HLA-B27: a registry of constitutive peptide ligands J.A. Lopez de Castro I. Alvarez M. Marcilla A. Paradela M. Ramos L. Sesma M. Va ´zquez Authors’ affiliation: J.A. Lopez de Castro, I. Alvarez, M. Marcilla, A. Paradela, M. Ramos, L. Sesma, M. Va ´ zquez Centro de Biologı ´a Molecular Severo Ochoa (Consejo Superior de Investigaciones Cientı ´ficas and Universidad Auto ´noma de Madrid), Universidad Auto ´ noma, Madrid, Spain Correspondence to: Dr Jose ´ A. Lo ´pez de Castro Centro de Biologı ´a Molecular Severo Ochoa Facultad de Ciencias Universidad Auto ´noma 28049 Madrid, Spain Tel.: þ34-91-497-8050 Fax: þ34-91-497-8087 e-mail: aldecastro@cbm. uam.es Abstract: The very strong association of human leukocyte antigen (HLA)- B27 with spondyloarthritis might be related to its peptide-presenting properties. The natural polymorphism of this molecule influences both peptide specificity and disease susceptibility. In this study, we present a comprehensive compilation of known natural ligands of HLA-B27 arising from endogenous proteins of human cells, together with a statistical assessment of residue usage among constitutive peptide repertoires of multiple HLA-B27 subtypes. This analysis provides evidence that every peptide position, including ‘non-anchor’ ones, may be subjected to selection on the basis of its contribution to HLA-B27 binding and also allows a quantization of residue preferences at known anchor positions. The present registry is intended as a basis on which to build up reliable criteria to assess the effect of HLA-B27 polymorphism on peptide presentation, for T-cell epitope predictions, and for molecular mimicry studies. The characterization of many natural ligands of B*2705 and, to a lower extent, other human leukocyte antigen (HLA)-B27 subtypes has been stimulated by the putative role of peptides in the strong association of HLA-B27 with spondyloarthritis (1, 2) and has been made possible largely through the use of mass spectrometry. From peptide sequen- cing, X-ray diffraction, and other studies, the peptide specificity of HLA-B27 and its molecular basis have been outlined with significant detail. The major feature of HLA-B27 ligands is an almost absolute restriction for R2, which is the main peptidic anchor residue (3, 4), with very few exceptions in B*2705 (5) and more in B*2701 (6). The C-terminal position (PO), considered to be the second most important anchor, is mostly restricted to basic, aliphatic, and aromatic residues and is modulated by subtype polymorphism (2). Secondary anchor positions, namely P1, P3, and P7 have more moderate restrictions in residue usage (3), and are also modulated to some extent by subtype polymorphism; for instance, P1 selectivity for basic residues is increased in B*2703 (7–9), and P3 and P7 are influenced by B*2706 Key words: antigen presentation; arthritis; HLA-B27; human; MHC; peptides; spondyloarthropathy Acknowledgments: We thank our colleagues Jose ´ Martı ´n (Department of Biology, Universidad Auto ´noma de Madrid) and Hilario Flores (Instituto de Diagno ´stico y Referencia Epidemiolo ´ gicos, Me ´xico) for help and advice on statistical analyses. This work was supported by grants SAF2002/00125 from the Ministry of Science and Technology, and 08.3/0005/2001.1 from the Comunidad Auto ´noma de Madrid. We also thank the Fundacio ´n Ramo ´n Areces for an institutional grant to the Centro de Biologı ´a Molecular Severo Ochoa. We will appreciate our colleagues and readers calling our attention on any inaccuracies or omissions in the present compilation of HLA-B27 ligands that may have escaped our notice (e-mail to: aldecastro@cbm.uam.es). Received 22 October 2003, revised 12 December 2003, accepted for publication 16 December 2003 Copyright ß Blackwell Munksgaard 2004 Tissue Antigens. Tissue Antigens 2004: 63: 424–445 Printed in Denmark. All rights reserved 424