The Involvement of Neutrophil Extracellular Traps in Disease Activity Associated With IgA Vasculitis

Abstract

ObjectivesThis aim of this study was to determine whether neutrophil extracellular traps (NETs) are involved in the pathogenesis of IgA vasculitis (IgAV) and investigate whether the circulating NETs levels are associated with disease activity in children.MethodsWe performed a case-control study and collected blood samples from 193 children with different stages of IgAV (61 were at the onset stage, 64 at the remission stage, 43 at the active stage, and 25 were undergoing drug withdrawal). A total of 192 healthy children were recruited as controls. Circulating cell free DNA (cf-DNA) was obtained from the plasma and quantified by using the Quant-iT PicoGreen DNA quantification kit. NETs-associated myeloperoxidase-DNA (MPO-DNA), citrullinated-histone H3 (cit-H3), neutrophil elastase (NE), and the deoxyribonuclease I (DNase I) concentrations were measured using enzyme-linked immunosorbent assays. The presence of NETs in the kidney and gastrointestinal tissues of onset and active IgAV patients was determined by multiple immunofluorescence staining in 15 IgAV nephritis patients and 9 IgAV patients without IgAV nephritis, respectively. NETs degradation potency of collected sera samples from IgAV patients were checked in vitro. Relationships between circulating levels of cf-DNA with MPO-DNA, NE, and DNase I and the patients were analyzed.ResultsCirculating levels of cf-DNA in onset and active IgAV patients were significantly higher than those in remission and drug withdrawal patients as well as healthy controls. The results were similar for MPO-DNA and NE. The levels of circulating cf-DNA correlated significantly with MPO-DNA, NE and DNase I. A significantly decreased degradation of NETs from the onset and active IgAV patients was observed, but was normal in healthy controls. Furthermore, presence of NETs was also confirmed in all renal and gastrointestinal tissues obtained from the onset and active IgAV patients but not control samples.ConclusionsOur data showed that NETs were released into the circulation of IgAV patients and are involved in the disease activity. The circulating levels of NETs maybe used to assess disease severity in children with IgAV.

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“…The ECG loading rate was determined from the ratio of the initial DNA content of the constructs and that 24 h after combination with ECG. The DNA content of the samples ( n = 5 per group) was quantified using a Quant-iT PicoGreen dsDNA assay (Invitrogen, Carlsbad, CA, United States) as previously described ( Chen et al, 2021 ).…”

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“…Aleyd et al ( 56 ) demonstrated that IgA enhances NETosis as an effective defense mechanism to eliminate pathogens at mucosal surfaces. In contrast, neutrophil activation by IgA immune complex is also known to contribute to the immunopathogenesis of autoimmune diseases, such as IgA vasculitis, and nephropathy ( 57–59 ). In respiratory viral disease models, such as influenza and SARS-CoV-2, the formation of an IgA-virus immune complex led to exacerbated NETosis of neutrophils isolated from peripheral blood mononuclear cells (PBMCs) ex vivo ( 60 ).…”

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“…Our previous study ( 13 ) revealed that serum degradation of NETs significantly declines in children with IgAV onset and active IgAV. Children in drug withdrawal had a normal level of NETs degradation.…”

“…The study evaluated components of NETs, which included cell-free DNA (cf-DNA), myeloperoxidase-DNA (MPO-DNA), citrullinated-histone H3 (cit-H3), neutrophil elastase (NE), and cathelicidin antimicrobial peptides (CAMP, LL37). The level of NETs significantly increased in children with IgAV onset and active stage, while the level of NETs gradually returned to normal in children in the remission stage and drug withdrawal ( 13 ). In autoimmune diseases, excessive NETs are known to act as an exposed autoantigen in vivo , inducing the production of autoantibodies, thereby increasing the intensity of the inflammatory response.…”

“…A recent study reported that MPO-DNA is significantly elevated in the circulation of patients with IgAV and positively correlates with IgA levels, which suggests that NETs are involved in the pathogenesis of IgAV ( 19 ). NETs may influence the activity or severity of IgAV ( 13 , 19 ).…”