title: T cell lines from systemic sclerosis patients and healthy controls recognize multiple epitopes on DNA topoisomerase I.
abstract: Anti-DNA topoisomerase I (topo-I) antibodies are exclusively detected in patients with systemic sclerosis (SSc). Participation of this topo-I-specific autoimmune response in the pathogenesis of SSc has been actively investigated, but remains unproven. Here we characterized the peripheral T cell proliferative response to recombinant topo-I (rtopo-I) in 16 SSc patients with circulating anti-topo-I antibody. A low level (cpm < 2000) T cell proliferation (SI > 3) was detected in 6 (38%) of 16 patients. This low level response was similar to those previously observed in healthy controls. We established 56 topo-I-specific T cell lines recognizing 13 distinct T cell epitopes on topo-I from 4 SSc patients and 2 healthy controls. These T cell lines were established from in vitro activated PBMC (CD25(+)) by rtopo-I antigen. However they did not have the phenotype of regulatory T cells. Notably, 40 (71%) of the 56 T cell lines recognizing a common epitope were established from one patient. DNA sequencing of the T cell receptor cDNA produced an identical sequence indicating these T cells were from a single topo-I-specific T cell precursor. These results suggest that topo-I-specific T cells can become clonally expanded in some patients and may contribute to the pathogenesis of this disease.
authors.affiliation: Division of Rheumatology & Clinical Immunology, Department of Medicine, University of Pittsburgh School of Medicine, PA, USA. hu1@ncifcrf.gov
authors.forename: Paul Q
authors.initials: PQ
authors.lastname: Hu
authors.forename: Joost J
authors.initials: JJ
authors.lastname: Oppenheim
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Medsger
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Wright
mesh_terms: D000595:Amino Acid Sequence; D001323:Autoantibodies / Q000097:blood; D004264:DNA Topoisomerases, Type I / Q000276:immunology*; D018604:Epitope Mapping / Q000379:methods; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D012595:Scleroderma, Systemic / Q000097:blood / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D018984:Epitopes, T-Lymphocyte; D004264:DNA Topoisomerases, Type I