Netting Neutrophils Activate Autoreactive B Cells in Lupus

Gestermann, Nicolas; Domizio, Jérémy Di; Lande, Roberto; Demaria, Olivier; Frasca, Loredana; Feldmeyer, Laurence; Lucca, Julie Di; Gilliet, Michel

doi:10.4049/jimmunol.1700778

Cited by 136 publications

(143 citation statements)

References 37 publications

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“…Furthermore, the autoantibodies against ADAMTS‐L5 or LL‐37 could be used as biomarkers to discriminate PsA from non‐PsA. Moreover, results of a very recent study suggested that the neutrophil extracellular trap (NET)–derived DNA–LL–37 complex could activate autoreactive B cells, leading to anti–LL‐37/anti‐NET autoantibody production in lupus . It would be intriguing in future studies to test whether the autoantibody (e.g., anti–LL‐37) production in psoriasis might be mediated via the activation of autoreactive B cells through NETosis pathways.…”

Section: Discussionmentioning

confidence: 99%

Identification of Novel Autoantibodies Associated With Psoriatic Arthritis

Yuan

Qiu

Lin

et al. 2019

Arthritis & Rheumatology

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Objective. The autoimmune etiology in psoriasis remains to be clarified. We therefore undertook this study to identify novel pathogenic autoantigens and autoantibodies in patients with psoriasis, with the aim of shedding light on the molecular and cellular basis of the pathogenesis of psoriasis and psoriatic arthritis (PsA).Methods. In this study, we developed an autoantigen array system that harbors a variety of antigens, including typical autoantigens in rheumatic diseases as well as skin antigens, inflammatory mediators, and putative autoantigens in psoriasis. Serum samples from patients with psoriasis (n = 73) were used to interrogate the antigens on the array. In addition, enzyme-linked immunosorbent assays of individual autoantibodies were used in validation studies.Results. Levels of several autoantibodies were found to be elevated in the serum of patients with psoriasis compared to healthy controls; in particular, IgG autoantibodies against 2 novel antigens, LL-37 and ADAMTS-L5, were significantly increased in patients with psoriasis. Importantly, serum levels of IgG autoantibodies against LL-37 and ADAMTS-L5 were correlated with the Psoriasis Area and Severity Index, and reflected disease progression in longitudinally collected serum samples from patients with psoriasis. Importantly, both anti-ADAMTS-L5 and anti-LL-37 autoantibody levels were also significantly elevated in psoriasis patients with PsA compared to those without PsA, suggesting that these molecules may be involved in the pathogenesis of PsA.Conclusion. Our findings indicate that these identified autoantibodies may be useful biomarkers and may serve as therapeutic targets in psoriasis and PsA.

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Section: Discussionmentioning

confidence: 99%

Identification of Novel Autoantibodies Associated With Psoriatic Arthritis

Yuan

Qiu

Lin

et al. 2019

Arthritis & Rheumatology

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“…NETs containing cathelicidin LL-37-DNA complexes can directly trigger human memory B cells and induce the production of anti-neutrophil and anti-LL-37 antibodies in B cells of SLE patients (Fig. 1) 77 .…”

Section: Nets In Systemic Lupus Erythematosusmentioning

confidence: 99%

In vivo evidence for extracellular DNA trap formation

et al. 2020

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Extracellular DNA trap formation is a cellular function of neutrophils, eosinophils, and basophils that facilitates the immobilization and killing of invading microorganisms in the extracellular milieu. To form extracellular traps, granulocytes release a scaffold consisting of mitochondrial DNA in association with granule proteins. As we understand more about the molecular mechanism for the formation of extracellular DNA traps, the in vivo function of this phenomenon under pathological conditions remains an enigma. In this article, we critically review the literature to summarize the evidence for extracellular DNA trap formation under in vivo conditions. Extracellular DNA traps have not only been detected in infectious diseases but also in chronic inflammatory diseases, as well as in cancer. While on the one hand, extracellular DNA traps clearly exhibit an important function in host defense, it appears that they can also contribute to the maintenance of inflammation and metastasis, suggesting that they may represent an interesting drug target for such pathological conditions. Facts •The demonstration of extracellular DNA traps in vivo requires sections of affected tissues, which are to be investigated with special staining techniques. These structures are seen in multiple inflammatory and cancer diseases.Is there a simple biomarker that reflects extracellular DNA trap formation?• What is the contribution of extracellular microbe killing compared to intracellular killing following phagocytosis?• The mechanism of DNA trap formation is unknown.

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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%

“…NET‐derived DNA complexed with danger‐associated molecular patterns, such as LL‐37 or high mobility group box chromosomal protein 1 (HMGB‐1) , converts the NET DNA to potent immunogenic structures . Indeed, NETs were demonstrated to activate plasmacytoid dendritic cells and autoreactive B cells in vitro , which resulted in the production of interferon‐α (IFNα) and autoantibodies, respectively. Furthermore, NETs also have direct cytotoxic effects on (glomerular) endothelial cells , mediated by histones and MPO , which, in a murine model, was found to lead to severe, crescentic GN .…”

Section: Introductionmentioning

confidence: 99%

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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Netting Neutrophils Activate Autoreactive B Cells in Lupus

Cited by 136 publications

References 37 publications

Identification of Novel Autoantibodies Associated With Psoriatic Arthritis

Identification of Novel Autoantibodies Associated With Psoriatic Arthritis

In vivo evidence for extracellular DNA trap formation

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

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