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Neutrophil-mediated mechanisms of drug-induced autoimmunity

Thursday, September 17, 2015 — Poster Session III

3:30 p.m. – 5:00 p.m.
FAES Terrace
NIAMS
IMMUNO-14

Authors

  • JA Irizarry-Caro
  • C Carmona-Rivera
  • E Novakovich
  • V Subramanian
  • P Thompson
  • MJ Kaplan
  • PC Grayson

Abstract

Certain medications are known to induce autoimmune disease in humans, triggering clinical features and autoantibody profiles that mirror idiopathic systemic lupus erythematosus (SLE) and ANCA-associated vasculitis (AAV). Neutrophil extracellular traps (NETs) have been implicated in both SLE and AAV and they contain the antigenic targets of autoantibodies typically identified in cases of drug-induced autoimmunity. This study explored whether medications commonly implicated in cases of drug-induced autoimmunity (hydralazine and procainamide) and medications less commonly implicated in drug-induced autoimmunity (minocycline and clozapine) induce NET formation. Human and murine neutrophils (PMNs) were incubated with the medications of interest for one and four hours, respectively, to address NET formation. To address the canonical pathway of NET formation-which involves generation of reactive oxygen species (ROS) and chromatin decondensation via histone citrullination by peptidyl arginine deiminase 4 (PAD4)-PMNs exposed to the medications were incubated with DPI (NADPH inhibitor), BB-Cl-amidine (PAD4 inhibitor) and muscarinic receptors antagonists. Release of hydrogen peroxide was measured by Amplex-Red H2O2 Assay Kit. Stimulation of a panel of toll-like receptors (TLRs) was assessed using a human ligand TLR screening platform. Hydralazine and procainamide, but not minocycline and clozapine, induced NETs in human and murine PMNs. Hydralazine, but not procainamide, induced significant release of hydrogen peroxide in PMNs, and NET formation was inhibited by DPI and BB-Cl-amidine. Induction of NETs by procainamide was inhibited by M1/M3 muscarinic receptors antagonists. Certain medications implicated in drug-induced autoimmunity trigger formation of NETs via different pathways. NETs likely play a causal role in drug-induced autoimmunity.

Category: Immunology