Diagnostic role of endothelial microparticles in vasculitis

Erdbruegger, Uta; Großheim, Marieke; Hertel, Barbara; Wyss, Kristin; Kirsch, Torsten; Woywodt, Alexander; Haller, Hermann; Haubitz, Marion

doi:10.1093/rheumatology/ken373

Cited by 107 publications

(85 citation statements)

References 33 publications

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“…MVs contain high levels of PS on their outer membrane and are formed during either cellular activation or apoptosis. During active vasculitis, plasma of patients contains increased numbers of MVs compared with healthy controls (17)(18)(19). Using RBL cells expressing enzymatically active PR3, we observed a significant reduction in MV production when PR3 was expressed at the membrane regardless of whether cells were activated or undergoing apoptosis.…”

Section: Discussionmentioning

confidence: 87%

“…Although produced at low levels during normal physiological conditions, MV production significantly increases during inflammatory and autoimmune diseases including vasculitis, atherosclerosis, diabetes, and malignancies (16). During active vasculitis, MV levels were significantly increased in the plasma of patients compared with healthy controls, and these originated from platelets, endothelial cells, and leukocytes (17)(18)(19). Additionally, levels of endothelial cell-derived MVs correlated with disease activity, possibly serving as a marker of endothelial cell activation or vascular damage (18,19).…”

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confidence: 99%

“…During active vasculitis, MV levels were significantly increased in the plasma of patients compared with healthy controls, and these originated from platelets, endothelial cells, and leukocytes (17)(18)(19). Additionally, levels of endothelial cell-derived MVs correlated with disease activity, possibly serving as a marker of endothelial cell activation or vascular damage (18,19). Whether MV production during vasculitis is simply a consequence of vascular dysfunction or is actively involved in the process is not yet known.…”

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confidence: 99%

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Proteinase 3 Is a Phosphatidylserine-binding Protein That Affects the Production and Function of Microvesicles

Martin¹,

Kantari‐Mimoun²,

Yin³

et al. 2016

Journal of Biological Chemistry

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Proteinase 3 (PR3), the autoantigen in granulomatosis with polyangiitis, is expressed at the plasma membrane of resting neutrophils, and this membrane expression increases during both activation and apoptosis. Using surface plasmon resonance and protein-lipid overlay assays, this study demonstrates that PR3 is a phosphatidylserine-binding protein and this interaction is dependent on the hydrophobic patch responsible for membrane anchorage. Molecular simulations suggest that PR3 interacts with phosphatidylserine via a small number of amino acids, which engage in long lasting interactions with the lipid heads. As phosphatidylserine is a major component of microvesicles (MVs), this study also examined the consequences of this interaction on MV production and function. PR3-expressing cells produced significantly fewer MVs during both activation and apoptosis, and this reduction was dependent on the ability of PR3 to associate with the membrane as mutating the hydrophobic patch restored MV production. Functionally, activation-evoked MVs from PR3-expressing cells induced a significantly larger respiratory burst in human neutrophils compared with control MVs. Conversely, MVs generated during apoptosis inhibited the basal respiratory burst in human neutrophils, and those generated from PR3-expressing cells hampered this inhibition. Given that membrane expression of PR3 is increased in patients with granulomatosis with polyangiitis, MVs generated from neutrophils expressing membrane PR3

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Section: Discussionmentioning

confidence: 87%

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confidence: 99%

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confidence: 99%

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Proteinase 3 Is a Phosphatidylserine-binding Protein That Affects the Production and Function of Microvesicles

Martin¹,

Kantari‐Mimoun²,

Yin³

et al. 2016

Journal of Biological Chemistry

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“…Under normal circumstances, most plasma MPs derive from platelets and erythrocytes (38)(39)(40). Under inflammatory conditions, MPs from nucleated cells such as lymphocytes, granulocytes, and endothelial cells become more prominent (41)(42)(43).…”

Section: Discussionmentioning

confidence: 99%

Increased IgG on cell‐derived plasma microparticles in systemic lupus erythematosus is associated with autoantibodies and complement activation

Nielsen

Østergaard

Stener

et al. 2012

Arthritis & Rheumatism

154

146

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Objective. To quantify immunoglobulin and C1q on circulating cell-derived microparticles (MPs) in patients with systemic lupus erythematosus (SLE) and to determine whether immunoglobulin and C1q levels are correlated with clinical and serologic parameters.Methods. Sixty-eight clinically well-characterized SLE patients, 38 healthy controls, 6 patients with systemic sclerosis (SSc), and 6 patients with rheumatoid arthritis (RA) were included. The numbers of annexin V-binding MPs displaying IgG, IgM, or C1q were enumerated by flow cytometry. MP protein levels were determined by mass spectrometry in clinically defined subsets of SLE patients and controls. The MP IgG load was determined by flow cytometric analysis of all samples from SLE patients and healthy controls.Results. SLE patients had significantly increased total and relative numbers of IgG-positive MPs (P ‫؍‬ 0.0004), with a much higher average IgG load per MP (P < 0.0001) than healthy controls. Quantitative mass spectrometry of purified MPs verified significantly increased IgG, IgM, and C1q levels in SLE patients. In RA and SSc patients, the average IgG load per MP was significantly lower than in SLE patients (P ‫؍‬ 0.006 and P ‫؍‬ 0.05, respectively). Also, the IgM load and C1q load per MP were significantly higher in SLE patients than in the control groups (P < 0.05), except for IgM in the RA group. IgG-positive MPs were significantly associated with the presence of anti-double-stranded DNA, anti-extractable nuclear antigen, and antihistone antibodies, with total IgG, and with decreased leukocyte counts. Average IgG load per MP was associated with lower concentrations of MPs, the presence of anti-C1q antibodies, and complement consumption. Systemic lupus erythematosus (SLE) is an autoimmune disease with a wide range of clinical manifestations (1). One of the serologic hallmarks of SLE is the presence of circulating, high-affinity autoantibodies against nuclear constituents (2). These autoantibodies may form circulating proinflammatory immune complexes (ICs) that directly trigger plasmacytoid dendritic cells (PDCs) and the complement system, e.g., in the kidneys (3). Also, IC and autoantibody activation of SLE neutrophils prone to NETosis, i.e., specialized neutrophil cell death, contributes to the sustained PDC activation that is typical of SLE (4,5). The etiology of antinuclear autoimmunity in SLE remains unclear, but persistent, poorly cleared circulating cellular remnants, including microparticles (MPs) and neutrophil extracellular traps, are likely sources of immunogenic autoantigens (6-9). Conclusion. Our findings indicate that circulating cell-derived MPs in SLE patients

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“…EMPs, quantified in plasma as particles that are CD31 1 (the constitutive endothelial marker PECAM), but CD42b 2 (the constitutive platelet-specific glycoprotein Ib), are present in low levels in plasma of healthy individuals and reflecting normal endothelial turnover (19,21,22). EMP levels are increased in a variety of vascular-related disorders (21,(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37). Using CD62 (E-selectin, an adhesion molecule expressed on activated endothelium), activation-induced EMPs have a high CD42b 2 CD62 1 / CD42b 2 CD31 1 ratio, and apoptosis-induced EMPs have a low ratio (19)(20)(21)34).…”

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confidence: 99%

Circulating Endothelial Microparticles as a Measure of Early Lung Destruction in Cigarette Smokers

Gordon

Gudi

Krause

et al. 2011

Am J Respir Crit Care Med

205

173

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Rationale: There is increasing evidence that emphysema is associated with primary loss of pulmonary capillary endothelium. Plasma levels of endothelial microparticles (EMPs), small vesicles released from activated or apoptotic endothelial cells, are elevated in vascularrelated disorders. Objectives: To evaluate whether plasma EMP levels are elevated in smokers with early lung destruction as assessed by normal spirometry but reduced diffusing capacity of the lung for carbon monoxide (DL CO ). Methods: Lung health was assessed by pulmonary function tests (PFTs: spirometry, total lung capacity, DL CO ) and chest X-ray; smoking status was assessed by urine nicotine and cotinine. EMP levels (CD42b 2 CD31 1 microparticles) were quantified as activated or apoptotic. The initial cohort (n 5 92) included healthy nonsmokers (normal PFTs), healthy smokers (normal PFTs), and smokers with early evidence of lung destruction (normal spirometry, low DL CO ). Two prospective cohorts were then tested: a group similar to the initial cohort and an HIV1 1 cohort. Measurements and Main Results: Healthy smokers had mildly increased levels of EMPs. Strikingly, 95% of smokers with normal spirometry, low DL CO had increased EMPs, with reduced CD62 1 / CD31 1 ratios (P , 10 24 ) and elevated CD42b 2 CD31 1 annexin V 1 EMPs (P , 10 24 ), suggesting derivation from endothelial apoptosis. Most elevated EMPs were angiotensin-converting enzyme positive, suggesting derivation from pulmonary capillaries. Both prospective cohorts confirmed the initial cohort data. Conclusions: Plasma EMPs with apoptotic characteristics are elevated in smokers with normal spirometry but reduced DL CO , consistent with the concept that emphysema is associated, in part, with capillary endothelium apoptosis, suggesting that the early development of emphysema might be monitored with plasma EMP levels.

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Diagnostic role of endothelial microparticles in vasculitis

Abstract: EMPs are elevated in active adult AAV. EMP levels correlate with disease activity and might serve as a marker of endothelial activation and damage. Differential detection of endothelial, platelet- and leucocyte-derived MPs may provide more insight in to the pathogenesis of AAV.

Cited by 107 publications

References 33 publications

Proteinase 3 Is a Phosphatidylserine-binding Protein That Affects the Production and Function of Microvesicles

Proteinase 3 Is a Phosphatidylserine-binding Protein That Affects the Production and Function of Microvesicles

Increased IgG on cell‐derived plasma microparticles in systemic lupus erythematosus is associated with autoantibodies and complement activation

Circulating Endothelial Microparticles as a Measure of Early Lung Destruction in Cigarette Smokers

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