Therapeutic doses of isoniazid (INH) interfere with NETosis by targeting Myeloperoxidase. A possible mechanism for INH-induced autoimmune reactions.

SCHIERLOH P; CASTILLO L; RODRIGUEZ-RODRIGUES N; GARCÍA M; FERNANDEZ G; LANDONI V

Buenos Aires

Congreso; ICID2018; 2018

International Clinical Infectiuous Deseases society

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). Beside, recent study has reported increased prevalence of anti-cytoplasmic Neutrophil antibodies (ANCA) in TB patients soon after INH-combined anti-TB therapy. 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 we found that it acted as a good substrate for human MPO at therapeutic concentrations (Km=30±5µM; Cmax=40±15µM) giving an active product with oxidant properties (p