Pharmaceutical immunoglobulins reduce neutrophil extracellular trap formation and ameliorate the development of MPO-ANCA-associated vasculitis

Abstract

Objectives Intravenous immunoglobulin (IVIG) therapy is effective against some autoimmune diseases. Although its efficacy on peripheral neuropathy due to eosinophilic granulomatosis with polyangiitis-one of myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA)-associated vasculitis (MPO-AAV)-has been established, that on other MPO-AAV remains undetermined. We examined the effects of pharmaceutical immunoglobulins on the formation of neutrophil extracellular traps (NETs) related to MPO-ANCA production and the development of MPO-AAV.Methods Peripheral blood neutrophils from healthy volunteers were pretreated with 5 mg/ml human sulfo-immunoglobulins (IVIG-S) and then exposed to 100 nM phorbol myristate acetate (PMA). Thereafter, neutrophils were stained with SYTOX Green and then subjected to flow cytometry. Next, Wistar-Kyoto rats were given oral administration of 10 mg/kg/day propylthiouracil for 28 days and intraperitoneal (i.p.) injection of 1 µg PMA on days 0 and 7. These rats were divided into two groups: Group 1 with i.p. injection of 400 mg/kg IVIG-S on days 8-12 and Group 2 with i.p. injection of vehicle similarly. ANCA titers were chronologically determined by indirect immunofluorescence. On day 28, all rats were killed to examine NET formation in the peritoneum and the development of AAV.Results IVIG-S significantly inhibited NET formation induced by PMA in vitro. NET amounts in the peritoneum in Group 1 were significantly smaller than in Group 2, and ANCA titers in Group 1 were significantly lower than in Group 2. The degree of pulmonary hemorrhage in Group 1 was also smaller than in Group 2. ConclusionPharmaceutical immunoglobulins reduce NET formation and ameliorate the development of MPO-AAV.

Neutrophil Extracellular Traps (NETs) and Damage-Associated Molecular Patterns (DAMPs): Two Potential Targets for COVID-19 Treatment

“…IVIg may also influence the number and function of Tregs which help to control inflammation and inhibit T-cell activation [244], TNF-α production, and IL-6 and matrix metalloproteinase 9 activity. IVIg also reduces NET formation [245] and may have a role in modulating a regulatory autophagy. Moreover, Fc fragment and IVIg may reduce cytokine and DAMP production [246,247] and protect against HMGB1-induced cell death, modulating TLR and RAGE expression [248].…”

Neutrophil Extracellular Traps (NETs) Take the Central Stage in Driving Autoimmune Responses

“…Intriguingly, the amount of PMA-induced NETs was significantly lower when neutrophils were pre-treated with IVIG before exposure to PMA [121]. Moreover, the inhibitory effect of IVIG on NETs, as well as decreased ANCA titers and pulmonary haemorrhage, also was seen in peritoneal tissue of MPO-AAV rats treated with IVIG [121]. To conclude, the presence of NETs and their autoantigenic properties in AAV patients is well-demonstrated.…”

“…NET-induced endothelial cell damage can be prevented when NETs are degraded with DNase1 [55]. Intravenous immunoglobulin (IVIG) is a potential treatment for AAV patients [121]. Intriguingly, the amount of PMA-induced NETs was significantly lower when neutrophils were pre-treated with IVIG before exposure to PMA [121].…”

“…Intravenous immunoglobulin (IVIG) is a potential treatment for AAV patients [121]. Intriguingly, the amount of PMA-induced NETs was significantly lower when neutrophils were pre-treated with IVIG before exposure to PMA [121]. Moreover, the inhibitory effect of IVIG on NETs, as well as decreased ANCA titers and pulmonary haemorrhage, also was seen in peritoneal tissue of MPO-AAV rats treated with IVIG [121].…”

Immunopathogenesis of ANCA-Associated Vasculitis

“…Antonelou et al showed that treatment with an MPO inhibitor reduced the production of NETs, ROS, and endothelial cell damage in mice and renal biopsies [ 175 ]. Intravenous immunogloblins, previously used to treat other autoimmune vasculitides, reduced the rate of pulmonary hemorrhage and peritoneal NETs in rat models of NETosis [ 176 ].…”