encoding antigens so that they can evade
the formation of peptide/MHC complexes
• The MHC has two strategies to prevent evasion by
pathogens
1. More than one type of MHC
molecule in each individual
2. Extensive differences in MHC
molecules between individuals
 Example: If MHC X was the only type of MHC molecule

MH
C
XX
Pathogen that
evades MHC
X

Survival of Population threatened with

individual extinction
threatened
Example: If each individual could make two MHC molecules,
MHC X and Y

MH
C
Pathogen that XX
evades
MHC X
but has MH
sequences C
that bind to YY
MHC Y
MH
C
XY
Impact on the
Population survives
individual depends
upon genotype
Example: If each individual could make two MHC molecules,
MHC X and Y……and the pathogen mutates

MH
C
Pathogen that
evades
XX
MHC X but has MH
sequences that C
bind to MHC Y
….until it
YY
mutates to evade MH
MHC Y C
XY
Survival of Population threatened with
individual extinction
threatened
 Populations need to express variants of each type of
MHC molecule
⮚Populations of microorganisms reproduce faster than humans
⮚Mutations that change MHC-binding antigens or MHC molecules can
only be introduced to populations after reproduction
⮚The ability of microorganisms to mutate in order to evade MHC
molecules will always outpace counter evasion measures that
involve mutations in the MHC
⮚The number of types of MHC molecules are limited

To counteract the superior flexibility of pathogens:

✔Human populations possess many variants of each type of MHC molecule
✔Variant MHC may not protect every individual from every pathogen.
However, the existence of a large number of variants means that the
population is prevented from extinction
 Variant MHC molecules protect the population
MH XX XXR XYR YXR YYR YY XRXR
C
XX
Pathogen that MH
evades MHC X C
and Y YRY XRY XY
…but binds to the YY From 2 MHC types and
R R
MH
variant MHC XR 2 variants…….
C 10 different genotypes
and MHC YR
XY

MH MH
C C
YYR XXR
Variants – alleles - of each type of MHC gene encode proteins that increase the
resistance of the population from rapidly mutating or newly encountered
pathogens without increasing the number of types of MHC molecule
 Simplified map of the HLA region

DP D LMP/TAP DQ DR B C A
β α α
Mβ βα β β3 β4 β5 α
1

MHC Class MHC

II Class Class I
III
Polygeny
CLASS I: 3 types HLA-A, HLA-B, HLA-C (sometimes called class Ia
genes)
CLASS II: 3 types HLA-DP, HLA-DQ , HLA-DR.
3 extra DRβ genes in some individuals can allow 3 extra HLA-DR molecules

⮚Maximum of 9 types of antigen presenting molecule allow

interaction with a wide range of peptides.
 MHC Genetics
• MHC Products Are Highly Polymorphic
– Vary considerably from person to person

• However, Crossover Rate Is Low

– 0.5% crossover rate
– Inherited as 2 sets (one from father, one from mother)
– Genes in the MHC are tightly LINKED and usually inherited
in a unit called an MHC HAPLOTYPE

• MHC Alleles Are Co-dominantly Expressed

– Both mother and father alleles are expressed
How diverse are MHC molecules in the population?
IF • each individual had 6 types of MHC
• the alleles of each MHC type were randomly
distributed in the population
• any of the 1,200 alleles could be present with
any other allele ~6 x 1015 unique combinations
In reality MHC alleles are NOT randomly distributed in the population
Alleles segregate with lineage and race

Frequency (%)
Group of alleles CAU AFR ASI
HLA-A1 15.18 5.72 4.48
HLA- A2 28.65 18.88 24.63
HLA- A3 13.38 8.44 2.64
HLA- A28 4.46 9.92 1.76
HLA- A36 0.02 1.88 0.01
Inheritance Of HLA Haplotypes
 Diversity of MHC molecules in the individual
D D D B C A
β α βα β α
P Q 1R
Polygeny

D D D B C A
β α βα β α Variant alleles
P Q 1R
HAPLOTYPE 1 polymorphism

D D D B C A
β α βα β α Additional set of
P Q 1R
HAPLOTYPE 2 variant alleles on
second chromosome

MHC molecules are CODOMINANTLY expressed

Two of each of the six types of MHC molecule are expressed
Genes in the MHC are tightly LINKED and usually inherited in a
unit called an MHC HAPLOTYPE
 DP-1,9
DP DQ DR B C A
DQ-3,7
Inheritance of MHC haplotypes DR-5,5
B-7,3 DP DQ DR B C A
C-9,1
A-11,9
Parent DP-1,8
DP-1,2 DP DQ DR B C A
s DR B C DQ-3,6
DP DQ A
DQ-3,4 DR-5,4
DR-5,6 B-7,2 DP DQ DR B C A
B-7,8 DP DQ DR B C A C-9,8
C-9,10 A-11,10
A-11,12
DP-2,8 DP DQ DR B C A
X Childre DQ-4,6
DR-6,4
DP-9,8 DP DQ DR B C A n B-8,2
DP DQ DR B C A
DQ-7,6
C-10,8
DR-5,4
A-12,10
B-3,2 DP DQ DR B C A
C-1,8 DP-2,9
DP DQ DR B C A
A-9,10 DQ-4,7
DR-6,5
B-8,3 DP DQ DR B C A
C-10,10
A-12,9
Errors in the inheritance of haplotypes generate polymorphism in
the MHC by gene conversion and recombination

A B C
A B C
A B C

Multiple distinct During meiosis Chromosomes separate

but closely related chromosomes misalign after meiosis DNA is
MHC genes exchanged between
haplotypes
GENE CONVERSION
A B C A B C
A B C

RECOMBINATION between haplotypes

In both mechanisms the type of MHC molecule remains the same, but
a new allelic variant may be generated
 A clinically relevant application of MHC genetics:
Matching of transplant donors and recipients
The biology, diversity and complexity of the MHC locus and its
pattern of inheritance explains:
• The need to match the MHC of the recipient of a graft with the
donor
• The difficulties faced in matching unrelated donors with recipients
• The ~20% chance of finding a match in siblings

http://www-medlib.med.utah.edu/WebPath/jpeg5/CV171 http://tpis.upmc.edu/tpis/images/C00005c
 Video links

• https://www.youtube.com/watch?v=qyt-yTy-EEM

• https://www.youtube.com/watch?v=-gHgp6EBWJc