Constitutive membrane expression of proteinase 3 (PR3) and neutrophil activation by anti-PR3 antibodies

Rossum, André P van; Rarok, Agnieszka A.; Huitema, Minke G.; Fassina, Giorgio; Limburg, Pieter C.; Kallenberg, Cees G. M.

doi:10.1189/jlb.0604319

Cited by 44 publications

(38 citation statements)

References 40 publications

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“…Neutrophil activation induced by a mouse anti-human PR3 monoclonal antibody (PR3G-3) or by PR3 ANCA-positive IgG fractions was evaluated by measuring oxidative burst using the dihydrorhodamine assay. Consistent with the results from previous studies, oxidative burst was detected only when neutrophils were primed with TNF␣ (results not shown) (26,27). Neutrophils from CD177-negative donors (n ϭ 3) could be activated by the anti-PR3 antibody and showed comparable levels of neutrophil activation as were observed in the neutrophils from donors with moderate expression of CD177 (40-70% positive; n ϭ 3) and donors with high expression of CD177 (Ͼ70% positive; n ϭ 3) ( Figure 4A).…”

Section: Expression Of Cd177 and Mpr3 In Asv 1551supporting

confidence: 82%

“…Although mPR3 is differentially expressed on neutrophils, the oxidative burst mediated by the anti-PR3 antibody has been uniformly induced in neutrophils from donors with bimodal mPR3 expression (26). In the present study, we showed that the level of neutrophil activation induced by the anti-PR3 antibody was not correlated with the percentage of CD177ϩ/mPR3 high neutrophils, and that CD177Ϫ neutrophils could also be activated by the anti-PR3 antibody.…”

mentioning

confidence: 47%

“…Intracellular hydrogen peroxide produced during neutrophil activation was measured by the DHR-123 oxidation assay, as described previously (26). Isolated neutrophils from healthy donors were suspended in HBSS with Ca 2ϩ /Mg 2ϩ to a concentration of 2.5 ϫ 10 6 cells/ml and incubated with cytochalasin B (5 g/ml; Serva Electrophoresis, Heidelberg, Germany) at 37°C, to enhance oxygen radical production.…”

Section: Methodsmentioning

confidence: 99%

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Coexpression of CD177 and membrane proteinase 3 on neutrophils in antineutrophil cytoplasmic autoantibody–associated systemic vasculitis: Anti–proteinase 3–mediated neutrophil activation is independent of the role of CD177‐expressing neutrophils

Hu¹,

Westra²,

Huitema³

et al. 2009

Arthritis & Rheumatism

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Objective. Wegener's granulomatosis (WG) is strongly associated with antineutrophil cytoplasmic autoantibodies (ANCAs) directed against proteinase 3 (PR3). Recent studies have shown that membranebound PR3 (mPR3) is differentially expressed and colocalizes with CD177/NB1 on circulating neutrophils. We undertook this study to assess the differential expression of CD177 on neutrophils from patients with ANCA-associated systemic vasculitis (ASV) in comparison with patients with systemic lupus erythematosus (SLE), patients with rheumatoid arthritis (RA), and healthy individuals, and to investigate whether colocalization of mPR3 and CD177 affects anti-PR3-mediated neutrophil activation.Methods. Expression of CD177 and mPR3 was analyzed by flow cytometry on isolated neutrophils from patients with ASV (n ‫؍‬ 53), those with SLE (n ‫؍‬ 30), those with RA (n ‫؍‬ 26), and healthy controls (n ‫؍‬ 31). Neutrophil activation mediated by anti-PR3 antibodies was assessed by measuring the oxidative burst with a dihydrorhodamine assay.Results. Percentages of CD177-expressing neutrophils were significantly higher in patients with ASV and those with SLE than in healthy controls. In 3 healthy donors, CD177 expression was not detected. After priming with tumor necrosis factor ␣, neutrophils remained negative for CD177 while mPR3 expression was induced. Neutrophils from CD177-negative donors or CD177؊ neutrophils sorted from donors with bimodal expression were susceptible to anti-PR3-mediated oxidative burst. Variation in the extent of anti-PR3-mediated neutrophil activation among different donors occurred independent of the percentage of CD177-expressing neutrophils.Conclusion. Membrane expression of CD177 on circulating neutrophils is increased in patients with ASV and in those with SLE, but not in RA patients. However, primed neutrophils from CD177-negative individuals also express mPR3 and are susceptible to anti-PR3-mediated oxidative burst, suggesting that recruitment of CD177-independent mPR3 is involved in anti-PR3-induced neutrophil activation.

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Section: Expression Of Cd177 and Mpr3 In Asv 1551supporting

confidence: 82%

mentioning

confidence: 47%

Section: Methodsmentioning

confidence: 99%

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Coexpression of CD177 and membrane proteinase 3 on neutrophils in antineutrophil cytoplasmic autoantibody–associated systemic vasculitis: Anti–proteinase 3–mediated neutrophil activation is independent of the role of CD177‐expressing neutrophils

Hu¹,

Westra²,

Huitema³

et al. 2009

Arthritis & Rheumatism

View full text Add to dashboard Cite

show abstract

“…Consistent with previous studies, 20 oxidative burst was detected only when neutrophils were primed with TNF-␣ (data not shown). IgG from healthy control subjects and patients with anti-glomerular basement membrane disease did not activate TNF-␣-primed neutrophils (data not shown).…”

Section: Endos Treatment Inhibits Anca Igg-induced Neutrophilsupporting

confidence: 80%

IgG Glycan Hydrolysis Attenuates ANCA-Mediated Glomerulonephritis

Timmeren

Veen²,

Stegeman

et al. 2010

Journal of the American Society of Nephrology

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Anti-neutrophil cytoplasmic autoantibodies (ANCA) directed against myeloperoxidase (MPO) and proteinase 3 (Pr3) are considered pathogenic in ANCA-associated necrotizing and crescentic glomerulonephritis (NCGN) and vasculitis. Modulation of ANCA IgG glycosylation may potentially reduce its pathogenicity by abolishing Fc receptor-mediated activation of leukocytes and complement. Here, we investigated whether IgG hydrolysis by the bacterial enzyme endoglycosidase S (EndoS) attenuates ANCA-mediated NCGN. In vitro, treatment of ANCA IgG with EndoS significantly attenuated ANCAmediated neutrophil activation without affecting antigen-binding capacity. In a mouse model of anti-MPO IgG/LPS-induced NCGN, we induced disease with either unmodified or EndoS-treated (deglycosylated) anti-MPO IgG. In separate experiments, we administered EndoS systemically after disease induction with unmodified anti-MPO IgG. Pretreatment of anti-MPO IgG with EndoS reduced hematuria, leukocyturia, and albuminuria and attenuated both neutrophil influx and formation of glomerular crescents. After inducing disease with unmodified anti-MPO IgG, systemic treatment with EndoS reduced albuminuria and glomerular crescent formation when initiated after 3 but not 24 hours. In conclusion, IgG glycan hydrolysis by EndoS attenuates ANCA-induced neutrophil activation in vitro and prevents induction of anti-MPO IgG/LPS-mediated NCGN in vivo. Systemic treatment with EndoS early after disease induction attenuates the development of disease. Thus, modulation of IgG glycosylation is a promising strategy to interfere with ANCA-mediated inflammatory processes.

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“…More evidence for genetically controlled PR3 membrane expression came from a study that found a strong correlation between the percentage of PR3-positive polymorphonuclear neutrophils in identical twins (204). Anti-PR3 antibody was shown to induce activation of neutrophils with high PR3 membrane expression in a dosagedependent manner, whereas high PR3 membrane expression seemed to be associated with relapse, possibly mimicking the initial activation step of induction of PR3-ANCA-positive vasculitis (205,206).…”

Section: Geneticsmentioning

confidence: 99%

Hypotheses on the Etiology of Antineutrophil Cytoplasmic Autoantibody–Associated Vasculitis

Wijngaarden¹,

Rijn²,

Hagen³

et al. 2008

Clinical Journal of the American Society of Nephrology

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The first description of what is now known as antineutrophil cytoplasmic autoantibody-associated necrotizing vasculitis appeared more than 140 yr ago. Since then, many aspects of the pathogenic pathway have been elucidated, indicating the involvement of antineutrophil cytoplasmic autoantibodies, but why antineutrophil cytoplasmic autoantibodies are produced in the first place remains unknown. Over the years, many hypotheses have emerged addressing the etiology of antineutrophil cytoplasmic antibody production, but no exclusive factor or set of factors can so far be held responsible. Herein is reviewed the most influential hypotheses regarding the causes of antineutrophil cytoplasmic antibody-associated vasculitis with the aim of placing in an epidemiologic background the different hypotheses that are centered on environmental and genetic influences.Clin J Am Soc Nephrol 3: 237-252, 2008237-252, . doi: 10.2215 A ntineutrophil cytoplasmic autoantibody (ANCA)-associated necrotizing vasculitis was probably first described in 1866 by Kussmaul and Maier (1) as "polyarteritis nodosa." It was not until the early 1930s when the first case of what was later named Wegener's granulomatosis (WG) was described (2). The disease was named after Friedrich Wegener, who described it as an entity in 1939 (3). In 1985, antibodies associated with the disease were detected and later became known as ANCA (4). WG is a systemic autoimmune disease that can cause damage in various organs. Later, microscopic polyangiitis (MPA) was distinguished as a separate ANCA-associated vasculitis. The disease-or its immunosuppressive treatment-can cause high levels of morbidity and death, especially in patients with renal involvement. Animal experiments have shown that ANCA directed against myeloperoxidase (MPO) can cause vasculitis that resembles human vasculitic disease (5,6); however, the cause of ANCA production remains unresolved.Theories have been developed to explain how ANCA could interact with neutrophils, along with monocytes and most probably T lymphocytes, to form the lesions that are characteristic of ANCA-associated vasculitis, such as fibrinoid necrosis and granulomas (7). A recent theory of interest has been postulated by Pendergraft et al. (8), stating that an antibody against the complementary peptide of proteinase-3 (PR3) in an idiotypic/anti-idiotypic network is essential to the development of ANCA and to the development of clinical vasculitis, but why and how these ANCA are produced in the first place remains unanswered. Nonetheless, many hypotheses have been developed about the initiating factor for ANCA production. Many factors, either directly or indirectly, have been considered important in the development of ANCA: Silica exposure (9); genetic predisposition (10); bacterial infection by Staphylococcus aureus (11); viral infection by, for instance, parvovirus B19 (12); and thyroid drugs (13) all have been correlated with and held to contribute to the incidence of ANCA-associated vasculitis. Some of these hypotheses are still th...

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Constitutive membrane expression of proteinase 3 (PR3) and neutrophil activation by anti-PR3 antibodies

Cited by 44 publications

References 40 publications

Coexpression of CD177 and membrane proteinase 3 on neutrophils in antineutrophil cytoplasmic autoantibody–associated systemic vasculitis: Anti–proteinase 3–mediated neutrophil activation is independent of the role of CD177‐expressing neutrophils

Coexpression of CD177 and membrane proteinase 3 on neutrophils in antineutrophil cytoplasmic autoantibody–associated systemic vasculitis: Anti–proteinase 3–mediated neutrophil activation is independent of the role of CD177‐expressing neutrophils

IgG Glycan Hydrolysis Attenuates ANCA-Mediated Glomerulonephritis

Hypotheses on the Etiology of Antineutrophil Cytoplasmic Autoantibody–Associated Vasculitis

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