Increased levels of immature and activated low-density granulocytes and altered degradation of circulating neutrophil extracellular traps (NETs) may contribute to the pathogenesis of granulomatosis with polyangiitis (GPA), a type of antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV), according to an article published in the journal PLOS One.
Researchers collected blood samples from 12 patients with GPA, 21 patients with systemic lupus erythematosus, and 21 healthy controls. They performed flow cytometry, investigated the NET production of peripheral blood neutrophils via NETosis assay, and used the ELISA test to quantify the amount of circulating NETs in peripheral blood. Furthermore, they performed a DNase 1 assay to investigate the participant’s sera NET-degrading capacity and statistically analyzed all the data.
According to the results, patients with GPA had increased levels of low-density granulocytes compared with healthy controls, which displayed an activated and more immature phenotype.
The propensity of normal-density granulocytes to release NETs and the levels of circulating NETs were similar in patients with GPA and healthy controls. However, the sera from patients with GPA was less effective in degrading NETs than the sera of healthy participants, which slightly correlated with disease activity markers.
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“Although GPA patient serum was deficient in NET degradation, NET levels were not elevated in GPA plasma. This could indicate that other pathways of NET degradation were activated that contribute to immunopathology, e.g. NET clearance by macrophages,” Lipka and colleagues noted. “In addition, this discrepancy may be explained by the accumulation of NETs in inflamed tissue lesions in the kidney or even the lungs of patients. Further research is required to confirm these notions.”
In relation to their findings, the authors also suggest a new treatment approach: “Inhibition or degradation of NETs could resemble an interesting novel treatment target in AAV. For example, enhanced NETosis may be disrupted therapeutically with the administration of DNase 1, which has been shown to be safe and tolerable in systemic lupus erythematosus patients and discussed as a potential treatment in AAV. Other potential agents include the NE inhibitors Alvelestat and BAY 85–8501, as recently discussed as a therapeutic option in myeloperoxidase AAV.”
Recent studies have implicated low-density granulocytes in the pathogenesis of GPA, as they are more likely than neutrophils from healthy blood donors to spontaneously release NETs. NETosis, a regulated necrotic death, is characterized by the leakage of chromatin into the extracellular space.
Lipka S, Ostendorf L, Schneider U, Hiepe F, Apel F, Alexander T. Increased levels of immature and activated low density granulocytes and altered degradation of neutrophil extracellular traps in granulomatosis with polyangiitis. PLoS One. Published online March 15, 2023. doi:10.1371/journal.pone.0282919