Severe glomerulonephritis involves cell necrosis as well as NETosis, programmed neutrophil death leading to expulsion of nuclear chromatin and neutrophil extracellular traps (NETs). Histones released by neutrophils undergoing NETosis killed glomerular endothelial cells, podocytes, and parietal epithelial cells. This was prevented by histone-neutralizing agents anti-histone IgG, activated protein C and heparin. Histone toxicity on glomeruli was TLR2/4-dependent. Anti-GBM glomerulonephritis involved NET formation and vascular necrosis. Pre-emptive anti-histone IgG administration significantly reduced all aspects of glomerulonephritis, including vascular necrosis, podocyte loss, albuminuria, cytokine induction, recruitment and activation of glomerular leukocytes and glomerular crescent formation. Subjects with established glomerulonephritis treated with anti-histone IgG, recombinant activated protein C, or heparin all abrogated severe glomerulonephritis suggesting that histone-mediated glomerular pathology is a subsequent, not initial event in necrotizing glomerulonephritis. Neutralizing extracellular histones is therapeutic in severe experimental glomerulonephritis.La glomérulonéphrite sévère implique la nécrose cellulaire ainsi que la NETose, mort programmée des neutrophiles conduisant à l'expulsion de la chromatine nucléaire et des pièges extracellulaires des neutrophiles (NET). Des histones libérées par les neutrophiles subissant une NETose tuent les cellules endothéliales glomérulaires, les podocytes, et les cellules épithéliales pariétales. Cela est empêché par des agents neutralisant les histones, IgG anti-histone, protéine C active et héparine. La toxicité des histones sur les glomérules dépend de TLR2/4. La glomérulonéphrite anti-GBM implique la formation de NET et la nécrose vasculaire. L'administration préventive d'IgG anti-histone réduit de manière significative tous les aspects de la glomérulonéphrite, y compris la nécrose vasculaire, la perte des podocyte
