Neutrophil extracellular traps as a potential source of autoantigen in
cocaine-associated autoimmunity
#MMPMID27354687
Lood C
; Hughes GC
Rheumatology (Oxford)
2017[Apr]; 56
(4
): 638-643
PMID27354687
show ga
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.
free
free
free
