Proteins derived from neutrophil extracellular traps may serve as self-antigens and mediate organ damage in autoimmune diseases

Knight, Jason S.; Carmona‐Rivera, Carmelo; Kaplan, Mariana J.

doi:10.3389/fimmu.2012.00380

Cited by 154 publications

(118 citation statements)

References 136 publications

Supporting

Mentioning

113

Contrasting

Unclassified

Order By: Relevance

“…The deposition of MSU into appendicular joints has an essential role in the development of acute gout (49), and recent studies have provided evidence that MSU-induced NETs initiate inflammatory responses in this disease (50,51). Whether a similar mechanism is applied to IgG4-related AIP requires further studies to demonstrate that MSU deposition occurs in IgG4-related pancreatic lesions as well as evaluation of whether uric acid-clearing agents have efficacy in patients with IgG4-related AIP.…”

Section: Discussionmentioning

confidence: 99%

Plasmacytoid Dendritic Cell Activation and IFN-α Production Are Prominent Features of Murine Autoimmune Pancreatitis and Human IgG4-Related Autoimmune Pancreatitis

Arai

Yamashita

Kuriyama

et al. 2015

The Journal of Immunology

132

View full text Add to dashboard Cite

The abnormal immune response accompanying IgG4-related autoimmune pancreatitis (AIP) is presently unclear. In this study, we examined the role of plasmacytoid dendritic cell (pDC) activation and IFN-α production in this disease as well as in a murine model of AIP (MRL/Mp mice treated with polyinosinic-polycytidylic acid). We found that the development of AIP in treated MRL/Mp mice occurred in parallel with pancreatic accumulation of pDCs producing IFN-α, and with pDC depletion and IFN-α-blocking studies, we showed that such accumulation was necessary for AIP induction. In addition, we found that the pancreas of treated MRL/Mp mice contained neutrophil extracellular traps (NETs) shown previously to stimulate pDCs to produce IFN-α. Consistent with these findings, we found that patients with IgG4-related AIP also exhibited pancreatic tissue localization of IFN-α–expressing pDCs and had significantly higher serum IFN-α levels than healthy controls. In addition, the inflamed pancreas of these patients but not controls also contained NETs that were shown to be capable of pDC activation. More importantly, patient pDCs cultured in the presence of NETs produced greatly increased levels of IFN-α and induced control B cells to produce IgG4 (but not IgG1) as compared with control pDCs. These data suggest that pDC activation and production of IFN-α is a major cause of murine AIP; in addition, the increased pDC production of IFN-α and its relation to IgG4 production observed in IgG4-related AIP suggest that this mechanism also plays a role in the human disease.

show abstract

Section: Discussionmentioning

confidence: 99%

Plasmacytoid Dendritic Cell Activation and IFN-α Production Are Prominent Features of Murine Autoimmune Pancreatitis and Human IgG4-Related Autoimmune Pancreatitis

Arai

Yamashita

Kuriyama

et al. 2015

The Journal of Immunology

132

View full text Add to dashboard Cite

show abstract

“…Furthermore, NETs is associated with altered patterns of epigenetic and posttranslational modifications, such as methylation, acetylation, and citrullination, which may represent an important source of autoantigens promoting the generation of autoantibodies (32). In particular, a growing body of evidence supports a pathogenic role for citrullinated autoantigens in triggering autoimmune responses in SLE, rheumatoid arthritis, and multiple sclerosis (33).…”

Section: Discussionmentioning

confidence: 99%

Increased Neutrophil Elastase and Proteinase 3 and Augmented NETosis Are Closely Associated With β-Cell Autoimmunity in Patients With Type 1 Diabetes

et al. 2014

View full text Add to dashboard Cite

Type 1 diabetes (T1D) is an autoimmune disease resulting from the self-destruction of insulin-producing β-cells. Reduced neutrophil counts have been observed in patients with T1D. However, the pathological roles of neutrophils in the development of T1D remain unknown. Here we show that circulating protein levels and enzymatic activities of neutrophil elastase (NE) and proteinase 3 (PR3), both of which are neutrophil serine proteases stored in neutrophil primary granules, were markedly elevated in patients with T1D, especially those with disease duration of less than 1 year. Furthermore, circulating NE and PR3 levels increased progressively with the increase of the positive numbers and titers of the autoantibodies against β-cell antigens. An obvious elevation of NE and PR3 was detected even in those autoantibody-negative patients. Increased NE and PR3 in T1D patients are closely associated with elevated formation of neutrophil extracellular traps. By contrast, the circulating levels of α1-antitrypsin, an endogenous inhibitor of neutrophil serine proteases, are decreased in T1D patients. These findings support an early role of neutrophil activation and augmented neutrophil serine proteases activities in the pathogenesis of β-cell autoimmunity and also suggest that circulating NE and PR3 may serve as sensitive biomarkers for the diagnosis of T1D.

show abstract

“…There are two sources of nucleic acid auto-antigens in SLE: apoptosis and NETosis [14,15]. Increased apoptosis of T lymphocytes, neutrophils, monocytes and macrophages has been documented in SLE cases [16,17,18].…”

Section: Introductionmentioning

confidence: 99%

Differential Immuno-Reactivity to Genomic DNA, RNA and Mitochondrial DNA is Associated with Auto-Immunity

Ivanova

Khaiboullina

Черенкова

et al. 2014

Cell Physiol Biochem

View full text Add to dashboard Cite

Background: Circulating auto-reactive antibodies are hallmark features of auto-immune diseases, however little is known with respect to the specificity of such bio-markers. In the present study, we investigated the specificity of anti-nucleic acid antibodies in the blood of subjects with systemic lupus erythematosus (SLE) and healthy controls. Methods: Sera from 12 SLE cases and 8 controls were evaluated for immuno-reactivity to purified RNA, DNA and mitochondrial DNA (mtDNA) by enzyme-linked immuno-sorbent assay (ELISA). Results: As expected, immuno-reactivity to total nucleic acids was significantly higher in subjects with SLE when compared to healthy controls, however a clear distinction was observed among the various nucleic acid sub-types, with sera from SLE subjects displaying the greatest immuno-reactivity to RNA followed by mtDNA and then total DNA. Conclusion: The identification of auto-reactive antibodies can serve as highly sensitive biomarkers, although their specificity may not always allow diagnostic certainty. The knowledge that auto-antibodies in subjects with SLE display differential immuno-reactivity may help to improve existing diagnostics and may lead to a better understanding of the pathogenesis of auto-immune disorders.

show abstract

Proteins derived from neutrophil extracellular traps may serve as self-antigens and mediate organ damage in autoimmune diseases

Cited by 154 publications

References 136 publications

Plasmacytoid Dendritic Cell Activation and IFN-α Production Are Prominent Features of Murine Autoimmune Pancreatitis and Human IgG4-Related Autoimmune Pancreatitis

Plasmacytoid Dendritic Cell Activation and IFN-α Production Are Prominent Features of Murine Autoimmune Pancreatitis and Human IgG4-Related Autoimmune Pancreatitis

Increased Neutrophil Elastase and Proteinase 3 and Augmented NETosis Are Closely Associated With β-Cell Autoimmunity in Patients With Type 1 Diabetes

Differential Immuno-Reactivity to Genomic DNA, RNA and Mitochondrial DNA is Associated with Auto-Immunity

Contact Info

Product

Resources

About