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 Mother

Kids

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 (blicher@cbs.dtu.dk

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

Supertypes Phenotype frequencies

Caucasian Black Japanese ChineseHispanic Average

A2,A3, B7 83 % 86 % 88 % 88 % 86 % 86%

+A1, A24, B44100 % 98 % 100 % 100 % 99 % 99 %

+B27, B58, B62100 % 100 % 100 % 100 % 100 % 100 %

HLA polymorphism - frequencies

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

A2 supertype

 

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