Mhc polymorphism
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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.

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MHC Polymorphism

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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


HLA polymorphism - frequencies

SupertypesPhenotype frequencies

CaucasianBlackJapaneseChineseHispanicAverage

A2,A3, B783 %86 %88 %88 %86 %86%

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

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

Sette et al, Immunogenetics (1999) 50:201-212


HLA clustering method

  • Extract data from SYFPEITHI and MHCpep databases

  • Construct amino acid frequency vectors for each HLA molecule

  • 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]:

  • 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

A2 supertype

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 GPBioinformatics 2001 Dec;17(12):1236-7

  • Web interfacehttp://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


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