title: Novel HLA-B27-restricted epitopes from Chlamydia trachomatis generated upon endogenous processing of bacterial proteins suggest a role of molecular mimicry in reactive arthritis.
abstract: Reactive arthritis (ReA) is an HLA-B27-associated spondyloarthropathy that is triggered by diverse bacteria, including Chlamydia trachomatis, a frequent intracellular parasite. HLA-B27-restricted T-cell responses are elicited against this bacterium in ReA patients, but their pathogenetic significance, autoimmune potential, and relevant epitopes are unknown. High resolution and sensitivity mass spectrometry was used to identify HLA-B27 ligands endogenously processed and presented by HLA-B27 from three chlamydial proteins for which T-cell epitopes were predicted. Fusion protein constructs of ClpC, Na(+)-translocating NADH-quinone reductase subunit A, and DNA primase were expressed in HLA-B27(+) cells, and their HLA-B27-bound peptidomes were searched for endogenous bacterial ligands. A non-predicted peptide, distinct from the predicted T-cell epitope, was identified from ClpC. A peptide recognized by T-cells in vitro, NQRA(330-338), was detected from the reductase subunit. This is the second HLA-B27-restricted T-cell epitope from C. trachomatis with relevance in ReA demonstrated to be processed and presented in live cells. A novel peptide from the DNA primase, DNAP(211-223), was also found. This was a larger variant of a known epitope and was highly homologous to a self-derived natural ligand of HLA-B27. All three bacterial peptides showed high homology with human sequences containing the binding motif of HLA-B27. Molecular dynamics simulations further showed a striking conformational similarity between DNAP(211-223) and its homologous and much more flexible human-derived HLA-B27 ligand. The results suggest that molecular mimicry between HLA-B27-restricted bacterial and self-derived epitopes is frequent and may play a role in ReA.
authors.affiliation: From the Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas and Universidad Autónoma, Madrid, Spain and.
authors.forename: Carlos
authors.initials: C
authors.lastname: Alvarez-Navarro
authors.affiliation: From the Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas and Universidad Autónoma, Madrid, Spain and.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Cragnolini
authors.affiliation: From the Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas and Universidad Autónoma, Madrid, Spain and.
authors.forename: Helena G
authors.initials: HG
authors.lastname: Dos Santos
authors.affiliation: the Faculty of Biology, Technion-Israel Institute of Technology, Haifa 32000, Israel.
authors.forename: Eilon
authors.initials: E
authors.lastname: Barnea
authors.affiliation: the Faculty of Biology, Technion-Israel Institute of Technology, Haifa 32000, Israel.
authors.forename: Arie
authors.initials: A
authors.lastname: Admon
authors.affiliation: From the Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas and Universidad Autónoma, Madrid, Spain and.
authors.forename: Antonio
authors.initials: A
authors.lastname: Morreale
authors.affiliation: From the Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas and Universidad Autónoma, Madrid, Spain and. Electronic address: aldecastro@cbm.uam.es.
authors.forename: José A
authors.initials: JA
authors.lastname: López de Castro
mesh_terms: D016918:Arthritis, Reactive / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D002692:Chlamydia trachomatis / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D015796:HLA-B27 Antigen / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D006801:Humans; D018716:Molecular Mimicry / Q000235:genetics / Q000276:immunology*; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D000091402:Prohibitins
chemical_list: D001426:Bacterial Proteins; D018984:Epitopes, T-Lymphocyte; D015796:HLA-B27 Antigen; C000717331:PHB2 protein, human; D010455:Peptides; D000091402:Prohibitins
keywords: Antigen Presentation; Antigen Processing; Arthritis; Autoimmunity; Chlamydia; Major Histocompatibility Complex (MHC); Molecular Dynamics; Pathogenesis