title: Autoreactive T cells to topoisomerase I in monozygotic twins discordant for systemic sclerosis.
abstract: OBJECTIVE
  To examine T and B cell responses to topoisomerase I (topo I) in a monozygotic twin pair discordant for systemic sclerosis (SSc).
  
  
  METHODS
  The peripheral blood T cell proliferative responses induced by topo I and in vitro anti-topo I antibody production in cultures of T and B cells were examined in an SSc patient with serum anti-topo I antibody and in her healthy monozygotic twin. Topo I-reactive T cell lines were generated from the twin pair and analyzed for antigenic specificity, major histocompatibility complex class II restriction, and T cell receptor (TCR) gene usage.
  
  
  RESULTS
  T cell proliferative responses to topo I were detected in both the SSc patient and her healthy twin, although the kinetics of the T cell response were accelerated in the patient compared with the healthy twin. The estimated frequency of circulating topo I-reactive T cells was 1/6,700 in the SSc patient and 1/39,000 in the healthy twin. Anti-topo I antibody production was observed in cultures of T and B cells from the SSc patient, but not in those from the healthy twin. When the cells from the twins were mixed in different combinations, T cells from the healthy twin did stimulate the SSc patient's B cells to produce anti-topo I antibody through a CD40-dependent mechanism. Topo I-reactive T cell lines generated from the twins had similar characteristics, including a CD4+ phenotype, restriction by HLA-DR, recognition of epitopes within amino acid residues 209-386 of topo I, and dominant usage of the TCR Vbeta20 gene segment.
  
  
  CONCLUSIONS
  These results indicate that topo I-reactive T cells were activated and clonally expanded in the SSc patient. However, there were no substantial differences in either phenotypic or functional properties of topo I-reactive T cells obtained from the SSc patient and those obtained from her healthy identical twin. It is likely, therefore, that the anti-topo I antibody response in the SSc patient is induced by in vivo activation of topo I-reactive T cells derived from the normal T cell repertoire.
authors.affiliation: University of Pittsburgh School of Medicine, Pennsylvania 15261, USA.
authors.forename: M
authors.initials: M
authors.lastname: Kuwana
authors.forename: C A
authors.initials: CA
authors.lastname: Feghali
authors.forename: T A
authors.initials: TA
authors.lastname: Medsger
authors.forename: T M
authors.initials: TM
authors.lastname: Wright
mesh_terms: D000368:Aged; D001323:Autoantibodies / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D016172:DNA Fingerprinting; D004264:DNA Topoisomerases, Type I / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D005260:Female; D006683:HLA-DQ Antigens / Q000276:immunology; D006684:HLA-DR Antigens / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory; D007700:Kinetics; D010641:Phenotype; D012595:Scleroderma, Systemic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000201:enzymology*; D014430:Twins, Monozygotic
chemical_list: D001323:Autoantibodies; D006683:HLA-DQ Antigens; D006684:HLA-DR Antigens; D004264:DNA Topoisomerases, Type I