Original Paper

Immunogenetics

, Volume 55, Issue 12, pp 797-810

Definition of supertypes for HLA molecules using clustering of specificity matrices

  • Ole LundAffiliated withCenter for Biological Sequence Analysis, BioCentrum-DTU, Technical University of Denmark Email author 
  • , Morten NielsenAffiliated withCenter for Biological Sequence Analysis, BioCentrum-DTU, Technical University of Denmark
  • , Can KesmirAffiliated withCenter for Biological Sequence Analysis, BioCentrum-DTU, Technical University of DenmarkTheoretical Biology/Bioinformatics, Utrecht University
  • , Anders Gorm PetersenAffiliated withCenter for Biological Sequence Analysis, BioCentrum-DTU, Technical University of Denmark
  • , Claus LundegaardAffiliated withCenter for Biological Sequence Analysis, BioCentrum-DTU, Technical University of Denmark
  • , Peder WorningAffiliated withCenter for Biological Sequence Analysis, BioCentrum-DTU, Technical University of Denmark
  • , Christina Sylvester-HvidAffiliated withDepartment of Experimental Immunology, Institute of Medical Microbiology and Immunology, University of Copenhagen
  • , Kasper LamberthAffiliated withDepartment of Experimental Immunology, Institute of Medical Microbiology and Immunology, University of Copenhagen
  • , Gustav RøderAffiliated withDepartment of Experimental Immunology, Institute of Medical Microbiology and Immunology, University of Copenhagen
    • , Sune JustesenAffiliated withDepartment of Experimental Immunology, Institute of Medical Microbiology and Immunology, University of Copenhagen
    • , Søren BuusAffiliated withDepartment of Experimental Immunology, Institute of Medical Microbiology and Immunology, University of Copenhagen
    • , Søren BrunakAffiliated withCenter for Biological Sequence Analysis, BioCentrum-DTU, Technical University of Denmark

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Abstract

Major histocompatibility complex (MHC) proteins are encoded by extremely polymorphic genes and play a crucial role in immunity. However, not all genetically different MHC molecules are functionally different. Sette and Sidney (1999) have defined nine HLA class I supertypes and showed that with only nine main functional binding specificities it is possible to cover the binding properties of almost all known HLA class I molecules. Here we present a comprehensive study of the functional relationship between all HLA molecules with known specificities in a uniform and automated way. We have developed a novel method for clustering sequence motifs. We construct hidden Markov models for HLA class I molecules using a Gibbs sampling procedure and use the similarities among these to define clusters of specificities. These clusters are extensions of the previously suggested ones. We suggest splitting some of the alleles in the A1 supertype into a new A26 supertype, and some of the alleles in the B27 supertype into a new B39 supertype. Furthermore the B8 alleles may define their own supertype. We also use the published specificities for a number of HLA-DR types to define clusters with similar specificities. We report that the previously observed specificities of these class II molecules can be clustered into nine classes, which only partly correspond to the serological classification. We show that classification of HLA molecules may be done in a uniform and automated way. The definition of clusters allows for selection of representative HLA molecules that can cover the HLA specificity space better. This makes it possible to target most of the known HLA alleles with known specificities using only a few peptides, and may be used in construction of vaccines. Supplementary material is available at http://​www.​cbs.​dtu.​dk/​researchgroups/​immunology/​supertypes.​html.

Keywords

HLA Supertype Classification Class I Class II