title: Neutrophil extracellular traps that are not degraded in systemic lupus erythematosus activate complement exacerbating the disease.
abstract: Ongoing inflammation including activation of the complement system is a hallmark of systemic lupus erythematosus (SLE). Antimicrobial neutrophil extracellular traps (NETs) are composed of secreted chromatin that may act as a source of autoantigens typical for SLE. In this study, we investigated how complement interacts with NETs and how NET degradation is affected by complement in SLE patients. We found that sera from a subset of patients with active SLE had a reduced ability to degrade in vitro-generated NETs, which was mostly restored when these patients were in remission. Patients that failed to degrade NETs had a more active disease and they also displayed lower levels of complement proteins C4 and C3 in blood. We discovered that NETs activated complement in vitro and that deposited C1q inhibited NET degradation including a direct inhibition of DNase-I by C1q. Complement deposition on NETs may facilitate autoantibody production, and indeed, Abs against NETs and NET epitopes were more pronounced in patients with impaired ability to degrade NETs. NET-bound autoantibodies inhibited degradation but also further increased C1q deposition, potentially exacerbating the disease. Thus, NETs are a potent complement activator, and this interaction may play an important role in SLE. Targeting complement with inhibitors or by removing complement activators such as NETs could be beneficial for patients with SLE.
authors.affiliation: Section of Medical Protein Chemistry, Department of Laboratory Medicine Malmö, Lund University, Skåne University Hospital, 205 02 Malmö, Sweden.
authors.forename: Jonatan
authors.initials: J
authors.lastname: Leffler
authors.forename: Myriam
authors.initials: M
authors.lastname: Martin
authors.forename: Birgitta
authors.initials: B
authors.lastname: Gullstrand
authors.forename: Helena
authors.initials: H
authors.lastname: Tydén
authors.forename: Christian
authors.initials: C
authors.lastname: Lood
authors.forename: Lennart
authors.initials: L
authors.lastname: Truedsson
authors.forename: Anders A
authors.initials: AA
authors.lastname: Bengtsson
authors.forename: Anna M
authors.initials: AM
authors.lastname: Blom
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000918:Antibody Specificity; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D002843:Chromatin / Q000378:metabolism / Q000648:ultrastructure; D003167:Complement Activation; D015922:Complement C1q / Q000276:immunology / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D003850:Deoxyribonuclease I / Q000378:metabolism; D005110:Extracellular Space; D005260:Female; D006801:Humans; D007370:Interferon Type I / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000276:immunology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000276:immunology / Q000502:physiology*; D012720:Severity of Illness Index; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D002843:Chromatin; D007370:Interferon Type I; D015922:Complement C1q; D004247:DNA; D003850:Deoxyribonuclease I