ISONIAZID - MAIN ANTI-TUBERCULOUS DRUGALTERS NEUTROPHIL EXTRACELLULAR TRAPS STRUCTURE AND TURNOVER

LUIS CASTILLO,; LANDONI VERÓNICA INÈS; NAHUEL RODRIGUEZ-RODRIGUES; JOSE LUIS MARIN; GARCIA MARINA; BALBOA, LUCIANA; SASIAIN, MARÍA DEL CARMEN; SCHIERLOH LP;

Congreso; Reinion de Biociencias; 2017

Abstract: Drug induced lupus-like reactions are characterized by the presence of anti-nuclear antibodies (ANA) without hypersensitivity to the drug itself. One of such drugs is the isoniazid (INH), an effective antimicrobial worldwide used to treat tuberculosis (TB). INH is a prodrug that needs to be activated by the mycobacterial peroxidase/catalase KatG (Rv1908c) to give the INH? toxic radical. Considering that Neutrophil Extracellular Traps (NETs) formation requires enzymatically active myeloperoxidase (MPO), we asked if the extensive neutrophil (PMN) activation typically observed during active TB may lead to undesirable autoimmune reactions when it is combined with an INH-based therapy. When primary granules -containing MPO- isolated from normal human blood PMN were incubated with INH or rifampicin -another anti-TB compound-, we found that only the first drug was a good substrate for human MPO at therapeutic serum concentrations (Km=30±5µM; Cmax=40±15µM) giving an active product with oxidant properties (p≤ 0.05) Moreover, in the presence of INH, in vitro induced NETs adopted a differential conformation with several unique features including reduced DNAse 1 sensitivity and diminished phagocytic removal by autologous macrophages(p≤ 0.05) As a clinical correlate, we observe that prevalence of ANA/ANCA+ sera were higher in a subset of TB patients under prolonged INH-combined chemotherapydespite lack of lupus related symptoms. Therefore, our results suggest a possible mechanism for a drug-induced autoimmune reaction in which MPO-oxidized INH alters somehow the NET structure and its later processing, leading to pathogenic accumulation of complexed self-antigens (i.e: DNA+ Core Histones+ primary granules enzymes).