Abstract
Neutrophil extracellular traps (NETs) are macromolecular structures programmed to trap circulating bacteria and viruses. The accumulation of NETs in the circulation correlates with the formation of anti-double-stranded (ds) DNA antibodies and is considered a causative factor for systemic lupus erythematosus (SLE). The digestion of DNA by DNase1 and DNases1L3 is the rate- limiting factor for NET accumulation. Mutations occurring in one of these two DNase genes determine anti-DNA formation and are associated with severe Lupus-like syndromes and lupus nephritis (LN). A second mechanism that may lead to DNase functional impairment is the presence of circulating DNase inhibitors in patients with low DNase activity, or the generation of anti-DNase antibodies. This phenomenon has been described in a relevant number of patients with SLE and may represent an important mechanism determining autoimmunity flares. On the basis of the reviewed studies, it is tempting to suppose that the blockade or selective depletion of anti-DNase autoantibodies could represent a potential novel therapeutic approach to prevent or halt SLE and LN. In general, strategies aimed at reducing NET formation might have a similar impact on the progression of SLE and LN.
Highlights
The unique indirect evidence is that neutrophils derived from patients with systemic lupus erythematosus (SLE)/lupus nephritis (LN), and stimulated with phorbol 12-myristate 13-acetate (PMA), produce more and different Neutrophil extracellular traps (NETs) compared to neutrophils derived from healthy subjects [15]
They performed a reliable assay for circulating DNase1L3 activity and found low levels in 50% of patients with LN compared to patients with uncomplicated SLE and the healthy controls
Genetic mutations affecting DNASE1, DNASE2, and DNASE1IL3, or the presence of DNases inhibitory agents could explain DNases functional impairment. All of these studies highlight the relevance of NET DNA and NETosis, as a whole, as a central pathomechanism directly implicated in the onset and progression of SLE and LN
Summary
The complex and interactive network of molecules activated during NETosis is part of the initial immune response against any type of infection [4]. Considering the elaborate structure involving chromatin-DNA and more than 300 proteins [6], and given the interactive nature of the functions, the significance of NETs goes beyond the immune response [3]. In the last decade, consolidated evidence has demonstrated that DNA, and proteins derived from NETs, may serve as autoantigens in several autoimmune diseases [6,7]. The link of NETs with autoimmunity is evident in the context of systemic lupus erythematosus (SLE) and lupus nephritis (LN), since NETs represent an important source of the two major antigens in both conditions [8]: DNA and oxidized (93 methionine sulfoxide) α-enolase. Studies measuring NET levels in SLE and LN suggest the relevance of maintaining a physiological balance between formation and removal that is critical for reducing the formation of autoantibodies in both conditions [9,10]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
