Molecular mimicry of an HLA-B27-derived ligand of arthritis-linked subtypes with chlamydial proteins.
HLA-B27 is strongly associated with spondyloarthropathies, including ankylosing spondylitis and reactive arthritis. The latter disease is triggered by various Gram-negative bacteria. A dodecamer derived from the intracytoplasmic tail of HLA-B27 was a natural ligand of three disease-associated subtypes (B*2702, B*2704, and B*2705) but not of two (B*2706 and B*2709), weakly or not associated to spondyloarthropathy. This peptide was strikingly homologous to protein sequences from arthritogenic bacteria, particularly to a region of the DNA primase from Chlamydia trachomatis. A synthetic peptide with this bacterial sequence bound in vitro disease-associated subtypes equally as the natural B27-derived ligand. The chlamydial peptide was generated by the 20 S proteasome from a synthetic 28-mer with the sequence of the corresponding region of the bacterial DNA primase. Molecular modeling suggested that the B27-derived and chlamydial peptides adopt very similar conformations in complex with B*2705. The results demonstrate that an HLA-B27-derived peptide mimicking arthritogenic bacterial sequences is a natural ligand of disease-associated HLA-B27 subtypes and suggest that the homologous chlamydial peptide might be presented by HLA-B27 on Chlamydia-infected cells.
Centro de Biologia Molecular Severo Ochoa (C.S.I.C.-U.A.M.), Universidad Autónoma de Madrid, Facultad de Ciencias, 28049 Madrid, Spain.
Manuel
M
Ramos
Iñaki
I
Alvarez
Laura
L
Sesma
Antoine
A
Logean
Didier
D
Rognan
José A
JA
López de Castro
D000595:Amino Acid Sequence; D000818:Animals; D001168:Arthritis / Q000276:immunology; D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics; D002689:Chlamydia / Q000235:genetics*; D000939:Epitopes / Q000276:immunology*; D015235:HLA-B Antigens / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D018716:Molecular Mimicry / Q000235:genetics*; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry; D011487:Protein Conformation; D017433:Protein Structure, Secondary
D001426:Bacterial Proteins; D000939:Epitopes; D015235:HLA-B Antigens; C103707:HLA-B57 antigen; D008024:Ligands; D010446:Peptide Fragments