Background/Purpose: Pediatric lupus (pSLE) is a multisystemic autoimmune disease characterized by autoantibody production leading to organ damage. Neutrophil extracellular traps (NETs) are considered a potential source of antigen, leading to autoantibody production. NETs activate plasmacytoid dendritic cells to produce high levels of interferon-α, a known driver of lupus pathogenesis. Impaired degradation of NETs by DNASEs may play a role in development of lupus, as low DNASE activity and mutations in DNASEIL3 have been associated with lupus. Here, we investigate levels of circulating NETs in pSLE and healthy children and elucidate mechanisms behind NETs accumulation.

Methods: Plasma from whole blood samples of 13 pSLE patients and 12 healthy children were evaluated for the presence of NETs using our multiplex ELISA and novel immunofluorescence smear assay. DNASE1L3 concentration was measured using ELISA and DNASE1L3 activity by nuclei digest. NET degradation assays were performed using healthy neutrophils stimulated with either pSLE or healthy plasma. Lupus disease activity was measured by SELENA-SLEDAI.

Results: Significantly higher levels of circulating NETs were found in pSLE plasma compared to healthy children, consistent with ELISA and smear assays (p < 0.05). The number of NETs were positively correlated with SELENA-SLEDAI scores and anti-double stranded DNA levels. Although DNASE1L3 levels were higher in pSLE patients, enzymatic activity was significantly reduced, compared to healthy children. Moreover, we found that pSLE plasma was not able to degrade NETs as effectively as plasma from healthy children, suggesting that NET degradation was impaired in pSLE, leading to accumulation of NETs.

Conclusion: Decreased DNASE1L3 activity may play a role in impaired clearance of NETs in plasma from pSLE patients leading to NETs accumulation. High levels of DNASE1L3 seen in pSLE patients are likely due to compensatory mechanisms to overcome reduced enzymatic activity in NET clearance. Interestingly, patients with higher SLEDAI scores had higher number of NETs. Thus, level of NETs accumulation in plasma detected by our newly developed assays could potentially be a useful biomarker for pSLE disease severity.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/levels-of-neutrophil-extracellular-traps-correlate-with-disease-activity-in-pediatric-lupus/