Allele-dependent similarity between viral and self-peptide presentation by HLA-B27 subtypes.
Molecular mimicry is discussed as a possible mechanism that may contribute to the development of autoimmune diseases. It could also be involved in the differential association of the human major histocompatibility subtypes HLA-B(*)2705 and HLA-B(*)2709 with ankylosing spondylitis. These two subtypes differ only in residue 116 of the heavy chain (Asp in B(*)2705 and His in B(*)2709), but the reason for the differential disease association is not understood. Using x-ray crystallography, we show here that the viral peptide pLMP2 (RRRWRRLTV, derived from latent membrane protein 2 (residues 236-244) of Epstein-Barr virus) is presented by the B(*)2705 and B(*)2709 molecules in two drastically deviating conformations. Extensive structural similarity between pLMP2 and the self-peptide pVIPR (RRKWRRWHL, derived from vasoactive intestinal peptide type 1 receptor (residues 400-408)) is observed only when the peptides are presented by B(*)2705 because of a salt bridge between Arg(5) of both peptides and the subtype-specific heavy chain residue Asp(116). Combined with functional studies using pLMP2/pVIPR-cross-reactive cytotoxic T cell lines and clones, together with target cells presenting these peptides or a modified peptide analogue, our results reveal that a pathogen-derived peptide can exhibit major histocompatibility complex class I subtype-dependent, drastically distinct binding modes. Furthermore, the results demonstrate that molecular mimicry between pLMP2 and pVIPR in the HLA-B27 context is an allele-dependent property.
Fiorillo
Maria Teresa
MT
Dipartimento di Biologia Cellulare e dello Sviluppo, Università di Roma La Sapienza, via dei Sardi 70, 00185 Roma, Italy.
Rückert
Christine
C
Hülsmeyer
Martin
M
Sorrentino
Rosa
R
Saenger
Wolfram
W
Ziegler
Andreas
A
Uchanska-Ziegler
Barbara
B
D000483:Alleles; D017951:Antigen Presentation; D000941:Antigens / Q000737:chemistry; D001327:Autoimmune Diseases / Q000378:metabolism; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D019309:Epstein-Barr Virus Nuclear Antigens / Q000378:metabolism; D005814:Genes, Viral; D015796:HLA-B27 Antigen / Q000737:chemistry* / Q000502:physiology*; D006801:Humans; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000737:chemistry*
D000941:Antigens; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D019309:Epstein-Barr Virus Nuclear Antigens; D015796:HLA-B27 Antigen; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D014763:Viral Matrix Proteins