TY - JOUR
T1 - Neutrophil extracellular traps profiles in patients with incident systemic lupus erythematosus and lupus nephritis
AU - Bruschi, M.
AU - Bonanni, A.
AU - Petretto, A.
AU - Vaglio, A.
AU - Pratesi, F.
AU - Santucci, L.
AU - Migliorini, P.
AU - Bertelli, R.
AU - Galetti, M.
AU - Belletti, S.
AU - Cavagna, L.
AU - Moroni, G.
AU - Franceschini, F.
AU - Fredi, M.
AU - Pazzola, G.
AU - Allegri, L.
AU - Sinico, R. A.
AU - Pesce, G.
AU - Bagnasco, M.
AU - Manfredi, A.
AU - Ramirez, G. A.
AU - Ramoino, P.
AU - Bianchini, P.
AU - Puppo, F.
AU - Pupo, F.
AU - Negrini, S.
AU - Mattana, F.
AU - Emmi, G.
AU - Garibotto, G.
AU - Santoro, D.
AU - Scolari, F.
AU - Ravelli, A.
AU - Tincani, A.
AU - Cravedi, P.
AU - Volpi, S.
AU - Candiano, G.
AU - Ghiggeri, G. M.
N1 - Funding Information:
From the Laboratory of Molecular Nephrology, Core Facilities-Proteomics Laboratory, Division of Paediatric Rheumatology and Division of Nephrology, Dialysis, and Transplantation, Scientific Institute for Research and Health Care (IRCCS) Istituto Giannina Gaslini, Genoa; Nephrology Unit, University Hospital, University of Parma; Clinical Immunology Unit, Department of Internal Medicine, University of Pisa; Italian Workers’ Compensation Authority (INAIL) Research Center at the University of Parma, Italy; S.Bi.Bi.T Department of the University of Parma, Parma; Division of Rheumatology, University and IRCCS Policlinico S. Matteo, Pavia; Division of Nephrology and Dialysis, IRCCS, Regina Elena, Milan; Rheumatology and Clinical Immunology, Spedali Civili and University of Brescia, Brescia; Nephrology and Dialysis, Arciospedale Santa Maria Nuova, Reggio Emilia; Department of Medicine and Surgery, University of Milan, Bicocca; Medical and Radiometabolic Therapy Unit, Department of Internal Medicine, University of Genoa; Unit of Internal Medicine and Immunology, IRCCS Ospedale San Raffaele, Milan; Department of Earth, Environment and Life Sciences (DISTAV), University of Genoa; Department of Nanophysics, Italian Institute of Technology (IIT); Department of Internal Medicine, University of Genoa; Division of Nephrology, University of Genoa and Policlinico San Martino, Genoa; Lupus Clinic Department of Biomedicine, University of Florence, University Hospital Careggi, Florence; Nephrology and Dialysis Unit, University of Messina and G. Martino Hospital, Messina; Division of Nephrology and Dialysis, University of Brescia and Ospedale di Montichiari, Brescia, Italy; Nephrology Division, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA. Supported by a grant from Fondazione Lupus Italia 2014. Further support from the Fondazione Malattie Renali del Bambino and grant no. ROL 9849 from Compagnia di San Paolo. PC is the recipient of US National Institutes of Health R01 grant AI132949. M. Bruschi, PhD, Laboratory of Molecular Nephrology, IRCCS Istituto Giannina Gaslini; A. Bonanni, MD, Laboratory of Molecular Nephrology,
Publisher Copyright:
The Journal of Rheumatology Copyright © 2020. All rights reserved.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/3/1
Y1 - 2020/3/1
N2 - 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).
AB - 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).
KW - Dnase activity
KW - Dnase level
KW - Dnase mutations
KW - Neutrophil extracellular traps
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U2 - 10.3899/jrheum.181232
DO - 10.3899/jrheum.181232
M3 - Article
C2 - 31092713
AN - SCOPUS:85081076028
VL - 47
SP - 377
EP - 386
JO - Journal of Rheumatology
JF - Journal of Rheumatology
SN - 0315-162X
IS - 3
ER -