Neutrophils are not consistently activated by antineutrophil cytoplasmic antibodies in vitro

Popat, Reena J; Robson, Michael G.

doi:10.1136/annrheumdis-2018-214405

Cited by 10 publications

(9 citation statements)

References 7 publications

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“…It has been shown that ANCA IgG has different affinities [25,26] and avidities [27] and can result in altered clinical or in vitro phenotypes. This was further supported in a brief report from Popat and Robson [28] who recently suggested that polyclonal ANCA IgG does not consistently stimulate TNF-α primed neutrophils, echoing the findings from Franssen et al, [29], much to the contrary of abundantly published literature in the field.…”

Section: Discussionsupporting

confidence: 57%

A novel 4-dimensional live-cell imaging system to study leukocyte-endothelial dynamics in ANCA-associated vasculitis

et al. 2019

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Neutrophils, monocytes and the endothelium are critical to ANCA-associated vasculitis (AAV) pathogenesis. This study aimed to develop a 4-dimensional (4D) live-cell imaging system that would enable investigation of spatial and temporal dynamics of these cells in health and disease. We further aimed to validate this system using autologous donor serum from AAV patients and polyclonal ANCA IgG, as well as exploring its potential in the pre-clinical testing of putative therapeutic compounds. Neutrophils and monocytes were isolated from peripheral venous blood of AAV patients or healthy controls and co-incubated on an endothelial monolayer in the presence of autologous serum. Alternatively, polyclonal ANCA IgG was used, following TNF-α priming, and imaged in 4-dimensions for 3 hours using a spinning disc confocal microscope. Volocity 6.3® analysis software was used for quantification of leukocyte dynamics. The use of autologous serum resulted in increased neutrophil degranulation (P = 0.002), transmigration (P = 0.0096) and monocyte transcellular transmigration (P = 0.0013) in AAV patients. Polyclonal MPO-ANCA IgG induced neutrophil degranulation (P < 0.001) in this system. C5aR1 antagonism reduced neutrophil degranulation (P < 0.0002). We have developed a novel 4D in vitro system that allows accurate quantification of multiple neutrophiland monocyte-endothelial interactions in AAV in a single assay. This system has the potential to highlight dynamics key to pathophysiology of disease, as well investigating the impact of potential therapeutics on these functions.

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Section: Discussionsupporting

confidence: 57%

A novel 4-dimensional live-cell imaging system to study leukocyte-endothelial dynamics in ANCA-associated vasculitis

et al. 2019

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“…Finally, it must be underlined that auto-immune activation of neutrophils by IgG ANCA was recently challenged by Popat and Robson. Indeed, purified IgG from AAV patient sera, even in active disease, did not induce neutrophil activation from two different healthy donors ( 59 ). Interestingly, the same IgG preparations obtained from MPO-ANCA positive patients but not from PR3-ANCA positive patients were used by the same group, in another study, and promoted inflammation through monocyte stimulation ( 60 ).…”

Section: Discussionmentioning

confidence: 99%

4C3 Human Monoclonal Antibody: A Proof of Concept for Non-pathogenic Proteinase 3 Anti-neutrophil Cytoplasmic Antibodies in Granulomatosis With Polyangiitis

et al. 2020

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“…The most compelling evidence for a role of ANCA in the pathogenesis comes from animal models of MPO-ANCA, where antibodies alone or antibody producing cells can transfer the disease (18). However, there are also data that do not support a direct role for ANCA in the pathogenesis; all purified IgG preparations from patients do not active neutrophils in a consistent manner (19, 20). IgA vasculitis (21) and cryoglobulinemic vasculitis (22) are immune complex mediated diseases, where polyclonal or monoclonal autoantibodies react with other immunoglobulins to form complexes.…”

Section: Autoantibodies Are Commonmentioning

confidence: 97%

Streptococcal Enzymes as Precision Tools Against Pathogenic IgG Autoantibodies in Small Vessel Vasculitis

Segelmark

Björck

2019

Front. Immunol.

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In primary systemic small vessel vasculitis autoantibodies are common and seem to play an important role in the pathogenesis. Autoantibodies in vasculitis are preferentially directed against components of the immune system or directly against components of the vessel wall. Plasmapheresis is often applied in emergency situationists when the function of vital organs is jeopardized, the level of clinical evidence to apply such therapy, however, varies between low and non-existing. Plasmapheresis is a blunt and unspecific instrument that requires several sessions to achieve a substantial reduction of autoantibody levels. IdeS and EndoS are two relatively recently discovered enzymes produced by S. pyogenes, that have a remarkable capacity to degrade and disarm IgG. They have shown positive results in several in vivo models of autoimmunity, and treatment with IdeS has successfully been used to inactivate HLA alloantibodies in patients undergoing renal transplantation. Both IdeS and EndoS have the potential to become precision tools to replace plasmapheresis in the treatment of vasculitic emergencies and a clinical trial of IdeS in anti-GBM vasculitis is now ongoing.

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Neutrophils are not consistently activated by antineutrophil cytoplasmic antibodies in vitro

Cited by 10 publications

References 7 publications

A novel 4-dimensional live-cell imaging system to study leukocyte-endothelial dynamics in ANCA-associated vasculitis

A novel 4-dimensional live-cell imaging system to study leukocyte-endothelial dynamics in ANCA-associated vasculitis

4C3 Human Monoclonal Antibody: A Proof of Concept for Non-pathogenic Proteinase 3 Anti-neutrophil Cytoplasmic Antibodies in Granulomatosis With Polyangiitis

Streptococcal Enzymes as Precision Tools Against Pathogenic IgG Autoantibodies in Small Vessel Vasculitis

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