Accumulation of plasma nucleosomes upon treatment with anti-tumour necrosis factor-α antibodies

Objective. Patients undergoing anti-tumour necrosis factor-alpha (TNF-alpha) treatment often develop autoantibodies. Apoptotic cell antigens are a potential initiating stimulus for autoantibodies. Our goal was to verify whether anti-cytokine therapy causes the release of nucleosomes, a major autoantigen generated during cell death. Design. Laboratory research study with comparison group. Setting. Clinical Immunology Unit and Lab, H San Raffaele University Hospital, Italy. Subjects. Eleven healthy controls and 87 rheumatic patients were studied, including 51 with rheumatoid arthritis (RA) and 33 patients with systemic lupus erythematosus (SLE). Interventions. Vein blood samples were taken via the antecubital vein. Blood was retrieved from 11 patients before and after injection of anti-TNF-alpha humanized antibodies. Nucleosomes were measured with an enzyme-linked immunosorbent assay. Cell death induced by anti-TNF-alpha antibodies and by the soluble cytokine was assessed in vitro. Main outcome measures. Nucleosome level by treatment. Results. Enzyme-linked immunosorbent assay effectively detected nucleosomes either released by dying cells in vitro or circulating in the plasma. SLE but not RA patients had circulating nucleosomes at the steady state. Eight of 11 patients had significantly higher levels of plasma nucleosomes after infliximab. Minute amounts of TNF-alpha enabled infliximab to induce cell death in vitro. Conclusions. The accumulation of nucleosomes possibly fosters the development of autoantibodies in subjects with appropriate genetic backgrounds.