title: Nucleotide sequencing of psoriatic arthritis tissue before and during methotrexate administration reveals a complex inflammatory T cell infiltrate with very few clones exhibiting features that suggest they drive the inflammatory process by recognizing autoantigens.
abstract: Psoriatic arthritis is an interesting MHC class I allele associated autoimmune disease where injury is likely mediated exclusively by T cells. We used TCR beta-chain nucleotide sequencing to gain insight into the adaptive immune events responsible for this injury and determine whether the numerous oligoclonal expansions of this disease represent extreme determinant spreading among driving clones that recognize autoantigen or were non-Ag-driven, inflammation-related expansions. Because methotrexate suppresses but does not eliminate this inflammation, we hypothesized that clones persisting during methotrexate treatment would likely drive the inflammation. Seventy-six percent of the T cell clones in active tissue were polyclonal and unexpanded, accounting for 31% of transcripts. They were decreased greatly by methotrexate. Strikingly, most expanded clones in the inflamed joint did not persist during methotrexate treatment, were found only in inflammatory sites, exhibited no structural homology to one another, and were either CD4 or CD8 in lineage, suggesting they were non-autoantigen-driven, inflammation-related expansions. Only 12% of the expanded clones could be grouped into clonal sets distinguished by structurally homologous CDR3 beta-chain amino acid motifs suggesting Ag drive. These were exclusively CD8 in lineage, persisted during methotrexate administration, and were present in both joint fluid and blood implying they were candidate driver clones that recognized an autoantigen. However, a major set of putative driver clones exhibited a previously described EBV-specific beta-chain motif, emphasizing that the dominant feature of the disease was activation of multiple clones apparently lacking specificity for an inciting autoantigen.
authors.affiliation: Division of Autoimmune and Molecular Disease, Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Shane A
authors.initials: SA
authors.lastname: Curran
authors.forename: Oliver M
authors.initials: OM
authors.lastname: FitzGerald
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Costello
authors.forename: Jeanette M
authors.initials: JM
authors.lastname: Selby
authors.forename: David J
authors.initials: DJ
authors.lastname: Kane
authors.forename: Barry
authors.initials: B
authors.lastname: Bresnihan
authors.forename: Robert
authors.initials: R
authors.lastname: Winchester
mesh_terms: D000595:Amino Acid Sequence; D015535:Arthritis, Psoriatic / Q000097:blood / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology*; D001324:Autoantigens / Q000276:immunology* / Q000378:metabolism; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects*; D002999:Clone Cells; D022801:Complementarity Determining Regions / Q000032:analysis / Q000235:genetics; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D008727:Methotrexate / Q000008:administration & dosage*; D008969:Molecular Sequence Data; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D017422:Sequence Analysis, DNA / Q000379:methods*; D013582:Synovial Fluid / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000473:pathology*
chemical_list: D001324:Autoantigens; D022801:Complementarity Determining Regions; D016693:Receptors, Antigen, T-Cell, alpha-beta; D008727:Methotrexate