Deciphering the role of neutrophil reactive oxygen species (ROS) in the SLE pathogenesis

Concept

Neutrophils of SLE patients have reduced ability to form reactive oxygen species (ROS), which is associated with increased disease severity and organ damage. We therefore wanted to investigate if this was due to genetic variants in the NCF1 gene.

ROS are important regulators of the immune system, and NCF1 gene variants were studied in relation to immunopathogenic mechanisms in SLE such as neutrophil extracellular traps (NETs), interferon (IFN) and presence of autoantibodies.

Facts and figures

Project lead
A Bengtsson
Lund University
Anders.Bengtsson@med.lu.se
FOREUM research grant: € 150.000
2016 - 2019

Meet the team

A Bengtsson
Lund University
Prof A Blom
Lund University
N Heegard
Statens Serum Institut
M Herrmann
Friedrich-Alexander University Erlangen
R Holmdahl
Karolinska Institutet
F Ivars
Lund University
S Jacobsen
Copenhagen University

Objectives

We have previously seen that reduced ability of neutrophils to produce reactive oxygen species (ROS) is associated with increased severity and organ damage in SLE. This prompted us to ask if SLE patients are genetically predisposed to have low ROS production and how this would influence pathogenesis. We are investigating the role of NCF1 gene variants in SLE and relate this to disease phenotypes. We are also characterizing the role of ROS and neutrophils in regulation of key immunopathogenic events in SLE, focusing on NETosis, type I interferon production and activation of adaptive immunity.

Patient voice

We are since many years always working in close collaboration with patients that are also taking part in the projects, letting us be influenced by patients from their perspectives.

Interim results

In this project, we have identified a novel SNP in the NCF1-gene (NCF1-339), strongly associated with SLE. We have genotyped 1087 SLE patients and 1301 healthy controls and found that the low-ROS-associated T-allele is present in 11 % of patients compared to 4 % in controls (p-value = 7x10-20). Patients with NCF1-339 T-dominant genotypes (T-genotypes) were diagnosed in average 6 years prior to patients with C-genotypes (p- value 2x10-6).

Neutrophils of SLE patients with NCF1-339 T-genotypes had decreased ROS production and NET-release (Figure 1).  NCF1-339 T-genotype is associated with high serum IFN (Figure 2) and anti-cardiolipin and anti- β2-glycoprotein-I, autoantibodies associated with antiphospholipid syndrome (APS) (Figure 2). A significantly increased frequency of SLE patients with NCF1-339 T-genotypes had secondary APS.

Publications

Lina M Olsson, Åsa C Johansson, Birgitta Gullstrand, Andreas Jönsen, Saedis Saevarsdottir, Lars Rönnblom, Dag Leonard, Jonas Wetterö, Christopher Sjöwall, Elisabet Svenungsson, Iva Gunnarsson, Anders A Bengtsson, Rikard Holmdahl. A SNP in the gene NCF1 leading to a reduced oxidative burst is associated with SLE. http://dx.doi.org/10.1136/annrheumdis-2017-211287. [Epub ahead of print].
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