Antiproteinase 3 Antineutrophil Cytoplasmic Antibodies and Disease Activity in Wegener Granulomatosis

Finkielman, Javier D.; Merkel, Peter A.; Schroeder, Darrell R.; Hoffman, Gary S.; Spiera, Robert; Clair, E. William St.; Davis, John C.; McCune, W. Joseph; Lears, Andrea; Ytterberg, Steven R.; Hummel, Amber M.; Viss, Margaret A.; Peikert, Tobias; Stone, John H.; Specks, Ulrich

doi:10.7326/0003-4819-147-9-200711060-00005

Cited by 240 publications

(176 citation statements)

References 39 publications

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“…As purified PR3-cANCA IgG preparations, but not cANCAs in whole blood, were able to bind to PR3 on the neutrophil surface, conformational alterations or steric inaccessibility of surface-bound PR3 was inferred to explain the low-affinity interaction between PR3 and cANCA. Although cANCA measurements are generally accepted as a valuable diagnostic tool and diseasespecific biomarker, their utility for the monitoring of WG patients appears to be unreliable (9). Titer decreases and increases were found to be weakly correlated with remissions and relapses, respectively, and disease activity in general.…”

Section: W Egener's Granulomatosis (Wg) Is An Autoimmunementioning

confidence: 96%

Mapping of Conformational Epitopes on Human Proteinase 3, the Autoantigen of Wegener’s Granulomatosis

Kuhl

Korkmaz

Utecht³

et al. 2010

The Journal of Immunology

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Anti-neutrophil cytoplasmic Abs (cANCAs) against conformational epitopes of proteinase 3 (PR3) are regarded as an important pathogenic marker in Wegener’s granulomatosis (WG). Although the three-dimensional structure of PR3 is known, binding sites of mAbs and cANCAs have not been mapped to date. Competitive binding and biosensor experiments suggested the existence of four nonoverlapping areas on the PR3 surface. In this paper, we present an approach to identify these discontinuous surface regions that cannot be mimicked by linear peptides. The very few surface substitutions found in closely related PR3 homologs from primates, which were further varied by the construction of functional human-gibbon hybrids, resulted in the differential loss of three Ab binding sites, two of which were mapped to the N-terminal β-barrel and one to the linker segment connecting the N- and C-terminal barrels of PR3. The sera from WG patients differed in their binding to gibbon PR3 and the gibbon-human PR3 hybrid, and could be divided into two groups with similar or significantly reduced binding to gibbon PR3. Binding of almost all sera to PR3–α1-protease inhibitor (α1–PI) complexes was even more reduced and often absent, indicating that major antigenic determinants overlap with the active site surface on PR3 that associates with α1-PI. Similarly, the mouse mAbs CLB12.8 and 6A6 also did not react with gibbon PR3 and PR3–α1-PI complexes. Our data strongly suggest that cANCAs from WG patients at least in part recognize similar surface structures as do mouse mAbs and compete with the binding of α1-PI to PR3.

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Section: W Egener's Granulomatosis (Wg) Is An Autoimmunementioning

confidence: 96%

Mapping of Conformational Epitopes on Human Proteinase 3, the Autoantigen of Wegener’s Granulomatosis

Kuhl

Korkmaz

Utecht³

et al. 2010

The Journal of Immunology

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“…Preliminary results suggest that the second-and third-generation tests predict relapses better than IF tests and/or first-generation tests [2,80]. Monitoring ANCA of the IgG3 subtype does not warrant additional benefits [68,88], nor does the detection of ANCA targeted against the proenzyme of PR3 [91].…”

Section: Serial Anca Measurements -Heterogeneity Between Studiesmentioning

confidence: 99%

Maintaining remission in patients with granulomatosis with polyangiitis or microscopic polyangiitis: the role of ANCA

Kemna¹,

Paassen²,

Damoiseaux³

et al. 2017

Expert Opinion on Orphan Drugs

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Introduction: Granulomatosis with Polyangiitis (GPA; formerly Wegener's) and Microscopic Polyangiitis (MPA) are inflammatory disease entities affecting small to medium vessels. They are characterized by the presence of anti-neutrophil cytoplasmic antibodies (ANCA) and are frequently grouped together with Eosinophilic Granulomatosis with Polyangiitis (EGPA; formerly Churg Strauss Syndrome) under the term ANCA-associated Vasculitis (AAV). Due to effective immunosuppressive therapy that was introduced more than 45 years ago, AAV has become a chronic disease in which relapses occur frequently during maintenance treatment or later on after all immunosuppressive therapy is stopped. Since relapses are associated with morbidity and mortality, early detection and prevention of relapses is of great importance. Areas covered: This review focuses on the potential strategies to guide maintenance therapy in patients with GPA or MPA, with an emphasis on patient classifications and the role of serial ANCA measurements. Expert opinion: Risk factors for relapses, e.g., genetic background of the patient, have been studied during the last three decades. Only few of these risk factors directly influence the management of patients. One potentially important factor that may influence therapeutic decisions in AAV patients is serial measurement of ANCA. Recently, it became clear that serial ANCA measurement is an attractive approach in AAV patients with (a history of) capillaritis, e.g., renal involvement or alveolar haemorrhage, but not in patients with more limited disease. Whether ANCA rises can be used to guide therapy andhence-to prevent relapses has been a great debate during the last three decades. At present, we conclude that small studies do support such an approach but that these findings require further validation in larger randomized clinical trials. ARTICLE HISTORY

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“…Around 90% of patients with generalized GPA have serology positive for C-ANCA (cytoplasmic-antineutrophil cytoplasm antibodies) [62,63], although this percentage is often much lower in patients with disease localized to the orbit, perhaps closer to 50% [64]. Within the orbit, GPA presents typically as a diffuse mass or with lacrimal involvement [64,65].…”

Section: Granulomatosis With Polyangitismentioning

confidence: 99%

Orbital inflammatory disease management

Moore

Rootman

2016

Expert Review of Ophthalmology

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Antiproteinase 3 Antineutrophil Cytoplasmic Antibodies and Disease Activity in Wegener Granulomatosis

Cited by 240 publications

References 39 publications

Mapping of Conformational Epitopes on Human Proteinase 3, the Autoantigen of Wegener’s Granulomatosis

Mapping of Conformational Epitopes on Human Proteinase 3, the Autoantigen of Wegener’s Granulomatosis

Maintaining remission in patients with granulomatosis with polyangiitis or microscopic polyangiitis: the role of ANCA

Orbital inflammatory disease management

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