Diversity and plasticity of the anti-DNA topoisomerase I autoantibody response in scleroderma

Objective. To examine domain recognition by anti-DNA topoisomerase I (anti- DNA topo I, or anti-topo I) antibodies over time in scleroderma patients. Methods. Serial serum samples from scleroderma patients with known reactivi ty to Scl-70, a 70-kd topo I breakdown product, were tested by immunoblot f or IgM, IgG, IgA, kappa, and lambda reactivity to Scl-70 and 8 overlapping recombinant peptide fragments (F1-F8) that span the human topo I molecule. Results, IgM, IgG, kappa, and lambda anti-topo I antibodies in both early-d isease and late-disease serum samples preferentially recognized the Scl-70 molecule rather than the F1-F8 peptides, suggesting preferential recognitio n of conformational determinants on Scl-70 throughout the disease course. A mounts of both primary and secondary anti-topo I antibodies to Scl-70 varie d over time, including increases in primary antibody responses late in the disease course. Striking variability in recognition of the F1-F8 peptides b y IgM, IgG, IgA, kappa, and lambda anti-topo I antibodies was seen in seria l samples. Most often, the change in FI-FS recognition from one sample to t he next was unpredictable, although occasionally patterns of antibody recog nition were reciprocal in serial samples. Of note, in several patients, wha t could have been interpreted as domain spreading among F1-F8 in 2 successi ve samples was just a part of changing antibody reactivity to these peptide s that again became more restricted in a third sample. Conclusion. Titers and immunodominant domains recognized by both primary an d secondary anti-topo I antibodies are highly variable over time. This sugg ests continual antigen presentation and regulation of the anti-topo I antib ody response in scleroderma, even late in the disease course.