Neutrophil extracellular traps as a potential source of autoantigen in cocaine-associated autoimmunity

Rheumatology (Oxford). 2017 Apr 1;56(4):638-643. doi: 10.1093/rheumatology/kew256.


Objective: Exposure to illicit cocaine and its frequent adulterant, levamisole, is associated with ANCAs targeting neutrophil elastase (NE), neutropenia and vasculitic/thrombotic skin purpura. The mechanisms of cocaine/levamisole-associated autoimmunity (CLAA) are unknown. The aim of this study was to assess the ability of cocaine and levamisole to induce the release of neutrophil extracellular traps (NETs), a potential source of autoantigen and tissue injury.

Methods: We performed quantitative and qualitative assessment of NET formation in neutrophils from healthy donors exposed to either drug in vitro . In addition, IgG from sera of individuals with CLAA (CLAA-IgG) was assessed for its ability to enhance formation of, and to bind to, drug-induced NETs.

Results: Both cocaine and levamisole could induce formation of NETs enriched in NE and, potentially, inflammatory mitochondrial DNA. Both drugs could also augment simultaneous release of B cell-activating factor belonging to the TNF family (BAFF). CLAA-IgG, but not IgG from healthy individuals, could potentiate drug-induced NETosis. Furthermore, CLAA-IgG, but not ANCA + control IgG, bound to drug-induced NETs in a pattern consistent with NE targeting.

Conclusion: Both cocaine and levamisole may contribute to the development of ANCAs by inducing release of potentially inflammatory NETs in association with NE autoantigen and BAFF. Enhancement of drug-induced NET release by CLAA-IgG provides a potential mechanism linking vasculitis/pupuric skin disease to acute drug exposure in patients with CLAA. Further study of this under-recognized form of autoimmunity will be likely to provide mechanistic insight into ANCA-associated vasculitis and other diseases associated with NETosis.

Keywords: anti-neutrophil cytoplasm antibody; autoantibodies; autoantigens; drug-induced rheumatic disease; neutrophils; vasculitis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / chemically induced
  • Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / immunology
  • Autoantigens / drug effects
  • Autoantigens / immunology
  • Autoimmunity / drug effects*
  • Autoimmunity / immunology
  • Case-Control Studies
  • Cocaine / adverse effects
  • Cocaine / immunology*
  • Cocaine-Related Disorders / immunology
  • Dopamine Uptake Inhibitors / adverse effects
  • Dopamine Uptake Inhibitors / immunology*
  • Enzyme-Linked Immunosorbent Assay
  • Extracellular Traps / drug effects*
  • Extracellular Traps / immunology
  • Extracellular Traps / metabolism
  • Humans
  • Immunoglobulin G / metabolism
  • Levamisole / adverse effects
  • Levamisole / immunology*
  • Neutrophils / drug effects
  • Neutrophils / immunology
  • Neutrophils / metabolism


  • Autoantigens
  • Dopamine Uptake Inhibitors
  • Immunoglobulin G
  • Levamisole
  • Cocaine