Peptidylarginine deiminases 2 and 4 modulate innate and adaptive immune responses in TLR-7–dependent lupus

Liu, Yudong; Lightfoot, Yaíma L.; Seto, Nickie; Carmona-Rivera, Carmelo; Moore, Eddie S.; Goel, Rishi R.; O’Neil, Liam J.; Mistry, Pragnesh; Hoffmann, Victoria; Mondal, Santanu; Premnath, Padmavathy Nandha; Gribbons, Katherine; Dell’Orso, Stefania; Jiang, Kan; Thompson, Paul R.; Sun, Hong; Coonrod, Scott A.; Kaplan, Mariana J.

doi:10.1172/jci.insight.124729

Cited by 76 publications

(77 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Second, citrullination appeared to be not essential for NET formation in both patients with AAV and patients with SLE, which is consistent with previous observations that confirmed the independence of PAD4, i.e., citrullination, for the formation of NETs in humans . These observations are in contrast to those in studies that demonstrated the involvement of PAD enzymes in murine lupus . It is noteworthy that in those studies, NET formation was induced with calcium ionophores , PMA , or imiquimod , and NET quantification was based on CitH3 positivity.…”

Section: Discussionsupporting

confidence: 87%

“…These observations are in contrast to those in studies that demonstrated the involvement of PAD enzymes in murine lupus . It is noteworthy that in those studies, NET formation was induced with calcium ionophores , PMA , or imiquimod , and NET quantification was based on CitH3 positivity. Importantly, PMA‐induced NET formation is truly independent of PAD enzymes, while calcium ionophore–induced NET formation is completely dependent on PAD enzymes .…”

Section: Discussionmentioning

confidence: 59%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 59%

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

View full text Add to dashboard Cite

show abstract

“…The most significantly down‐regulated gene, PADI4 , has been shown to modulate immune responses in lupus, and to be associated with risk for ILD in rheumatoid arthritis . Critically, 2 patient lung biopsy sections from radiographically and grossly unaffected areas of the lung tissue had much less severe histopathologic features, with only focal areas of inflammation.…”

Section: Resultsmentioning

confidence: 99%

Systemic Juvenile Idiopathic Arthritis–Associated Lung Disease: Characterization and Risk Factors

Schulert

Yasin

Carey

et al. 2019

Arthritis & Rheumatology

160

251

View full text Add to dashboard Cite

Objective Systemic juvenile idiopathic arthritis (JIA) is associated with a recently recognized, albeit poorly defined and characterized, lung disease (LD). The objective of this study was to describe the clinical characteristics, risk factors, and histopathologic and immunologic features of this novel inflammatory LD associated with systemic JIA (designated SJIA‐LD). Methods Clinical data collected since 2010 were abstracted from the medical records of patients with systemic JIA from the Cincinnati Children's Hospital Medical Center. Epidemiologic, cellular, biochemical, genomic, and transcriptional profiling analyses were performed. Results Eighteen patients with SJIA‐LD were identified. Radiographic findings included diffuse ground‐glass opacities, subpleural reticulation, interlobular septal thickening, and lymphadenopathy. Pathologic findings included patchy, but extensive, lymphoplasmacytic infiltrates and mixed features of pulmonary alveolar proteinosis (PAP) and endogenous lipoid pneumonia. Compared to systemic JIA patients without LD, those with SJIA‐LD were younger at the diagnosis of systemic JIA (odds ratio [OR] 6.5, P = 0.007), more often had prior episodes of macrophage activation syndrome (MAS) (OR 14.5, P < 0.001), had a greater frequency of adverse reactions to biologic therapy (OR 13.6, P < 0.001), and had higher serum levels of interleukin‐18 (IL‐18) (median 27,612 pg/ml versus 5,413 pg/ml; P = 0.047). Patients with SJIA‐LD lacked genetic, serologic, or functional evidence of granulocyte–macrophage colony‐stimulating factor pathway dysfunction, a feature that is typical of familial or autoimmune PAP. Moreover, bronchoalveolar lavage (BAL) fluid from patients with SJIA‐LD rarely demonstrated proteinaceous material and had less lipid‐laden macrophages than that seen in patients with primary PAP (mean 10.5% in patients with SJIA‐LD versus 66.1% in patients with primary PAP; P < 0.001). BAL fluid from patients with SJIA‐LD contained elevated levels of IL‐18 and the interferon‐γ–induced chemokines CXCL9 and CXCL10. Transcriptional profiling of the lung tissue from patients with SJIA‐LD identified up‐regulated type II interferon and T cell activation networks. This signature was also present in SJIA‐LD human lung tissue sections that lacked substantial histopathologic findings, suggesting that this activation signature may precede and drive the lung pathology in SJIA‐LD. Conclusion Pulmonary disease is increasingly detected in children with systemic JIA, particularly in association with MAS. This entity has distinct clinical and immunologic features and represents an uncharacterized inflammatory LD.

show abstract

“…For instance, the role of peptidylarginine deiminase 4 (PAD4), an enzyme that catalyzes citrullination of histones, has been intensively studied in association with NET formation. Several reports have argued that PAD4 activity is essential for NET formation 14,[35][36][37][38][39][40][41] , and contrary others disputed that PAD4 is not crucial for NET formation or the antimicrobial defense mechanism in vivo [42][43][44][45] . Specifically, NET formation in Klebsiella pneumonia-induced pneumonia was investigated showing NET-like structures surrounding Klebsiella bacteria at sites of immune infiltration in both Pad4 −/− and Pad4 +/+ mice.…”

Section: Nets and Eets In Bacterial Infectionsmentioning

confidence: 99%

In vivo evidence for extracellular DNA trap formation

et al. 2020

View full text Add to dashboard Cite

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.

show abstract

Peptidylarginine deiminases 2 and 4 modulate innate and adaptive immune responses in TLR-7–dependent lupus

Cited by 76 publications

References 62 publications

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

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

Systemic Juvenile Idiopathic Arthritis–Associated Lung Disease: Characterization and Risk Factors

In vivo evidence for extracellular DNA trap formation

Contact Info

Product

Resources

About