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FUNCTION OF MHC MOLECULES. THE STRUCTURE OF MHC GENE PRODUCTS. 2. 1. 1. 1. 3. 2. 2. 2m. 1 2 3. 1 2. 1 2. 3 and 2m Ig supergene family 2 and 2. 2. 1. 2 m. 3. THREE DIMENSIONAL STRUCTURE OF THE MHC CLASS I MOLECULE. PEPTIDE. - PowerPoint PPT Presentation
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COOHNH2
TM CCOOHNH2
MHC class II
TM
NH2NH2
COOHCOOH
HOOCC
COOHNH2 COOHNH2
TM C
Transmembrane region (TM)
Cytoplasmic region ©
– carbohydrate
NH2
Peptide binding site
MHC class II
THE STRUCTURE OF MHC GENE PRODUCTS
3 2m
2
1 1
2 2
1
1 2 3 1 2 1 2
3 and 2m Ig supergene family 2 and 2
PEPTIDEPEPTIDE
1
3
2
2m
THREE DIMENSIONAL STRUCTURE OF THE MHC CLASS I MOLECULE
EXPRESSED IN ALL NUCLEATED CELLS
2
1
2
1
PEPTIDE
PEPTIDE
EXPRESSED ON PROFESSIONAL ANTIGEN PRESENTING CELLS
THE THREE DIMENSIONAL STRUCTURE OF MHC CLASS II MOLECULES
MHC class I accommodate
peptides of 8-10 amino acids
Cleft geometry
MHC class II accommodatepeptides of >13 amino acids
-M
-chain
Peptide
-chain
-chainPeptide
MHCI
P1P2P3P4P5P6P7P8P9Octapeptide
Decapeptide
anchoringamino acids
NH2 COOH
MHCII
P1
NH2
NH2
COOH
COOH
-1 1011-2 P4 P6 P9
anchoringamino acids
MHC MOLECULES ARE EXPRESSED WITH BOUND PEPTIDES DERIVED FROM SELF OR NON-SELF PROTEINS
B-cell, macrophage, dendritic cell
Kidney epithelial cell
Liver cell
Present intracellular environment
Present intra- and extracellular environment
Class I MHC – code of 6Immunological 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
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
P E IYS F H I
A V TYK Q T L
P S AYS I K I
R T RYT Q L VN C
Tethering amino acids need not be identical but must be related
Y & F are aromaticV, L & I are hydrophobic
Side chains of anchor residues bind into POCKETS in the MHC molecule
S I I FN E K L
A P G YN P A L
R G Y YV Q Q L
Different types of MHC molecule bind peptides with different patterns of conserved amino acids
A common sequence in a peptide antigen that binds to an MHC molecule is called a MOTIF
Amino acids common to many peptides tether the peptide to structural features
of the MHC moleculeANCHOR RESIDUES
1
3
2
2m 2
1
2
1
Allelic polymorphism is concentrated inthe peptide antigen binding site
Polymorphism in the MHC affects peptide antigen binding
Allelic variants may differ by 20 amino acids
Class II(HLA-DR)
Class I
DPB1*01011 TAC GCG CGC TTC GAC AGC GAC GTG GGG GAG TTC CGG GCG GTG ACG GAG CTG GGG CGG CCT GCT GCG GAG TAC TGG AAC AGC CAG AAG GAC ATC CTG GAG GAG DPB1*01012 --- --- --- --- --- --- --- --- --A --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*02012 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*02013 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -AC -A- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*0202 CT- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -AG --- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*0301 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --C --- --- --- --- --- --- --- C-- --- --- --- DPB1*0401 -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*0402 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*0501 CT- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -AG --- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*0601 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --C --- --- --- --- --- --- --- C-- --- --- --- DPB1*0801 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*0901 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --C --- --- --- --- --- --- --- --- --- --- --- DPB1*1001 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*11011 --- --- --- --- --- --- --- --- --A --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- C-- --- --- --- DPB1*11012 --- --- --- --- --- --- --- --- --A --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- C-- --- --- --- DPB1*1301 --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*1401 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --C --- --- --- --- --- --- --- C-- --- --- --- DPB1*1501 --- --- --- --- --- --- --- --- --A --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- C-- --- --- --- DPB1*1601 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*1701 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --C --- --- --- --- --- --- --- --- --- --- --- DPB1*1801 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*1901 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -AG --- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*20011 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --C --- --- --- --- --- --- --- C-- --- --- --- DPB1*20012 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --C --- --- --- --- --- --- --- C-- --- --- --- DPB1*2101 CT- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -AG --- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*2201 CT- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -AG --- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*2301 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*2401 -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -AG --- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*2501 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --- --- --- --- --- --- --- --- C-- --- --- --- DPB1*26011 --- --- --- --- --- --- --- --- --A --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*26012 --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- ---
30 HLA-DP allele sequences betweenNucleotides 204 and 290
(amino acids 35-68)
Most polymorphisms are point mutations
Y-F A-V Silent A-D A-EE-A
I-L
Polymorphic nucleotides encode amino acids associated with the peptide binding site
A DQB1DRB1Loci:
Person 1 Person 2
Haplotype
Alle
les
Alle
les
Gen
etic
pol
ymor
hism
of t
he p
opul
atio
n
Gen
otyp
e
Haplotype
21
2625
23113
271813
7
743
1824 2 3
B
138
32
113735
18
32
321
271 4 1
38 987
A DQB1DRB1
2
1
24
23
25
38
37
27
18
13
4
3
2
3511
3
2
1
1 3
B
138
32
113735
18
3
21
271 3 21
38 874
39
COMBINATION OF MHC ALLOTYPES IN INDIVIDUALS AND IN THE POPULATION
* * * *
* *
Molecular basis of MHC types and variants
POLYMORPHISMVariation >1% at a single genetic locus in a
population of individualsMHC 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 levelThis sharply contrast diversity in T and B cell antigen receptors which
exists within the individual
POLYGENISM
Several MHC class I and class II genes encoding different types of MHC molecule
with a range of peptide-binding specificities.
Populations need to express variantsof 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
MHC-GenMHC-Gen
vv
vv
vv
v
vv
v
v
v
v
v v v
v
vv
v
vv
v
vv
Example: If MHC X was the only type of MHC molecule
Population threatenedwith extinction
Pathogen that evades MHC
X
MHCXX
Population is protected
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 MHC-restricted 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
TNF
LMP TAP
21-hydroxilase
Class III Non polymorphic genesClass II Class I
E G F
HSP
Class II
DMA/B
MICA/B
B C A
C2/C4
DQDP DN DR
B2 B2 B2A2 A2 B3B1 B1 (B4)A1 A1 AB B1A
DO
Classical MHC genes POLYMORPHIC
HLA – Human Leukocyte Antigen
HLA –A,B, C class I
EXPRESSED IN ALL NUCLEATED CELLS
HLA – DR, DP, DQ class II
EXPRESSED IN PROFESSIONAL APC
Non- classical MHC genes
E, G, F
Chromosome 6 short arm MHC
Chromosome 15 2m
LOCALIZATION OF MHC GENES
Class III genes
OTHER GENES IN THE MHC – not polymorphicMHC Class 1b genes
Encoding MHC class I-like proteins that associate with -2 microglobulinRestricted 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 genesEncoding several antigen processing genes
HLA-DMand in professional APC, proteasome components (LMP-2 & 7), peptide transporters (TAP-1 & 2), HLA-DO and DO
Many pseudogenes
MHC Class III genesEncoding complement proteins C4A and C4B, C2 and FACTOR B
TUMOUR NECROSIS FACTORS-
Immunologically irrelevant genesGenes encoding 21-hydroxylase, RNA Helicase, Caesin kinase
Heat shock protein 70, Sialidase