Transcript MHC Polymorphism - CBS

MHC Polymorphism
Ole Lund
Objectives
• What is HLA polymorphism?
• What is it good for?
• How does it make life difficult for vaccine
design?
• Definition of HLA supertypes
• HLA class I
• HLA class II
MHC Class I pathway
Figure by Eric A.J. Reits
Expression of HLA is codominant
Father
Kids
Mother
Polymorphism and polygeny
Two different properties make it difficult for pathogens to
evade immune responses
Human MHC (HLA) encoded on
cromosome 6
Heterozygous advantage
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
Figure 5-13
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
HLA polymorphism
Figure by Thomas Blicher ([email protected]
MHC polymorphism
• Selection pressure
• Pathogens
• Hosts (MHC diversity is driven by disassortative mating
preferences)
• 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
HLA Diversity.
2 x 3 HLA’s per person
http://www.stanford.edu/dept/HPS/transplant/html/tt_1.html
HLA polymorphism and vaccine design
• Few human beings will share the same set
of HLA alleles
– Different persons will react to a pathogen
infection in a non-similar manner
• A CTL based vaccine must include
epitopes specific for each HLA allele in a
population
– A CTL based vaccine must consist of ~800
HLA class I epitopes and ~400 class II
epitopes
Sets of MHC types
Solution
• 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 binds essentially 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
Novel HLA supertypes
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
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
HLA class II supertypes
We suggest to
– 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
Conclusions
• The HLA polymorphism is enormous
• Great for competing pathogen infections
• Bad for vaccine design
• Not all HLA’s are equally different
• Allows definition of supertypes
• Selecting one epitope from 6 supertypes
gives close to 98%-100% population
coverage