Table 4.

List of studies showing association between NETs and autoimmune diseases.

Authors, reference	Study design	Main study findings
Kessenbrock et al. [100]	Cell experiments (neutrophils isolated from human peripheral blood) and analyzing 15 kidney needle biopsies from SVV patients with glomerulonephritis.	NETs are released by ANCA-stimulated neutrophils and contain the targeted autoantigens PR3 and MPO. NETs were prominent in specimens with strong neutrophil infiltration.
Sangaletti et al. [103]	Using a mouse model	Myeloid DCs uploaded with and activated by NET components induce ANCA and autoimmunity. NET intermingling with myeloid DC positive for neutrophil MPO in MPO-ANCA-associated microscopic polyangiitis.
Kusunoki et al. [35]	Using a mouse model	PAD inhibitor suppresses NETs formation and MPO-ANCA production in mouse models with MPO-ANCA production.
Tang et al. [104] [97]	Cell experiments (neutrophils isolated from human peripheral blood) and analyzing 6 kidney needle biopsies from AVV patients.	Enhanced NET formation, which contains LAMP-2, was observed in kidney biopsies and neutrophils from AAV patients. Anti-LAMP-2 antibody can further promote NETs formation.
Garcia-Romo et al. [111]	Analyzing the human neutrophils.	Mature SLE neutrophils are primed in vivo by type I IFN and die upon exposure to SLE-derived antiribonucleoprotein antibodies, releasing NETs. SLE NETs facilitate the uptake and recognition of mammalian DNA by pDCs and activate pDCs to produce high levels of IFN-α.
Guo et al. [112]	Analyzing the human neutrophils.	Neutrophils derived from SLE patients with decreased RIPK1 expression are more likely to form NETs, and RIPK1 inhibitor can greatly increase NETs formation.
Carmona-Rivera et al. [18]	Cell experiments.	MMP-9 is externalized during NET formation, and MMP-9 induces endothelial dysfunction by activating MMP-2. Inhibition of MMP-2 activation can restore endothelium-dependent function and decreased NET-induced vascular cytotoxicity.
Hakkim et al. [113]	Analysis of sera from 61 unrelated patients with SLE, 54 healthy controls, 30 RA patients, and 4 patients with IgA nephropathy.	A subset of SLE patients' sera DNase I inhibitors or anti-NET antibodies prevented DNase1 access to NETs.
Knight et al. [114]	Using a mouse model	Neutrophils in SLE mouse model have a significantly higher ability to release NETs compared with controls. PAD inhibition can reduce NET formation, protecting against lupus-related damage to the vasculature, kidneys, and skin.
Campbell et al. [115] [107]	Using a mouse model	NETs does not contribute to SLE in Nox2-deficient lupus-prone mice.
Spengler et al. [118]	Analysis of synovial fluid from patients with RA, patients with osteoarthritis, and patients with psoriatic arthritis.	Extracellular DNA levels were significantly higher in RA patient than in OA patients, and correlated with neutrophil concentrations and PAD activity in RA. PAD2 and PAD4 were attached to NETs and also freely diffused in the supernatant.
Khandpur et al. [119]	Experiments using neutrophils, sera, and synovial fluid obtained from RA patients, healthy controls, and patients with osteoarthritis.	Neutrophils from RA patients display a significantly enhanced capacity to form NETs, and NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in RA.
Seri et al. [120]	Using a mouse model	Deletion of the PAD4 gene reduces the severity of arthritis induced by recombinant human glucose-6-phosphate isomerase.
Rohrbach et al. [121]	Using a mouse model	PAD4 deficiency did not affect the severity of arthritis in the K/BxN murine.
Mor-Vaknin et al. [122]	Using a mouse model	DEK is detected in spontaneously forming NETs from JIA patient synovial neutrophils, and DEK-targeted aptamers significantly reduces joint inflammation in vivo and greatly impairs the ability of neutrophils to form NETs.
Perez-Sanchez et al. [123]	Experiments using neutrophils and plasma obtained from RA patients and healthy controls.	NETs was found increased in RA patients. Inhibition of NETs extrusion can further abridge the endothelial dysfunction and the activation of immune cells, thus influencing the global activity of the vascular system.
Sur Chowdhury et al. [124]	Human study.	Neutrophils from RA cases exhibited increased spontaneous NET formation, and NETs-derived in RA serum products demonstrated diagnostic potential.
Wang et al. [125]	Analysis of serum from 74 RA patients and 50 healthy controls.	RA patients exhibited significantly higher levels of MPO-DNA complexes, and these levels were associated with increased neutrophil counts and positivity for rheumatoid factor and anticitrullinated protein/peptide antibodies.

NET: neutrophil extracellular traps; ANCA: antineutrophil cytoplasmic antibody; SVV: small-vessel vasculitis; PR3: proteinase 3; MPO: myeloperoxidase; DCs: dendritic cells; PAD: peptidylarginine deiminase; LAMP-2: lysosomal-associated membrane protein-2; pDCs: plasmacytoid dendritic cells; IFN: interferon; AAV: ANCA-associated vasculitis; RIPK1: receptor interacting serine/threonine kinase 1; SLE: systemic lupus erythematosus RA: rheumatoid arthritis; MMP: matrix metalloproteinase; OA: osteoarthritis; JIA: juvenile idiopathic arthritis.