Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro.

Falk, Ronald J.; Terrell, Regina S.; Charles, Linda; Jennette, J. Charles

doi:10.1073/pnas.87.11.4115

Cited by 1,161 publications

(775 citation statements)

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“…In this assay, wells coated with PR3 (Bio Advance) were first treated with 100 l of 20 mM freshly prepared periodic acid (HIO 4 ; SigmaAldrich) at 4°C for 30 minutes, in order to prevent nonspecific binding of lectins to carbohydrate determinants on PR3. Desialylation of PR3 does not affect the binding of anti-PR3 antibodies, since the levels of anti-PR3 antibodies determined on HIO 4 -treated PR3 were strongly and significantly correlated with the levels of anti-PR3 antibodies determined on native PR3. After 2 washes with 300 l of sample buffer (Bio Advance), 100 l of each human serum, diluted 1:50, was added in duplicate and incubated for 60 minutes at 37°C.…”

Section: Methodsmentioning

confidence: 90%

Sialylation levels of anti-proteinase 3 antibodies are associated with the activity of granulomatosis with polyangiitis (Wegener's)

Espy

Morelle²,

Kavian

et al. 2011

Arthritis & Rheumatism

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Objective. To investigate whether the glycosylation and sialylation levels of anti-proteinase 3 (anti-PR3) antibodies could affect their pathogenicity, and whether these levels could be correlated with the activity of granulomatosis with polyangiitis (Wegener's) (GPA).Methods. Forty-two serum samples positive for anti-PR3 antibodies from 42 patients with active or weakly active/inactive GPA were included. Anti-PR3 antibodies were assayed by enzyme-linked immunosorbent assay, and their levels of glycosylation and sialylation were assessed by enzyme-linked lectin assay. The glycosylation and sialylation levels of IgG purified from the serum of healthy donors and patients with active, remitted, or weakly active disease were assessed by permethylation and mass spectrometry analysis of glycans, following neuraminidase digestion. The neutrophil oxidative burst induced by purified IgG was assayed by spectrofluorimetry.Results. The mean sialylation ratio of anti-PR3 antibodies was significantly lower in patients with active disease than in patients with weakly active or inactive disease, and this was inversely correlated with the Birmingham Vasculitis Activity Score (BVAS) (P < 0.0001). Similar results were obtained using the BVAS/ GPA. The area under the receiver operating characteristic curve for the sialylation ratio of anti-PR3 antibodies, as a test to determine the activity of GPA, was 0.82 (P ‫؍‬ 0.0006). The characterization of N-glycans showed a decrease in 2,6-linked sialylated N-glycans and an increase in dHex 1 Hex 3 HexNAc 4 (mass/charge 1,836) agalactosylated structures in purified IgG from patients with active disease compared with controls. The anti-PR3 antibody-induced oxidative burst of neutrophils was inversely correlated with the sialylation levels of anti-PR3 IgG.

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Section: Methodsmentioning

confidence: 90%

Sialylation levels of anti-proteinase 3 antibodies are associated with the activity of granulomatosis with polyangiitis (Wegener's)

Espy

Morelle²,

Kavian

et al. 2011

Arthritis & Rheumatism

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“…Possibly, these autoantibodies are simply an epiphenomenon of chronic inflammation. Falk et a1 (42), however, showed that ANCA recognizing PR3 and MPO can induce the respiratory burst and degranulation of primed neutrophils in vitro. Initial studies in our laboratory have shown that anti-LF antibodies from RA patients are also capable of inducing activation of primed granulocytes.…”

Section: Discussionmentioning

confidence: 99%

Antineutrophil cytoplasmic antibodies in rheumatoid arthritis. characterization and clinical correlations

Mulder¹,

Horst²,

Leeuwen³

et al. 1993

Arthritis & Rheumatism

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Objective. To study the prevalence, interrelationships, and target antigens of antineutrophil cytoplasmic antibodies (ANCA) in rheumatoid arthritis (RA) and to relate their presence to disease duration and to the occurrence of extraarticular manifestations, including vasculitis. Methods. Sera from 94 patients with RA (31 with recent‐onset disease, 35 with longstanding disease but without extraarticular manifestations, and 28 with extraarticular disease) were studied for the presence of ANCA by indirect immunofluorescence. All sera were tested by enzyme‐linked immunosorbent assay (ELISA) for the presence of antibodies to proteinase 3, myeloperoxidase (MPO), elastase, lactoferrin (LF), and cathepsin G (CG), and by Western blotting for antibodies to neutrophil proteins. Results. Seventy percent of the 94 sera showed staining of the nuclei of ethanol‐fixed neutrophils; 32% of the 94 were proven to have ANCA, as manifested by their cytoplasmic staining pattern on paraformaldehyde‐fixed neutrophils. In the ELISA, 19 sera reacted with LF, 1 with MPO, and 1 with CG. By Western blotting, 21 sera reacted with LF, and 15 reacted with previously unknown polypeptides (7 sera with a 67/66‐kd doublet and 8 with a 63/54‐kd doublet). Neither of these antibodies was associated with a particular subset of the disease, but the prevalence of the antibodies tended to increase among patients with longstanding disease. Conclusion. ANCA in RA patients are directed toward diverse cytoplasmic antigens of the neutrophil, in particular, LF and other, not yet fully characterized polypeptides. The antibodies are not a marker for a disease subset, but are probably a corollary of chronic inflammation.

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“…pathogenesis of ANCA.associated vasculitis and could be used as a marker for disease activity [8]. In vitro, ANCA can activate neutrophils to produce reactive oxygen species, degranulate and damage target cells [9]. Standardized indirect immunofluorescence tests to diagnose and monitor patients have been developed, based on the typical cytoplasmic pattern (cANCA) of alcohol-fixed neutrophils using patient's sera.…”

Section: Introductionmentioning

confidence: 99%

Characterization of a recombinant proteinase 3, the autoantigen in Wegener's granulomatosis and its reactivity with anti‐neutrophil cytoplasmic autoantibodies

et al. 1996

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Using the bnculovlrus/Insect cells system, we have expmmed n recombinant protelnase 3 (PR3) --the neutrophil.derived sedne protease autonntlgen In Wegener's gntnulomatosis --as a illyemyiated Intrncellular and membrane-associated protein, OIIgosnochnrldes accounted for the difference in molecular weights between recombinant (34 kDa) and neutrophiI-PR3 (29 kDn), Whereas rabbit-anti-PR3 igG recognized both recombinant and nentrophll-derlved PR3, autoantibodies from Wegener patient sent reeognl~l only neutrophil-derived PR3, Although ollgosaeeharides were not involved in PR3 epitope recognition, autoantibodles did not recognize the amino acid primary structure of recombinant PR3, Improper disulfide bond formation and/or lack of post-translational events in insect cells, may affect the conformation of PR3, precluding its reactivity with sera from WG patients.

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Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro.

Cited by 1,161 publications

References 34 publications

Sialylation levels of anti-proteinase 3 antibodies are associated with the activity of granulomatosis with polyangiitis (Wegener's)

Sialylation levels of anti-proteinase 3 antibodies are associated with the activity of granulomatosis with polyangiitis (Wegener's)

Antineutrophil cytoplasmic antibodies in rheumatoid arthritis. characterization and clinical correlations

Characterization of a recombinant proteinase 3, the autoantigen in Wegener's granulomatosis and its reactivity with anti‐neutrophil cytoplasmic autoantibodies

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