Neutrophil Extracellular Traps Profiles in Patients with Incident Systemic Lupus Erythematosus and Lupus Nephritis

Maurizio Bruschi, Alice Bonanni, Andrea Petretto, Augusto Vaglio, Federico Pratesi, Laura Santucci, Paola Migliorini, Roberta Bertelli, Maricla Galetti, Silvana Belletti, Lorenzo Cavagna, Gabriella Moroni, Franco Franceschini, Micaela Fredi, Giulia Pazzola, Landino Allegri, Renato Alberto Sinico, Giampaola Pesce, Marcello Bagnasco, Angelo ManfrediGiuseppe A. Ramirez, Paola Ramoino, Paolo Bianchini, Francesco Puppo, Francesca Pupo, Simone Negrini, Federico Mattana, Giacomo Emmi, Giacomo Garibotto, Domenico Santoro, Francesco Scolari, Angelo Ravelli, Angela Tincani, Paolo Cravedi, Stefano Volpi, Giovanni Candiano, Gian Marco Ghiggeri

Research output: Contribution to journalArticle

Abstract

OBJECTIVE: Neutrophil extracellular traps (NET) expose modified antigens for autoantibodies in vasculitis. Little is known about levels and removal pathways of NET in systemic lupus erythematosus (SLE), especially in lupus nephritis (LN). We determined circulating levels and defined NET removal in large subsets of patients with incident SLE (iSLE), some of whom had new-onset nephritis. METHODS: Serum levels of NET (ELISA), DNase1/DNase1L3 (ELISA), and DNase activity (functional assay) were determined in 216 patients with iSLE [103 had incident LN (iLN)], in 50 patients with other primary glomerulonephritis, and in healthy controls. Ex vivo NET production by neutrophils purified from a random selection of patients was quantified as elastase/DNA release and by immunofluorescence techniques. RESULTS: Serum NET levels were very high in iSLE/iLN compared to all groups of controls and correlated with anti-dsDNA, C3-C4, and proteinuria; iLN had the highest levels. DNase activity was decreased in iLN compared to SLE (20% had one-half DNase activity) despite similar serum levels of DNase1/DNase1L3. In these cases, pretreatment of serum with protein A restored DNase efficiency; 1 patient was homozygous for a c.289_290delAC variant of DNASE1L3. Ex vivo NET production by neutrophils purified from LN, SLE, and normal controls was similar in all cases. CONCLUSION: Patients with iLN have increased circulating NET and reduced DNase activity, the latter being explained by the presence of inhibitory substances in circulation and/or by rare DNase1L3 mutations. Accumulation of NET derives from a multifactorial mechanism, and is associated and may contribute to disease severity in SLE, in particular to renal lesions. (Clinical trial registration: The Zeus study was registered at ClinicalTrials.gov, study number NCT02403115).

Original languageEnglish
Pages (from-to)377-386
Number of pages10
JournalThe Journal of rheumatology
Volume47
Issue number3
DOIs
Publication statusPublished - Mar 1 2020

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Keywords

  • DNASE ACTIVITY
  • DNASE LEVEL
  • DNASE MUTATIONS
  • NEUTROPHIL EXTRACELLULAR TRAPS

ASJC Scopus subject areas

  • Rheumatology
  • Immunology and Allergy
  • Immunology

Cite this

Bruschi, M., Bonanni, A., Petretto, A., Vaglio, A., Pratesi, F., Santucci, L., Migliorini, P., Bertelli, R., Galetti, M., Belletti, S., Cavagna, L., Moroni, G., Franceschini, F., Fredi, M., Pazzola, G., Allegri, L., Sinico, R. A., Pesce, G., Bagnasco, M., ... Ghiggeri, G. M. (2020). Neutrophil Extracellular Traps Profiles in Patients with Incident Systemic Lupus Erythematosus and Lupus Nephritis. The Journal of rheumatology, 47(3), 377-386. https://doi.org/10.3899/jrheum.181232