Neutrophil extracellular trap release is associated with antinuclear antibodies in systemic lupus erythematosus and anti-phospholipid syndrome

Linden, Maarten van der; Hoogen, Lucas L van den; Westerlaken, Geertje H. A.; Fritsch-Stork, Ruth; Roon, Joël A G van; Radstake, Timothy R D J; Meyaard, Linde

doi:10.1093/rheumatology/key067

Cited by 78 publications

(76 citation statements)

References 22 publications

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“…Importantly, neutrophil activation is related to inflammation, the formation of neutrophil extracellular traps and ANA increment. 49 However, we could not detect a reduction in neutrophil infiltration in kidneys (see Supplementary material, Fig. S8), suggesting a leading inflammatory context, which would be associated with a consequent increase of Treg cell number tending to reduce inflammation and damage.…”

Section: Discussionmentioning

confidence: 69%

Tolerogenic dendritic cell transfer ameliorates systemic lupus erythematosus in mice

et al. 2019

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Summary Current treatments for systemic autoimmune diseases partially improve the health of patients displaying low pharmacological efficacy and systemic immunosuppression. Here, the therapeutic potential of transferring tolerogenic dendritic cells (tolDCs) generated with heme‐oxygenase inductor cobalt (III) protoporphyrin IX (CoPP), dexamethasone and rosiglitazone for the treatment of systemic autoimmunity was evaluated in two murine models of systemic lupus erythematosus (SLE), MRL‐Faslpr and NZM2410 mice. Dendritic cells treated ex vivo with these drugs showed a stable tolerogenic profile after lipopolysaccharide stimulation. Regular doses of tolDCs were administered to anti‐nuclear antibody‐positive mice throughout 60–70 days, and the clinical score was evaluated. Long‐term treatment with these tolDCs was well tolerated and effective to improve the clinical score on MRL‐Faslpr lupus‐prone mice. Additionally, decreased levels of anti‐nuclear antibodies in NZM2410 mice were observed. Although tolDC treatment increased regulatory T cells, no significant reduction of renal damage or glomerulonephritis could be found. In conclusion, these results suggest that the transfer of histone‐loaded tolDCs could improve only some SLE symptoms and reduced anti‐nuclear antibodies. This is the first study to evaluate antigen‐specific tolDC administration to treat SLE. Our report strengthens the clinical relevance of tolDC generation with CoPP, dexamethasone and rosiglitazone and the use of these modified cells as a therapy for systemic autoimmunity.

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Section: Discussionmentioning

confidence: 69%

Tolerogenic dendritic cell transfer ameliorates systemic lupus erythematosus in mice

et al. 2019

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“…In clinical studies, we and others have demonstrated that excessive NET formation or impaired NET degradation is present both in patients with active AAV and in patients with severe SLE , and this is correlated with the severity of disease activity. Thus, preclinical and clinical studies have demonstrated an important role for NETs in the pathogenesis of both AAV and SLE.…”

Section: Introductionmentioning

confidence: 83%

Intrinsically Distinct Role of Neutrophil Extracellular Trap Formation in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis Compared to Systemic Lupus Erythematosus

Dam

Kraaij

Kamerling

et al. 2019

Arthritis & Rheumatology

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Objective. Different studies have demonstrated that neutrophil extracellular traps (NETs) may be involved in the pathophysiology of both antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and systemic lupus erythematosus (SLE). AAV and SLE are clinically and pathologically divergent autoimmune diseases with different autoantibodies. However, the respective autoantigens recognized in AAV and SLE have been shown to be an intricate part of NETs. This study aimed to examine whether the mechanisms of NET formation and the composition of NETs are distinct between AAV and SLE.Methods. To investigate this hypothesis, healthy neutrophils were stimulated with serum from patients with AAV (n = 80) and patients with SLE (n = 59), and the mechanisms of NET formation and NET composition were compared.Results. Both patients with AAV and patients with SLE had excessive NET formation, which correlated with the extent of disease activity (in AAV r = 0.5, P < 0.0001; in SLE r = 0.35, P < 0.01). Lytic NET formation over several hours was observed in patients with AAV, as compared to rapid (within minutes), non-lytic NET formation coinciding with clustering of neutrophils in patients with SLE. AAV-induced NET formation was triggered independent of IgG ANCAs, whereas SLE immune complexes (ICx) induced NET formation through Fcγ receptor signaling. AAV-induced NET formation was dependent on reactive oxygen species and peptidyl arginine deaminases, and AAV-induced NETs were enriched for citrullinated histones (mean ± SEM 23 ± 2%). In contrast, SLE-induced NETs had immunogenic properties, including binding with high mobility group box chromosomal protein 1 (mean ± SEM 30 ± 3%) and enrichment for oxidized mitochondrial DNA, and were involved in ICx formation.Conclusion. The morphologic features, kinetics, induction pathways, and composition of excessive NET formation are all intrinsically distinct in AAV compared to SLE. Recognizing the diversity of NET formation between AAV and SLE provides a better understanding of the pathophysiologic role of NETs in these different autoimmune diseases.

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“…The association of NETs with the autoimmune response in SLE and RA [8,9] might involve (i) the ineffective clearance of NETs contributing to the autoimmune response, (ii) the formation of neoepitopes due to modification of NET-associated proteins by neutrophil proteases and/or (iii) the formation of immune complexes when antibodies to NET components are already present, propagating the inflammatory process. Our data confirm the presence of anti-NET autoantibodies in SLE and RA sera, with a higher frequency in SLE.…”

Section: Discussionmentioning

confidence: 99%

“…Patients with autoimmune diseases such as SLE and RA often have autoantibodies against NET components in their sera [8,9]. The immunogenicity of the NETs might be due in part be to generation of neoepitopes by neutrophil protease activities.…”

Section: Neutrophil Proteases Affect Autoepitopes On Netsmentioning

confidence: 99%

“…Autoimmune diseases were among the first diseases that were reported to be associated with (aberrant) NET formation [7]. Neutrophils from patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and other autoimmune diseases were shown to have an increased propensity to form NETs in vitro [8][9][10]. Furthermore, antibodies of patients with these diseases were shown to bind NETs, and their plasma was also able to induce NET formation in healthy control neutrophils, due probably to an inflammatory feedforward loop [11,12].…”

Section: Introductionmentioning

confidence: 99%

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Neutrophil proteases degrade autoepitopes of NET-associated proteins

Bont

Eerden

Boelens

et al. 2019

Clinical &Amp; Experimental Immunology

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Summary Neutrophils can form neutrophil extracellular traps (NETs) to capture microbes and facilitate their clearance. NETs consist of decondensed chromatin decorated with anti‐microbial proteins. Here, we describe the effect of neutrophil proteases on the protein content of NETs. We show that the neutrophil serine proteases degrade several neutrophil proteins associated with NETs. Interestingly, the anti‐bacterial proteins associated with NETs, such as myeloperoxidase, calgranulin B and neutrophil elastase (NE), seem to be less susceptible to proteolytic degradation than other NET proteins, such as actin and MNDA. NETs have been proposed to play a role in autoimmune reactions. Our data demonstrate that a large number of the autoepitopes of NET proteins that are recognized by autoantibodies produced by systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) patients are also removed by the proteases. In conclusion, neutrophil serine proteases have a major impact on the NET proteome and the proteolytic changes of NET‐associated proteins may counteract autoimmune reactions to NET components.

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Neutrophil extracellular trap release is associated with antinuclear antibodies in systemic lupus erythematosus and anti-phospholipid syndrome

Abstract: Increased NET release is associated with autoimmunity and inflammation in SLE and APS. Inhibition of NET release thus could be of potential benefit in a subset of patients with SLE and APS.

Cited by 78 publications

References 22 publications

Tolerogenic dendritic cell transfer ameliorates systemic lupus erythematosus in mice

Tolerogenic dendritic cell transfer ameliorates systemic lupus erythematosus in mice

Intrinsically Distinct Role of Neutrophil Extracellular Trap Formation in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis Compared to Systemic Lupus Erythematosus

Neutrophil proteases degrade autoepitopes of NET-associated proteins

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