Mapping of topoisomerase II alpha epitopes recognized by autoantibodies inidiopathic pulmonary fibrosis

Autoantibodies against DNA topoisomerase II alpha have been identified in t he sera of patients with idiopathic pulmonary fibrosis (IPF). To map topois omerase II autoepitopes, we tested by ELISA and immunoblotting the IPF anti -topoisomerase II-positive sera against a series of recombinant proteins wh ich covered the full length of topoisomerase II alpha. Specific patterns of reactivity were observed, indicating the existence of multiple epitopes on topoisomerase II, either highly complex or conformational/discontiguous or conformational/contiguous ones. The latter resided in amino acid residues 854-1147 and 1370-1447. A detailed analysis of these regions was undertaken , but we were not able to pinpoint a sequential peptide-sized epitope, or a ny significant homology with foreign pathogens. Further, we observed a sign ificant correlation between the progression from a contiguous to a quaterna ry/tertiary structure-dependent autoepitope and the disease duration but no t with the disease severity. Therefore, this result supports the hypothesis that anti-topoisomerase II autoreactivity evolves following an antigen-dri ven process.