Longitudinal analysis of autoantibody response to topoisomerase I in systemic sclerosis

Objective. To examine serial changes in serum anti-topoisomerase I (anti-to po I) antibody levels in patients with systemic sclerosis (SSc), as well as associations with clinical features and the in vivo activation status of c irculating topo I-reactive T and B cells. Methods. Serum anti-topo I antibody levels were serially measured at differ ent time points in 28 SSc patients who were positive for anti-topo I antibo dy at their first visit (range of followup 6-29 years). The patients were s ubgrouped according to the disappearance (group 1) or persistence (group 2) of anti-topo I antibody. Clinical findings as well as T and B cell respons es to topo I were compared between these 2 groups. Results. Serum anti-topo I antibody disappeared during the period of follow up in 6 patients (group 1), but persisted in 22 patients (group 2), Loss of anti-topo I antibody occurred within 10 years after the first visit and in dependently of treatment. Group 1 patients had less extensive skin and lung involvement and better survival rates than did group 2 patients. Complete loss of anti-topo I antibody followed a reduction in isotype expression and epitope reactivities. The kinetics of in vitro T cell proliferation induce d by topo I were delayed and circulating topo I-reactive T cells were less frequently detected in group 1 versus group 2 patients, suggesting that the disappearance of anti-topo I antibody was due to loss of activation of top o I-reactive T cells. In vitro production of anti-topo I antibody in periph eral blood mononuclear cell cultures in response to antigenic stimulation i n both group 1 and group 2 patients indicated persistence of anti-topo I an tibody-producing "memory" B cells even after the loss of serum anti-topo I antibody. Conclusion. Our results indicate that there is a distinct subset of anti-to po I-positive SSc patients who lose anti-topo I antibody during the disease course and have a favorable outcome. In vivo production of anti-topo I aut oantibody may require antigenic stimulation that activates topo I-reactive T and B cells.