Download MHC Class II genes

THE STRUCTURE OF MHC GENES AND PROTEINS
MEMBERS OF THE IMMUNOGLOBULIN SUPERGENE FAMILY
H
s
s
s
L
s
s
s
s
s
s
s
s
s
s
s
s
s
s
S
s
s
L
MOLECULES CONTAINING ONE
OR MORE Ig DOMAIN(S)
H
s s
s s
V or C domain related
s
s
s s
s s
s s
s s
s s
s s
s s
s s
ss
ss
s s
s s
ss
Thy-1
IgM
s
s
s
s
s s
s s
s s
s s
ss
CD79
TCR MHCI
s
s
s
s
s
s
s
s
MHCII ICAM-1 Fc RII
s
s
s
s
s
s
CD2
g
d
e
s
s
s
s
s
s
s
s
a
b
s
s
s
s
s
s
CD3
CD4
s s
s s
s s
s s
ss
ss
CD8
CD28
s
s
s
s
s
s
s
s
B-7
Poly-Ig
FUNCTION
RECOGNITION
Ig, TCR, MHC-I, MHC-II
ADHESION
ICAM-1, ICAM-2, VCAM-1,
NCAM
BINDING
CD4, CD8, CD28, B7, IL-1RI,
PDGFR, FcRII, poly-IgR
THE STRUCTURE OF MHC GENE PRODUCTS
MHC class II
MHC class II
Peptide binding site
2
1
1
2m
2
NH2
1
NH2
NH2
3
2
Transmemb rane region
(TM)
COOH
Cytopla sm ic region ©
COOH
HOOC
TM C
NH2
TM C
COOH
1
2
NH2
NH2
3
COOH
1
COOH
2
NH2
TM C
COOH
1
2
– c arbohydrate
3 and 2m
Ig supergene family
2 and 2
MAP OF THE HUMAN MHC
FROM THE HUMAN GENOME PROJECT
3,838,986 bp
224 genes
on chromosome 6
The MHC
sequencing
consortium
Nature 401, 1999
http://webace.sanger.ac.uk/cgi-bin/ace/pic/6ace?name=MHC&class=Map&click=400-1
LOCALIZATION OF MHC GENES
Chromosome 6 short arm
MHC
Chromosome 15
2m
Class II
Class II
DMA/B
21-hydroxilase
C2/C4
LMP TAP
DP
B2 A2 B1 A1
Class III
DN
DO
A
B
HLA – Human Leukocyte Antigen
C
E
A
G
F
DR
B1 B2 B3 (B4) A
Non- classical MHC genes
E, G, F
class I
EXPRESSED IN ALL NUCLEATED CELLS
HLA – DR, DP, DQ
B
HSP MICA/B
DQ
B2 A2 B1 A1
Classical MHC genes POLYMORPHIC
HLA –A, B, C
TNF
Class I Non polymorphic genes
class II
EXPRESSED IN PROFESSIONAL APC
Class III genes
Differential distribution of MHC molecules
Tissue
MHC class I
MHC class II
T cells
B cells
Macrophages
Other APC
+++
+++
+++
+++
+/+++
++
+++
Epithelial
cells of thymus
+
+++
+++
+
+
+
-
-
Neutrophils
Hepatocytes
Kidney
Brain
Erythrocytes
Cell activation affects the level of MHC expression
The pattern of expression reflects the function of MHC molecules
Class I is involved in anti-viral immune responses
Class II involved in activation of other cells of the immune system
INHERITANCE OF MHC CLASS I AND CLASS II GENES
HUMAN LEUKOCYTE
ANTIGEN
A24
A11
HLA
A24
A2
A24
A1
1.
B27
C1
C6
A1
A2
2.
A11
A1
A11
A2
4.
3.
transz
transz
A24
B8
A1
CLASS II
α1β1
CLASS I
EVERY CELL
B8
C1
A24
α2β2
PROFESSIONAL APC
a1
b1
a2
b2
cisz
transz
B27
C6
A1
cisz
DQ1
DQ2
POLYMORPHISM OF MHC MOLECULES
IN THE HUMAN POPULATION
POSTULATION
• every individual has 6 MHC class I molecules
• alleles of all MHC types are distributed randomly in the population
• every one of the 1 200 different alleles can be expressed with any
other allele
~6 x 1015 individual combinations
Only monozygous twins are identical at the HLA locus
The human population is extensively outbred
MHC genetics in humans is extremely complex
POLYGENIC & POLYMORPHIC
DISTRIBUTION OF MHC ALLELES IN THE HUMAN
POPULATION
381
Polymorphism (number of alleles)
Class I
185
91
A B C
317
Class II
492 alleles
89
19
20 45
2
     
DR
Frequency (%)
657 alleles
DP
DQ
Allelic groups
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
Alleles are not distributed evenly in the
population
Alleles are segregated among races
SELECTION
Inheritance of MHC haplotypes
Parents
DP-1,2
DQ-3,4
DR-5,6
B-7,8
C-9,10
A-11,12
DP
DP
DQ DR
DQ DR
BC
BC
DP-9,8
DQ-7,6
DR-5,4
B-3,2
C-1,8
A-9,10
DP-1,8
DQ-3,6
DR-5,4
B-7,2
C-9,8
A-11,10
A
A
Children
X
DP
DQ DR
BC
A
DP
DQ DR
BC
A
DP-1,9
DQ-3,7
DR-5,5
B-7,3
C-9,1
A-11,9
DP-2,8
DQ-4,6
DR-6,4
B-8,2
C-10,8
A-12,10
DP-2,9
DQ-4,7
DR-6,5
B-8,3
C-10,10
A-12,9
DP
DQ DR
BC
A
DP
DQ DR
BC
A
DP
DQ DR
BC
A
DP
DQ DR
BC
A
DP
DQ DR
BC
A
DP
DQ DR
BC
A
DP
DQ DR
BC
A
DP
DQ DR
BC
A
FUNCTIONS OF MHC MEMBRANE PROTEINS
STRUCTURE OF CLASS I MHC MOLECULES
PEPTIDE
2
3
1
2m
EXPRESSED BY ALL NUCLEATED CELLS
STRUCTURE OF CLASS II MHC MOLECULES
PEPTIDE
1
1
2
2
EXPRESSED BY PROFESSIONAL ANTIGEN PRESENTING CELLS
CAN BE INDUCED IN OTHER CELLS (endothel, microglia, astocyte)
MEMBRANE RECEPTORS
Intracellular peptide binding
capacity
One binding site can
accomodate multiple peptides
MHC – PEPTIDE COMPLEXES
Allelic polymorphism is concentrated in
the peptide antigen binding site
Class I
2
3
1
1
1
2m
2
2
Class II
(HLA-DR)
Polymorphism in the MHC affects peptide antigen binding
Allelic variants may differ by 20 amino acids
Cleft geometry
-chain
-chain
Peptide
2-M
MHC class I accommodate
peptides of 8-10 amino acids
Peptide
-chain
MHC class II accommodate
peptides of >13 amino acids
Most polymorphisms are point mutations
30 HLA-DP allele sequences between
Nucleotides 204 and 290
(amino acids 35-68)
Polymorphic nucleotides encode amino acids
associated with the peptide binding site
Y-F A-V
DPB1*01011
DPB1*01012
DPB1*02012
DPB1*02013
DPB1*0202
DPB1*0301
DPB1*0401
DPB1*0402
DPB1*0501
DPB1*0601
DPB1*0801
DPB1*0901
DPB1*1001
DPB1*11011
DPB1*11012
DPB1*1301
DPB1*1401
DPB1*1501
DPB1*1601
DPB1*1701
DPB1*1801
DPB1*1901
DPB1*20011
DPB1*20012
DPB1*2101
DPB1*2201
DPB1*2301
DPB1*2401
DPB1*2501
DPB1*26011
DPB1*26012
TAC
---T-TCT-T-T-TCT-T-T-T-T-------T---T-T-T-T-T-TCTCT-T-T-T-----
GCG
---T-T-T-T---T-T-T-T-T-T-------T---T-T-T-T-T-T-T-T-T---T-----
CGC
-------------------------------------------------------------
Silent
TTC
-------------------------------------------------------------
GAC
-------------------------------------------------------------
AGC
-------------------------------------------------------------
GAC
-------------------------------------------------------------
GTG
-------------------------------------------------------------
GGG
--A
------------------------A
--A
------A
------------------------A
---
GAG
-------------------------------------------------------------
TTC
-------------------------------------------------------------
CGG
-------------------------------------------------------------
GCG
-------------------------------------------------------------
GTG
-------------------------------------------------------------
ACG
-------------------------------------------------------------
GAG
-------------------------------------------------------------
CTG
-------------------------------------------------------------
GGG
-------------------------------------------------------------
CGG
-------------------------------------------------------------
E-A
A-D A-E
CCT
-------------------------------------------------------------
GCT
---A-AC
-AG
-A---A-AG
-A-A-A-A-------A---A-A-A-AG
-A-A-AG
-AG
---AG
-A-----
GCG
---A-A---A---A---A-A-A-A-------A---A-A-A---A-A---------A-----
GAG
----------C
--------C
----C
----------C
------C
------C
--C
---------------
TAC
-------------------------------------------------------------
I-L
TGG
-------------------------------------------------------------
AAC
-------------------------------------------------------------
AGC
-------------------------------------------------------------
CAG
-------------------------------------------------------------
AAG
-------------------------------------------------------------
GAC
-------------------------------------------------------------
ATC
--------C-------C-------C-C---C-C---------C-C---------C------
CTG
-------------------------------------------------------------
GAG
-------------------------------------------------------------
GAG
-------------------------------------------------------------
STRUCTURE OF THE PEPTIDE BINDING SITE
anchoring
amino a cids
anchoring
amino a cids
Decapeptide
NH2 P1
P2 P3
P4 P5 P6
COOH
P7 P8P9
-2
-1 P1
P4
P6
Octapeptide
COOH
NH2
P2 & P9 interact with
hydrophobic pockets
11
COOH
NH2
MHCI
P9 10
MHCII
Amino acid side chains of the ‘core’ region
occupy evenly distributed pockets
Peptides can be eluted from MHC molecules
Acid elute
peptides
Eluted peptides from MHC molecules have different
sequences but contain motifs
Peptides bound to a particular type of MHC class I molecule have
conserved patterns of amino acids
A common sequence in a peptide
antigen that binds to an MHC
molecule is called a MOTIF
N T Y Q R T R L V C
Amino acids common to many peptides
tether the peptide to structural features
of the MHC molecule
ANCHOR RESIDUES
Tethering amino acids need not be
identical but must be related
Y & F are aromatic
V, L & I are hydrophobic
S Y F P E I H
I
K Y Q A V T T L
S Y I P S A K I
R G Y V Y Q Q L
S I
I N F E K L
A P G N Y P A L
Side chains of anchor residues bind
into POCKETS in the MHC molecule
Different types of MHC molecule bind peptides with different patterns
of conserved amino acids
PEPTIDE MOTIFS IN SELF AND FOREIGN PROTEINS
MHC MOLECULES ARE EXPRESSED IN THE CELL SURFACE
MEMBRANE WITH BOUND PEPTIDES DERIVED FROM SELF OR NONSELF PROTEINS
Kidney epithelial cell
B-cell, macrophage,
dendritic cell
Present intra- and extracellular
environment
Liver cell
Present intracellular environment
Class I MHC – code of 6
Immunological ID
Peptides of restricted size, which
derive from cytosolic or
nuclear proteins
Class II MHC
Overlapping peptides of various
sizes, which derive from
membrane/exogeneous proteins
70% derives from MHC molecules
BENEFITS OF MHC POLYMORPHISM IN THE POPULATION
A
3
Genotype
11
B DRB1DQB1
1
13
1
2
18
1
2
23
7
1
2
3
27
24
8
2
3
11
35
1
25
13
3
23
37
2
26
18
4
24
38
3
27
7
25
39
4
8
1
8
13
2
13
1
18
3
18
2
1
1
27
4
1
1
27
3
2
2
35
7
2
2
35
4
3
3
37
8
3
3
37
7
11
38
9
11
38
8
*P e*rs o n
*
1
H a p lo ty p e
H a p lo ty p e
* e rs
* on 2
P
3
Alleles
A B DRB1 DQB1
*
Alleles
L o ci:
Genetic polymorhism of the population
COMBINATION OF MHC ALLOTYPES IN INDIVIDUALS
AND IN THE POPULATION
Populations need to express variants
of each type of MHC molecule
• The rate of replication by pathogenic microorganisms is faster than
human reproduction
• In a given time a pathogen can mutate genes more frequently than
humans and can easily evade changes in MHC molecules
• The number of types of MHC molecules are limited
To counteract the flexibility of pathogens
• The MHC has developed many variants of each type of MHC
molecule
• These variants may not necessarily protect all individuals from every
pathogen, but will protect the population from extinction
THE OUTCOME OF INFECTION IN A POPULATION
WITH POLYMORPHIC MHC GENES
Example: If MHC X was the only type of MHC molecule
MHC-Gen
MHC
XX
v
v
Pathogen that
evades MHC
X
v
Population threatened
with extinction
v
v
v
v
v
v
v
v
v
v
v
v
v
v
v
v
v
v
v
v
v
v
Population is protected
Molecular basis of MHC types and variants
POLYGENISM
Several MHC class I and class II genes
encoding different types of MHC molecule
with a range of peptide-binding specificities.
POLYMORPHISM
Variation >1% at a single genetic locus in a
population of individuals
MHC genes are the most polymorphic known
The type and variant MHC molecules do not vary in the lifetime of the
individual
The diversity in MHC molecules exists at the population level
This sharply contrast diversity in T and B cell antigen receptors which
exists within the individual
Foreign peptides
Peptides
recognized by an
individual
CHANGES OF GENETIC POLYMORPHISM IN THE POPULATION
Kialakulás
Csökkenés
Növekedés
Nagy csökkenés
Multiple heterozygous allele
Homozygous
Molecular basis of MHC types and variants
POLYGENISM
Several MHC class I and class II genes
encoding different types of MHC molecule
with a range of peptide-binding specificities.
POLYMORPHISM
Variation >1% at a single genetic locus in a
population of individuals
MHC genes are the most polymorphic known
The type and variant MHC molecules do not vary in the lifetime of the
individual
The diversity in MHC molecules exists at the population level
This sharply contrast diversity in T and B cell antigen receptors which
exists within the individual
FUNCTIONS OF MHC
•
CLASSICAL MHC GENE PRODUCTS
– Presentation of peptides derived from self proteins – continuos presentation
of self for the immune system
– Determination of immunological self
• Self MHC + self peptides
– Presentation of peptides derived from foreign (antigenic) proteins
– Determination of non-self
• Self MHC + non-self peptides
– Allogeneic immune response against non-self MHC (transplantation)
• Recognition of non-self MHC + peptide combinations – consequence of MHCrestricted T-cell recognition
– NK cell recognition
– T-lymphocyte differentiation and selection in the thymus
– T-lymphocyte survival in the periphery
•
NON CLASSICAL MHC GENES
– Specialized functions
•
PROTEINS STRUCTURALLY RELATED TO CLASSICAL MHC
MOLECULES
OTHER GENES IN THE MHC – not polymorphic
MHC Class 1b genes
Encoding MHC class I-like proteins that associate with -2 microglobulin
Restricted tissue expression
HLA-G trophoblast, interacts CD94 (NK-cell receptor). Inhibits NK cell attack of
foetus/ tumours
HLA-E in the membrane of certain cells, binds conserved leader peptides from
HLA-A, B, C. Interacts with CD94
HLA-F fetal liver, eosinophil surface, function unknown
MHC Class II genes
Encoding several antigen processing genes
HLA-DM and  in professional APC, proteasome components (LMP-2 & 7), peptide
transporters (TAP-1 & 2), HLA-DO and DO
Many pseudogenes
MHC Class III genes
Encoding complement proteins C4A and C4B, C2 and FACTOR B
TUMOUR NECROSIS FACTORS-/
Immunologically irrelevant genes
Genes encoding 21-hydroxylase, RNA Helicase, Caesin kinase
Heat shock protein 70, Sialidase