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

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 t...

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Bibliographic Details
Published in:Rheumatology (Oxford, England) Vol. 56; no. 4; p. 638
Main Authors: Lood, Christian, Hughes, Grant C
Format: Journal Article
Language:English
Published: England 01.04.2017
Subjects:
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
drug-induced rheumatic disease
vasculitis
autoantibodies
neutrophils
autoantigens
anti-neutrophil cytoplasm antibody
ISSN:1462-0332, 1462-0332
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Summary: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. 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. 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. 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.
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ISSN:1462-0332
1462-0332
DOI:10.1093/rheumatology/kew256