Allele-dependent Similarity between Viral and Self-peptide Presentation by HLA-B27 Subtypes

Abstract

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 subtypedependent, 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.

A Structural Basis for Antigen Presentation by the MHC Class Ib Molecule, Qa-1b

“…There are a number of crystal structures of different MHC molecules binding the one peptide (2,60,61). Typically, these involve highly related allotypes that exhibit limited sequence differences, which nevertheless often result in biologically significant changes in conformation of the peptide and/or the MHC-I molecule (2,(61)(62)(63).…”

Additional human β2‐microglobulin curbs HLA–B27 misfolding and promotes arthritis and spondylitis without colitis in male HLA–B27–transgenic rats

“…Although some evidence exists for disease-related, B27-specific T cell adaptive immunity (14)(15)(16)(17), other mechanisms have been proposed in recent years, on the basis of the unusual features of B27-specific biologic processes. Part of the impetus for these hypotheses has come from the observation that inflammatory disease in the B27-transgenic rats occurs in only the lines with a relatively high transgene copy number and increased expression level of B27 (10,18).…”

HLA‐B27: portraying immunodominant viral epitopes

“…Second, a better basis is provided to address the molecular mimicry between self and foreign HLA-B27 ligands, an issue that might be of outstanding relevance in the pathogenesis of spondyloarthropathies [4]. An elegant example of how X-ray crystallography may explain molecular mimicry involving HLA-B27 was recently reported [23]. Third, that a viral epitope fails to interact with KIR3DL1 suggests that microbial peptides presented by HLA-B27 may have a proinflammatory effect, through increased NK activation.…”

“…One peptide showed a dual, canonical and non-canonical, conformation [18]. The other one adopted only the non-canonical binding mode [23]. Both peptides bound canonically to B*2709, which has a D116H change.…”