Discrimination and variable impact of ANCA binding to different surface epitopes on proteinase 3, the Wegener’s autoantigen

Silva, Francisco; Hummel, Amber M.; Jenne, Dieter E.; Specks, Ulrich

doi:10.1016/j.jaut.2010.06.021

Cited by 33 publications

(75 citation statements)

References 46 publications

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“…2C) clearly indicates that the major binding site of MCPR3-7 is on the carboxyl-terminal half of PR3. These functional data are fully consistent with our previous observation that the epitope of MCPR3-7 could be reconstructed at least in part by a murine to human residue swap in the carboxyl-terminal half of murine PR3 (T146A,R218W,Q223L) (30).…”

Section: Discussionsupporting

confidence: 91%

“…In contrast, unlabeled MCPR3-7 did not interfere with the binding of FITC-conjugated MCPR3-2 (lower left panel), and unlabeled MCPR3-2 inhibited the binding of FITC-conjugated MCPR3-7 by only 21% (upper right panel). These findings corroborated previous data (30), clearly indicating that MCPR3-7 recognized a unique epitope on pro-PR3 that is different from that of MCPR3-2 and all other mAbs. The precise binding site of MCPR3-7, however, remained uncertain as the epitope on human PR3 was not lost after replacing Ala 146 , Trp 218 , and Leu 223 with the respective residues of murine PR3.…”

Section: Identification Of New Mabs With Preferential Binding Tosupporting

confidence: 91%

“…Bead-based Flow Cytometry-The possible competition between the two mAbs MCPR3-2 and MCPR3-7 in binding to pro-PR3 was analyzed by bead-based flow cytometry using the carboxyl-terminally tagged PR3 variant PR3ctp-S195A-cmyc (pro-PR3) (30). Stably transfected HEK 293 cells expressing the proforms were grown in serum-free medium for 2 days.…”

Section: Methodsmentioning

confidence: 99%

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A Monoclonal Antibody (MCPR3-7) Interfering with the Activity of Proteinase 3 by an Allosteric Mechanism

Hinkofer

Seidel

Korkmaz

et al. 2013

Journal of Biological Chemistry

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Background: Proteinase 3 is an abundant serine protease with high similarity to neutrophil elastase and a major autoimmune target in systemic vasculitis. Results:We identified a monoclonal antibody that inhibits PR3 activity. Conclusion: PR3-inhibiting antibodies can change its conformation and impair interactions with ␣ 1 -proteinase inhibitor. Significance: PR3-inhibiting antibodies may play a role in autoimmune vasculitis and could be exploited as highly selective inhibitors.

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Section: Discussionsupporting

confidence: 91%

Section: Identification Of New Mabs With Preferential Binding Tosupporting

confidence: 91%

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A Monoclonal Antibody (MCPR3-7) Interfering with the Activity of Proteinase 3 by an Allosteric Mechanism

Hinkofer

Seidel

Korkmaz

et al. 2013

Journal of Biological Chemistry

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“…This caveat holds true for patient sera, as well as for the reference antibody preparations. Antibodies differ in terms of their IgG subclass composition as well as the avidity, glycosylation and epitope specificity of the antibodies [65][66][67][68][69][70][71][72][73][74] . In particular, epitope specificity might affect standardization of different assay formats, as the accessibility of epitopes might differ between different assay formats.…”

Section: Harmonization and Standardization Of Anca Testingmentioning

confidence: 99%

Revised 2017 international consensus on testing of ANCAs in granulomatosis with polyangiitis and microscopic polyangiitis

et al. 2017

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| Anti-neutrophil cytoplasmic antibodies (ANCAs) are valuable laboratory markers used for the diagnosis of well-defined types of small-vessel vasculitis, including granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). According to the 1999 international consensus on ANCA testing, indirect immunofluorescence (IIF) should be used to screen for ANCAs, and samples containing ANCAs should then be tested by immunoassays for proteinase 3 (PR3)-ANCAs and myeloperoxidase (MPO)-ANCAs. The distinction between PR3-ANCAs and MPO-ANCAs has important clinical and pathogenic implications. As dependable immunoassays for PR3-ANCAs and MPO-ANCAs have become broadly available, there is increasing international agreement that high-quality immunoassays are the preferred screening method for the diagnosis of ANCA-associated vasculitis. The present Consensus Statement proposes that high-quality immunoassays can be used as the primary screening method for patients suspected of having the ANCA-associated vaculitides GPA and MPA without the categorical need for IIF, and presents and discusses evidence to support this recommendation.NATURE REVIEWS | RHEUMATOLOGY VOLUME 13 | NOVEMBER 2017 | 683 CONSENSUS STATEMENT © 2 0 1 7 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d .Given the improvements in antigen-specific immuno assays, the international consensus on the testing of ANCAs in small-vessel vasculitis seems in need of updating [7][8][9][10] . In this manuscript, a revised 2017 international consensus is proposed by a group of international experts (from North and Central America, Australia, Europe and Asia) in the ANCA field. This Consensus Statement highlights the value of ANCA testing as a tool for diagnosis (but not follow-up) of GPA and MPA and gives a historical perspective of ANCAs in small-vessel vasculitis. This Consensus Statement does not, however, present evidence-based guidelines or a meta-analysis. MethodsThis Consensus Statement was prepared by a group of experts from four European laboratories (X.B., J.D., N.R., J.W.C.T. and E.C.) in person and by correspondence. The draft was circulated to each contributor and modified, and the resulting document was distributed by e-mail to 16 experts from four continents, selected based on their expertise and knowledge in clinical and/or laboratory aspects of AAV. This revised document resulted in a second round of discussions and revisions. The final document was returned to all contributors for ratification.The Consensus Statement is based on the results of a multicentre European Vasculitis Study Group (EUVAS) evaluation of the value of IIF versus antigen-specific immunoassays for ANCA detection 6,11,12 . This study, which showed a large variability between different IIF methods and a good diagnostic performance of PR3-ANCA and MPO-ANCA immunoassays 6 , indicated that the 1999 international consensus on ANCA testing for AAV needed revision. When the consensus was put toget...

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“…Several factors affect the potential of ANCA activation. Certain epitopes for both MPO-ANCA (Roth et al 2013) and PR3-ANCA have been suggested to be of importance in AAV (Kuhl et al 2010, Silva et al 2010). In the case of MPO-ANCA, it has been shown that epitope specificity varies with disease activity and that ANCA activate neutrophils to produce ROS more profoundly during active disease (Roth et al 2013).…”

Section: Ancamentioning

confidence: 99%

The Contribution of Innate Immunity to the Pathogenesis of ANCA-associated Vasculitis

Söderberg¹

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"Nog finns det mål och mening med vår färd -men det är vägen som är mödan värd" − Karin Boye SupervisorMårten Segelmark, Linköping University, Sweden Co-supervisorsPer Eriksson, Linköping University, Sweden Jan Ernerudh, Linköping University, Sweden Tino Kurz, Linköping University, Sweden Faculty opponentPeter Heeringa, University of Groningen, The Netherlands Abstract Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) constitute a group of vasculitides characterized by neutrophil-rich necrotizing inflammation of small vessels and the presence of ANCA in the circulation. Dying neutrophils surrounding the walls of small vessels are a histological hallmark of AAV. Traditionally it has been assumed that these neutrophils die by necrosis, but neutrophil extracellular traps (NETs) have recently been visualized at the sites of vasculitic lesions. NETs were first described to be involved in capture and elimination of pathogens but dysregulated production and/or clearance of NETs are thought to contribute to vessel inflammation in AAV; directly by damaging endothelial cells and indirectly by acting as a link between the innate and adaptive immune system through the generation of pathogenic PR3-ANCA and MPO-ANCA that can activate neutrophils. ANCA can, however, be found in all individuals and are therefore suggested to belong to the repertoire of natural antibodies produced by innate-like B cells, implying that not all ANCA are pathogenic.In paper I, we found neutrophils in patients to be more prone to undergo NETosis/necrosis spontaneously compared with neutrophils in healthy controls (HC), as well as that active patients possessed elevated levels of NETs in the circulation. Our results also suggest that ANCA during remission could contribute to the clearance of NETs as we observed an inverse relation between ANCA and NETs. In paper II, we observed neutrophils in patients to be more easily activated upon ANCA stimulation as they produced more ROS than neutrophils in HC. In paper III, we showed for the first time that cells of adaptive immunity (B and T cells)

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Discrimination and variable impact of ANCA binding to different surface epitopes on proteinase 3, the Wegener’s autoantigen

Cited by 33 publications

References 46 publications

A Monoclonal Antibody (MCPR3-7) Interfering with the Activity of Proteinase 3 by an Allosteric Mechanism

A Monoclonal Antibody (MCPR3-7) Interfering with the Activity of Proteinase 3 by an Allosteric Mechanism

Revised 2017 international consensus on testing of ANCAs in granulomatosis with polyangiitis and microscopic polyangiitis

The Contribution of Innate Immunity to the Pathogenesis of ANCA-associated Vasculitis

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