Presentation of a Self-peptide in Two Distinct Conformations by a Disease-associated HLA-B27 Subtype

The MHC locus on human chromosome 6 harbors the most polymorphic genes in the human genome, and the large number of alleles in human populations has permitted key structural features of MHC class I and class II genes that influence susceptibility to several human autoimmune diseases to be delineated. In this issue, Hülsmeyer et al. adds a new twist to the already rich literature on MHC polymorphisms and human disease (1). The authors determined the crystal structures of two HLA-B27 subtypes (B * 2705 and B * 2709) with the same self-peptide (pVIPR, derived from vasoactive intestinal peptide type 1 receptor). These two subtypes are remarkable in that they differ only at one heavy chain residue but are differentially associated with susceptibility to anky-losing spondylitis (AS), a chronic inflammatory joint disease. The pVIPR peptide bound in a conventional conformation to both HLA-B27 subtypes but in a second unique confor-mation to the AS-associated B * 2705 subtype. In the conventional binding mode, an arginine at position 5 of the peptide was solvent exposed and thus available for TCR recognition. In the second conformation, this arginine instead formed a salt bridge with a buried polymorphic residue located at the floor of the binding site (Asp 116) (Fig. 1). The drastically altered position of this central peptide residue also changed the conformation of the entire central peptide segment from positions 3 to 7 (1). A single, buried poly-morphic MHC class I residue can thus affect the global conformation of a bound peptide. HLA-B27 and Ankylosing Spondylitis. In 1973, a striking association between HLA-B27 and AS was reported (2, 3). Even though susceptibility to many other human diseases has since been shown to be associated with particular alleles of MHC class I and/or class II genes, it remains one of the strongest associations between a MHC gene and a chronic inflammatory disease. An extensive search failed to identify other genes in the MHC class I region with a tighter linkage to AS, leading to the conclusion that the HLA-B gene itself is responsible. HLA-B27 is associated with AS in different ethnic groups across the world, and the analysis of HLA-B27 subtypes in different populations laid the foundation for the structure-function study by Hülsmeyer et al. (1), since it resulted in the identification of two HLA-B27 subtypes (B * 2706 and B * 2709) that are not associated with susceptibility to the disease (4, 5). …