Certain medications associated with drug-induced autoimmunity were previously shown to trigger NET formation and to impair NET degradation. The thyroid medication propylthiouracil, linked to drug-induced AAV, can induce NET formation and impair NET degradation.2 Also, cocaine that has been contaminated with levamisole, an antihelmintic drug, can induce NETs, doing so through cholinergic receptors, Dr. Grayson says.3
For this study, researchers examined the effect of four medications causally linked to drug-induced autoimmunity—procainamide, hydralazine, minocycline and clozapine—on NET formation, NET degradation and NET protein content. The rationale of the research was to demonstrate that some drugs linked with drug-induced autoimmunity enhance NET formation. These findings could then potentially provide evidence that neutrophils and NETs “are involved in the pathogenesis of specific drug-induced and idiopathic autoimmune diseases,” according to the published report.
In the study, neutrophils were first isolated from heparinized blood, and then the neutrophils were treated with the four drugs. After four hours of stimulation, procainamide and hydralazine induced significant NET formation, whereas the NET formation induced by clozapine and minocycline was not significant.
“This provides some indirect evidence that neutrophils are implicated in drug-induced autoimmunity and that the drugs may trigger NETs as a potential inciting event in why these patients develop autoantibodies,” Dr. Grayson says. “One of the hallmarks of drug-induced autoimmunity is that these patients usually develop multiple different antibodies, so the same patient can make an antibody seen in lupus and ANCA vasculitis at the same time.”
The research also provides new information about the signaling pathways by which the drugs trigger NETs. According to Dr. Grayson, hydralazine triggers NETs by altering intracellular calcium levels in neutrophils. Procainamide, which is no longer used in clinical practice, triggers NETs by binding to cholinergic receptors on the surface of neutrophils. “That suggests that there is crosstalk between neutrophils, or innate immune cells, and the autonomic nervous system transmitters.”
The results indicate the class of drugs that could potentially triggers NETs. “We would predict that drugs that basically bind and modulate cholinergic receptors would be more likely to trigger NETs, and similarly, drugs that modulate intracellular calcium levels could also potentially trigger NETs,” Dr. Grayson says. The onset of autoimmunity by a hydralazine or similar drug will not necessarily occur when the patient first starts taking it. In fact, it can happen months or years later, he says.
Drug-Induced Autoimmunity: A Disease Model
Drug-induced autoimmunity is providing an “excellent disease model to further understand idiopathic disease,” according to an editorial published with the research report.4 “Additional exploration and characterization of drug-induced NETosis and the autoantigen ‘cargo’ carried within released NETs will help us better understand autoimmune mechanisms,” Amr H. Sawalha, MD, at the University of Michigan, Ann Arbor, wrote in his editorial.
