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Neutrophil Extracellular Traps That Are Not Degraded in Systemic Lupus Erythematosus Activate Complement Exacerbating the Disease.

Leffler, Jonatan LU ; Martin, Myriam LU ; Gullstrand, Birgitta LU ; Tydén, Helena LU ; Lood, Christian LU ; Truedsson, Lennart LU ; Bengtsson, Anders LU and Blom, Anna LU (2012) In Journal of immunology (Baltimore, Md. : 1950) 188(7). p.3522-3531
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... (More)
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. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of immunology (Baltimore, Md. : 1950)
volume
188
issue
7
pages
3522 - 3531
publisher
American Association of Immunologists
external identifiers
  • wos:000302150300066
  • pmid:22345666
  • scopus:84859375702
ISSN
1550-6606
DOI
10.4049/jimmunol.1102404
language
English
LU publication?
yes
id
844e6d15-c2fe-4f04-b3c2-2d9e5fd7ef42 (old id 2366707)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/22345666?dopt=Abstract
date added to LUP
2012-03-02 12:38:10
date last changed
2017-09-10 04:52:29
@article{844e6d15-c2fe-4f04-b3c2-2d9e5fd7ef42,
  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.},
  author       = {Leffler, Jonatan and Martin, Myriam and Gullstrand, Birgitta and Tydén, Helena and Lood, Christian and Truedsson, Lennart and Bengtsson, Anders and Blom, Anna},
  issn         = {1550-6606},
  language     = {eng},
  number       = {7},
  pages        = {3522--3531},
  publisher    = {American Association of Immunologists},
  series       = {Journal of immunology (Baltimore, Md. : 1950)},
  title        = {Neutrophil Extracellular Traps That Are Not Degraded in Systemic Lupus Erythematosus Activate Complement Exacerbating the Disease.},
  url          = {http://dx.doi.org/10.4049/jimmunol.1102404},
  volume       = {188},
  year         = {2012},
}