title: Peptides presented by HLA-DR molecules in synovia of patients with rheumatoid arthritis or antibiotic-refractory Lyme arthritis.
abstract: Disease-associated HLA-DR molecules, which may present autoantigens, constitute the greatest genetic risk factor for rheumatoid arthritis (RA) and antibiotic-refractory Lyme arthritis (LA). The peptides presented by HLA-DR molecules in synovia have not previously been defined. Using tandem mass spectrometry, rigorous database searches, and manual spectral interpretation, we identified 1,427 HLA-DR-presented peptides (220-464 per patient) from the synovia of four patients, two diagnosed with RA and two diagnosed with LA. The peptides were derived from 166 source proteins, including a wide range of intracellular and plasma proteins. A few epitopes were found only in RA or LA patients. However, two patients with different diseases who had the same HLA allele had the largest number of epitopes in common. In one RA patient, peptides were identified as originating from source proteins that have been reported to undergo citrullination under other circumstances, yet neither this post-translational modification nor anti-cyclic citrullinated peptide antibodies were detected. Instead, peptides with the post-translational modification of S-cysteinylation were identified. We conclude that a wide range of proteins enter the HLA-DR pathway of antigen-presenting cells in the patients' synovial tissue, and their HLA-DR genotype, not the disease type, appears to be the primary determinant of their HLA-DR-peptide repertoire. New insights into the naturally presented HLA-DR epitope repertoire in target tissues may allow the identification of pathogenic T cell epitopes, and this could lead to innovative therapeutic interventions.
authors.affiliation: Center for Biomedical Mass Spectrometry, Department of Biochemistry, Boston University School of Medicine, and Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, Massachusetts 02118, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Seward
authors.forename: Elise E
authors.initials: EE
authors.lastname: Drouin
authors.forename: Allen C
authors.initials: AC
authors.lastname: Steere
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Costello
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017951:Antigen Presentation / Q000187:drug effects / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000473:pathology; D002648:Child; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D005260:Female; D006684:HLA-DR Antigens / Q000276:immunology*; D006801:Humans; D008193:Lyme Disease / Q000188:drug therapy / Q000276:immunology*; D008297:Male; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000276:immunology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D013582:Synovial Fluid / Q000187:drug effects / Q000276:immunology*; D053719:Tandem Mass Spectrometry
chemical_list: D000900:Anti-Bacterial Agents; D000939:Epitopes; D006684:HLA-DR Antigens; D010455:Peptides