Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Netting neutrophils in autoimmune small-vessel vasculitis.

ABSTRACT: Small-vessel vasculitis (SVV) is a chronic autoinflammatory condition linked to antineutrophil cytoplasm autoantibodies (ANCAs). Here we show that chromatin fibers, so-called neutrophil extracellular traps (NETs), are released by ANCA-stimulated neutrophils and contain the targeted autoantigens proteinase-3 (PR3) and myeloperoxidase (MPO). Deposition of NETs in inflamed kidneys and circulating MPO-DNA complexes suggest that NET formation triggers vasculitis and promotes the autoimmune response against neutrophil components in individuals with SVV.

SUBMITTER: Kessenbrock K

PROVIDER: S-EPMC2760083 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Netting neutrophils in autoimmune small-vessel vasculitis.

Kessenbrock Kai K Krumbholz Markus M Schönermarck Ulf U Back Walter W Gross Wolfgang L WL Werb Zena Z Gröne Hermann-Josef HJ Brinkmann Volker V Jenne Dieter E DE

Nature medicine 20090601 6

Small-vessel vasculitis (SVV) is a chronic autoinflammatory condition linked to antineutrophil cytoplasm autoantibodies (ANCAs). Here we show that chromatin fibers, so-called neutrophil extracellular traps (NETs), are released by ANCA-stimulated neutrophils and contain the targeted autoantigens proteinase-3 (PR3) and myeloperoxidase (MPO). Deposition of NETs in inflamed kidneys and circulating MPO-DNA complexes suggest that NET formation triggers vasculitis and promotes the autoimmune response a ...[more]

PMID: 19448636

Similar Datasets

Immunomodulation with eicosapentaenoic acid supports the treatment of autoimmune small-vessel vasculitis.

Project description:Small-vessel vasculitis is a life-threatening autoimmune disease that is frequently associated with anti-neutrophil cytoplasmic antibodies (ANCAs). Conventional immunotherapy including steroids and cyclophosphamide can cause serious adverse events, limiting the efficacy and safety of treatment. Eicosapentaenoic acid (EPA), a key component of fish oil, is an omega-3 polyunsaturated fatty acid widely known to be cardioprotective and beneficial for vascular function. We report two elderly patients with systemic ANCA-associated vasculitis (AAV) in whom the administration of EPA in concert with steroids safely induced and maintained remission, without the use of additioal immunosuppressants. To explore the mechanisms by which EPA enhances the treatment of AAV, we employed SCG/Kj mice as a spontaneous murine model of AAV. Dietary enrichment with EPA significantly delayed the onset of crescentic glomerulonephritis and prolonged the overall survival. EPA-derived anti-inflammatory lipid mediators and their precursors were present in the kidney, plasma, spleen, and lungs in the EPA-treated mice. Furthermore, a decrease in ANCA production and CD4/CD8-double negative T cells, and an increase in Foxp3(+) regulatory T cells in the lymph nodes of the kidney were observed in the EPA-treated mice. These clinical and experimental observations suggest that EPA can safely support and augment conventional therapy for treating autoimmune small-vessel vasculitis.

| S-EPMC4166948 | biostudies-literature

Pathogenesis of antineutrophil cytoplasmic autoantibody-associated small-vessel vasculitis.

Project description:Clinical, in vitro, and experimental animal observations indicate that antineutrophil cytoplasmic autoantibodies (ANCA) are pathogenic. The genesis of the ANCA autoimmune response is a multifactorial process that includes genetic predisposition, environmental adjuvant factors, an initiating antigen, and failure of T cell regulation. ANCA activate primed neutrophils (and monocytes) by binding to certain antigens expressed on the surface of neutrophils in specific inflammatory microenvironments. ANCA-activated neutrophils activate the alternative complement pathway, establishing an inflammatory amplification loop. The acute injury elicits an innate inflammatory response that recruits monocytes and T lymphocytes, which replace the neutrophils that have undergone karyorrhexis during acute inflammation. Extravascular granulomatous inflammation may be initiated by ANCA-induced activation of extravascular neutrophils, causing tissue necrosis and fibrin formation, which would elicit an influx of monocytes that transform into macrophages and multinucleated giant cells. Over time, the neutrophil-rich acute necrotizing lesions cause the accumulation of more lymphocytes, monocytes, and macrophages and produce typical granulomatous inflammation.

| S-EPMC5507606 | biostudies-other

Multiple Myeloma Mimicking a Small Vessel Vasculitis Presentation.

Project description:Multiple myeloma can have different clinical manifestations, and not all patients present with classic CRAB component. We describe a 46-year-old woman admitted to our hospital with a complaint of a bluish-to-black discoloration of the second toe that was rapidly progressive and acute kidney injury. We documented a Kappa light chain monoclonal gammopathy, increased presence of plasmacytes in bone marrow aspiration, and multiple lytic bone lesions, which led to a diagnosis of multiple myeloma. Although multiple myeloma presenting with blue finger syndrome is uncommon, it must always be considered as a differential diagnosis with this clinical finding.

| S-EPMC7037530 | biostudies-literature

Rituximab for the Treatment of Pediatric Double-Positive Small-Vessel Vasculitis.

Project description: Not available

| S-EPMC7000840 | biostudies-literature

Patient perceptions about illness self-management in ANCA-associated small vessel vasculitis.

Project description:To characterize patient perceptions, related to eight self-management behaviours relevant for adults with ANCA-associated small vessel vasculitis (ANCA-SVV), and to determine if these perceptions were associated with performance of each behaviour.Adults with ANCA-SVV (n = 202) completed a self-administered questionnaire that assessed eight self-management behaviours (adherence to recommendations for medication, health service use, diet, exercise, infection avoidance and symptom monitoring; prompt reporting of symptoms and side effects; and adjusting activities in response to symptoms), perceptions about these behaviours, socio-demographics, clinical factors and social desirability bias. Descriptive statistics were generated to characterize patients' perceptions about difficulty of, importance of, and specific barriers to performing each behaviour. Regression analyses explored whether these variables were associated with performing each behaviour, controlling for potential confounders.With few exceptions, higher perceived importance and lower perceived difficulty of each behaviour were associated with more frequent performance of the behaviour. For each behaviour, several specific barriers were frequently endorsed by patients and a number of these were associated with lower levels of self-management.This study reveals that patient perceptions about the illness and its treatment influence ANCA-SVV self-management. Perceived barriers to medication, health services, diet and exercise adherence were similar to those in other illnesses. This study also provides insight into barriers experienced by patients in performing behaviours (infection avoidance, symptom monitoring, reporting symptoms and side-effects and adjusting activities) not often previously studied. How the identification of these barriers can help inform future interventions for ANCA-SVV patients is to be discussed.

| S-EPMC4084613 | biostudies-literature

Constitutively active Lyn kinase causes a cutaneous small vessel vasculitis and liver fibrosis syndrome.

Project description:Neutrophilic inflammation is a hallmark of many monogenic autoinflammatory diseases; pathomechanisms that regulate extravasation of damaging immune cells into surrounding tissues are poorly understood. Here we identified three unrelated boys with perinatal-onset of neutrophilic cutaneous small vessel vasculitis and systemic inflammation. Two patients developed liver fibrosis in their first year of life. Next-generation sequencing identified two de novo truncating variants in the Src-family tyrosine kinase, LYN, p.Y508*, p.Q507* and a de novo missense variant, p.Y508F, that result in constitutive activation of Lyn kinase. Functional studies revealed increased expression of ICAM-1 on induced patient-derived endothelial cells (iECs) and of β2-integrins on patient neutrophils that increase neutrophil adhesion and vascular transendothelial migration (TEM). Treatment with TNF inhibition improved systemic inflammation; and liver fibrosis resolved on treatment with the Src kinase inhibitor dasatinib. Our findings reveal a critical role for Lyn kinase in modulating inflammatory signals, regulating microvascular permeability and neutrophil recruitment, and in promoting hepatic fibrosis.

| S-EPMC10022554 | biostudies-literature

Caspase-8 activation in neutrophils facilitates autoimmune kidney vasculitis through regulating CD4<sup>+</sup> effector memory T cells.

Project description:Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) are closely associated with neutrophil recruitment and activation, but the impact of the neutrophil apoptosis process in autoimmune disease has been rarely explained. Here, by integrating and analyzing single-cell transcriptome datasets, we found that the caspase-8-associated pathway in neutrophils was highly activated in the kidney rather than in the blood. To verify the function of caspase-8 in neutrophils on AAVs progression, we constructed neutrophil-specific caspase-8 knockout mice combined with an AAVs model induced by human ANCA from AAVs patients, a rapid and powerful model developed in this study. Our results show that caspase-8 activation of neutrophils up-regulates the expression of several inflammatory and immunoregulatory factors, especially IL23A, regulating the activation and differentiation of tissue-resident CD4+ effector memory T cells. This study reveals that the activation of caspase-8 in neutrophils can worsen glomerulonephritis of AAVs by regulating inflammation and immunity.

| S-EPMC9732547 | biostudies-literature

Crescentic poststreptococcal acute glomerulonephritis accompanied by small vessel vasculitis: case report of an elderly male.

Project description:BackgroundPoststreptococcal acute glomerulonephritis (PSAGN) in the elderly tends to have a severe clinical course and often presents with crescentic necrotizing glomerulonephritis in the renal biopsy. However, vasculitis lesions are unusual.Case presentationWe present a 71-year-old man who was admitted to our hospital for a recurrent gout attack with a rapid decline of renal function. Low C3 levels and a high anti-streptolysin O titer were observed, while myeloperoxidase- and proteinase 3- antineutrophil cytoplasmic antibody (ANCA) were negative. In addition to cellular crescent and necrosis lesions, diffuse peritubular capillaritis and venulitis as well as small arteriole vasculitis in the glomerular hilus were also apparent. Although granular C3c deposits in the capillary wall and hump lesions were not found, immunofluorescent staining for nephritis-associated plasmin receptor (NAPlr) and in situ zymography for plasmin activity were both positive. We thus diagnosed PSAGN accompanied by small vessel vasculitis. Steroid therapy gradually improved the patient's renal function, and hemodialysis was discontinued after 1 month.ConclusionsIn our case, streptococcus infection might have concurrently provoked vasculitis, and NAPlr staining was useful for confirming diagnosis.

| S-EPMC6921464 | biostudies-literature

Identification and functional characterization of a novel susceptibility locus for small vessel vasculitis with MPO-ANCA.

Project description:ObjectiveTo identify and characterize genetic loci associated with the risk of developing ANCA-associated vasculitides (AAV).MethodsGenetic association analyses were performed after Illumina sequencing of 1853 genes and subsequent replication with genotyping of selected single nucleotide polymorphisms in a total cohort of 1110 Scandinavian cases with granulomatosis with polyangiitis or microscopic polyangiitis, and 1589 controls. A novel AAV-associated single nucleotide polymorphism was analysed for allele-specific effects on gene expression using luciferase reporter assay.ResultsPR3-ANCA+ AAV was significantly associated with two independent loci in the HLA-DPB1/HLA-DPA1 region [rs1042335, P = 6.3 × 10-61, odds ratio (OR) 0.10; rs9277341, P = 1.5 × 10-44, OR 0.22] and with rs28929474 in the SERPINA1 gene (P = 2.7 × 10-10, OR 2.9). MPO-ANCA+ AAV was significantly associated with the HLA-DQB1/HLA-DQA2 locus (rs9274619, P = 5.4 × 10-25, OR 3.7) and with a rare variant in the BACH2 gene (rs78275221, P = 7.9 × 10-7, OR 3.0), the latter a novel susceptibility locus for MPO-ANCA+ granulomatosis with polyangiitis/microscopic polyangiitis. The rs78275221-A risk allele reduced luciferase gene expression in endothelial cells, specifically, as compared with the non-risk allele.ConclusionWe identified a novel susceptibility locus for MPO-ANCA+ AAV and propose that the associated variant is of mechanistic importance, exerting a regulatory function on gene expression in specific cell types.

| S-EPMC9348767 | biostudies-literature

Checks and Balances in Autoimmune Vasculitis.

Project description:Age-associated changes in the immune system including alterations in surface protein expression are thought to contribute to an increased susceptibility for autoimmune diseases. The balance between the expression of coinhibitory and costimulatory surface protein molecules, also known as immune checkpoint molecules, is crucial in fine-tuning the immune response and preventing autoimmunity. The activation of specific inhibitory signaling pathways allows cancer cells to evade recognition and destruction by the host immune system. The use of immune checkpoint inhibitors (ICIs) to treat cancer has proven to be effective producing durable antitumor responses in multiple cancer types. However, one of the disadvantages derived from the use of these agents is the appearance of inflammatory manifestations termed immune-related adverse events (irAEs). These irAEs are often relatively mild, but more severe irAEs have been reported as well including several forms of vasculitis. In this article, we argue that age-related changes in expression and function of immune checkpoint molecules lead to an unstable immune system, which is prone to tolerance failure and autoimmune vasculitis development. The topic is introduced by a case report from our hospital describing a melanoma patient treated with ICIs and who subsequently developed biopsy-proven giant cell arteritis. Following this case report, we present an in-depth review on the role of immune checkpoint pathways in the development and progression of autoimmune vasculitis and its relation with an aging immune system.

| S-EPMC5827159 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data