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MHC Polymorphism
MHC Class I pathway
Figure by Eric A.J. Reits
Expression of HLA is codominant
Polymorphism and polygeny
The MHC gene region
http://www.ncbi.nlm.nih.gov/mhc/MHC.fcgi?cmd=init&user_id=0&probe_id=0&source_id=0&locus_id=0&locus_group=0&proto_id=0&banner=1&kit_id=0&graphview=0
Human Leukocyte antigen (HLA=MHC in humans)
polymorphism - alleles
http://www.anthonynolan.com/HIG/index.html
HLA variability
http://rheumb.bham.ac.uk/teaching/immunology/tutorials/mhc%20polymorphism.jpg
MHC polymorphism
•Selection pressure
•Pathogens
•Hosts
•Cause of MHC polymorphism
•Heterozygote advantage
•Different MHC molecules bind different peptides
•Heterozygous hosts have a broader immune response
•Degree of MHC heterozygocity correlates with a delayed onset
of progress to AIDS
•Frequency-dependent selection by host-pathogen coevolution
•Pathogens adapt to the most common MHC alleles
•Rare alleles have a selective advantage
Sets of MHC types
•Each MHC molecule has a different specificity
•If a vaccine needs to contain a unique peptide for each of these
molecules it will need to comprise hundreds of peptides
•Solution 1
•Select sets of a few HLA molecules that together have a broad
distribution in the human population
•Gulukota and DeLisi [1996] compiled lists with 3, 4, and 5
alleles which give the maximal coverage of different ethnic
groups
MHC Supertypes
•Many of the different HLA molecules have similar specificities
•HLA molecules with similar specificities can be grouped together
•Methods to define supertypes
•Structural similarities
•Primary (sequence)
•Tertiary (structure)
•Shared peptide binding motifs
•Identification of cross-reacting peptides
•Ability to generate methods that can predict cross-binding peptides
HLA polymorphism - supertypes
•Each HLA molecule within a supertype essentially binds the same peptides
•Nine major HLA class I supertypes have been defined
•HLA-A1, A2, A3, A24,B7, B27, B44, B58, B62
Sette et al, Immunogenetics (1999) 50:201-212
HLA polymorphism - frequencies
Supertypes
Phenotype frequencies
Caucasian
Black
Japanese
Chinese
Hispanic
Average
A2,A3, B7
83 %
86 %
88 %
88 %
86 %
86%
+A1, A24, B44
100 %
98 %
100 %
100 %
99 %
99 %
+B27, B58, B62
100 %
100 %
100 %
100 %
100 %
100 %
Sette et al, Immunogenetics (1999) 50:201-212
HLA clustering method
1. Extract data from SYFPEITHI and MHCpep databases
2. Construct amino acid frequency vectors for each HLA molecule
3. Calculate distance between HLA molecules
• The distance dij between two HLA molecules (i, j) is calculated as
the sum over each position in the two motifs of one minus the
normalized vector products of the amino acid’s frequency vectors
(= cosine to the angle between the vectors) [Lyngsø et al., 1999]:
4. The distance matrices were used as input to the program neighbor
from
the
PHYLIP
package
(http://evolution.genetics.washington.edu/phylip.html)
O Lund et al., Immunogenetics. 2004 55:797-810
Logos of
HLA-A
alleles
O Lund et al., Immunogenetics. 2004 55:797-810
Clustering of HLA alleles
O Lund et al., Immunogenetics. 2004 55:797-810
Logos of
HLA-B
alleles
O Lund et al., Immunogenetics. 2004 55:797-810
O Lund et al., Immunogenetics. 2004 55:797-810
Conclusions
We suggest to
– split some of the alleles in the A1 supertype into a
new A26 supertype
– split some of the alleles in the B27 supertype into
a new B39 supertype.
– the B8 alleles may define their own supertype
– The specificities of the class II molecules can be
clustered into nine classes, which only partly
correspond to the serological classification
O Lund et al., Immunogenetics. 2004 55:797-810
MHC class II pathway
Figure by Eric A.J. Reits
Virtual matrices
HLA-DR molecules sharing the same pocket
amino acid pattern, are assumed to have
identical amino acid binding preferences.
MHC Class II binding
Virtual matrices
– TEPITOPE: Hammer, J., Current Opinion in Immunology 7, 263-269, 1995,
– PROPRED: Singh H, Raghava GP Bioinformatics 2001 Dec;17(12):1236-7
Web interface
http://www.imtech.res.in/raghava/propred
Prediction Results
MHC class II Supertypes
•5 alleles from the DQ locus (DQ1, DQ2, DQ3, DQ4, DQ5) cover 95% of
most populations [Gulukota and DeLisi, 1996]
•A number of HLA-DR types share overlapping peptide-binding
repertoires [Southwood et al., 1998]
Logos of
HLA-DR
alleles
O Lund et al., Immunogenetics. 2004 55:797-810
O Lund et al., Immunogenetics. 2004 55:797-810