Endothelial cells and renal epithelial cells do not express the Wegener's autoantigen, proteinase 3 (original) (raw)
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Pathophysiology of ANCA-associated vasculitides: Are ANCA really pathogenic?
Kidney International, 2004
The strong relation between antineutrophil cytoplasmic autoantibodies (ANCA) and primary vasculitic syndromes suggests a pathophysiological role for ANCA. Experimental evidence for the pathogenic potential of ANCA has been derived from in vitro studies that demonstrate that ANCA can activate tumour necrosis factor ␣ primed neutrophils, monocytes and/or endothelial cells. The binding of ANCA to primed neutrophils results in activation of these cells by a process that is largely dependent on engagement of -2 integrins and on the interaction of the Fc portion of ANCA. An Fc-independent mechanism is, however, also operative. In experimental animal models, it has been demonstrated that immunisation with myeloperoxidase (MPO) induces MPO-ANCA. The induction of ANCA, however, is not sufficient to induce vasculitis in rats since immune complexes first have to be deposited along the vessel wall before lesions develop. When MPO-deficient mice are, however, immunised with murine MPO, anti-MPO immunoglobulins are purified and subsequently injected into mice that are not deficient for MPO, systemic vasculitis and glomerulonephritis is induced. These experiments suggest that ANCA indeed induces vasculitis. Risk factors for breaking self-tolerance to ANCA antigens are genetic factors, drugs, chemical substances and/or infectious agents.
Pathophysiology of ANCA-associated small vessel vasculitis
Current rheumatology reports, 2010
Antineutrophil cytoplasmic autoantibodies (ANCAs) directed to proteinase 3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA) are strongly associated with the ANCA-associated vasculitides--Wegener's granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome. Clinical observations, including the efficacy of B-cell depletion via rituximab treatment, support--but do not prove--a pathogenic role for ANCA in the ANCA-associated vasculitides. In vitro experimental studies show that the interplay of ANCA, neutrophils, the alternative pathway of the complement system, and endothelial cells could result in lysis of the endothelium. A pathogenic role for MPO-ANCA is strongly supported by in vivo experimental studies in mice and rats, which also elucidate the pathogenic mechanisms involved in lesion development. Unfortunately, an animal model for PR3-ANCA-associated Wegener's granulomatosis is not yet available. Here, cellular immunity appears to play a major role as well, particularly...
Scientific Reports, 2015
ANCA vasculitis encompasses several autoimmune conditions characterised by destruction of small vessels, inflammation of the respiratory tract and glomerulonephritis. Most patients harbour autoantibodies to myeloperoxidase (MPO) or proteinase 3 (PR3). Clinical and experimental data suggest that pathogenesis is driven by ANCA-mediated activation of neutrophils and monocytes. We investigated a potential role for distinct monocyte subsets. We found that the relative proportion of intermediate monocytes is increased in patients versus control individuals, and both MPO and PR3 are preferentially expressed on these cells. We demonstrate that MPO and PR3 are expressed independently of each other on monocytes and that PR3 is not associated with CD177. MPO expression correlates with that of Fc receptor CD16 on intermediate monocytes. Monocyte subsets respond differently to antibodies directed against MPO and PR3, with anti-MPO but not anti-PR3 leading to increased IL-1β, IL-6 and IL-8 production. In concordance with the observed higher surface expression of MPO on intermediate monocytes, this subset produces the highest quantity of IL-1β in response to anti-MPO stimulation. These data suggest that monocytes, specifically, the intermediate subset, may play a role in ANCA vasculitis, and also indicate that substantial differences exist between the effect of anti-MPO and anti-PR3 antibodies on these cells. Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) refers to a group of severe multi system autoimmune diseases affecting the microvasculature 1. This encompasses microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA, formally known as Wegner's granulomatosis) and eosinophilic granulomatosis with polyangiitis (EGPA, formerly known as Churg-Strauss syndrome). In most cases AAV is characterised by autoantibodies to myeloperoxidase (MPO) or proteinase-3 (PR3) 2,3. These proteins are primarily found in the cytoplasmic granules of neutrophils and lysosomes of monocytes. Substantial clinical and experimental evidence indicates that these autoantibodies drive pathogenesis of the disease 4,5. GPA, EGPA and MPA share the same pathology of necrotising vasculitis of small vessels, the primary difference between them being the development of granuloma in EGPA and GPA but not MPA, with marked eosinophilia and asthma in EGPA. The majority of AAV research to date has
New pathophysiological insights and treatment of ANCA-associated vasculitis
Kidney International, 2011
ANCA-associated-vasculitis (AAV) comprises three different diseases entities: Churg-Strauss syndrome, microscopic polyangiitis, and Wegener's granulomatosis. AAV is an autoimmune disease with complex pathophysiology. Anti-neutrophil cytoplasmic antibodies (ANCAs) with specificity for proteinase-3 (PR3) or myeloperoxidase (MPO) are hallmarks of AAV and have a pivotal role in disease development. In addition to ANCA, the cellular immune system contributes to the pathogenesis of the disease. ANCA-mediated degranulation of neutrophils causes vasculitic damage; T cells drive granuloma formation, promote vasculitic damage by several different pathways, and enhance autoantibody production by B cells. Recently, complementary PR3 and lysosomal membrane protein-2 were suggested as novel autoantigens in AAV. New findings also indicate the importance of complement, danger-associated molecular patterns, and dendritic cells in AAV. This review highlights novel pathophysiological findings in AAV and puts them into context with the current understanding of disease mechanisms. Furthermore, implications for present and new therapeutic strategies are discussed.
Journal of Experimental Medicine, 1998
Anti-neutrophil cytoplasmic antibodies (ANCAs) targeting proteinase 3 (PR3) have a high specifity for Wegener's granulomatosis (WG), and their role in activating leukocytes is well appreciated. In this study, we investigated the influence of PR3-ANCA and murine monoclonal antibodies on human umbilical vascular endothelial cells (HUVECs). Priming of HUVECs with tumor necrosis factor ␣ induced endothelial upregulation of PR3 message and surface expression of this antigen, as measured by Cyto-ELISA, with a maximum occurrence after 2 h. Primed cells responded to low concentrations of both antibodies (25 ng-2.5 g/ml), but not to control immunoglobulins, with pronounced, dose-dependent phosphoinositide hydrolysis, as assessed by accumulation of inositol phosphates. The signaling response peaked after 20 min, in parallel with the appearance of marked prostacyclin and platelet-activating factor synthesis. The F(ab) 2 fragment of ANCA was equally potent as ANCA itself. Disrupture of the endothelial F-actin content by botulinum C2 toxin to avoid antigen-antibody internalization did not affect the response. In addition to the metabolic events, anti-PR3 challenge, in the absence of plasma components, provoked delayed, dose-dependent increase in transendothelial protein leakage. We conclude that anti-PR3 antibodies are potent inductors of the preformed phosphoinositide hydrolysis-related signal tranduction pathway in human endothelial cells. Associated metabolic events and the loss of endothelial barrier properties suggest that anti-PR3-induced activation of endothelial cells may contribute to the pathogenetic sequelae of autoimmune vasculitis characterizing WG.
Journal of the American Society of Nephrology, 2002
Wegener granulomatosis (WG) is strongly associated with the presence of antineutrophil cytoplasm autoantibodies (ANCA) with specificity for proteinase 3 (PR3). Relapses of WG are frequently preceded by a rise of autoantibody titer and PR3-ANCA are able to activate primed neutrophils in vitro. Except being stored intracellularly and translocated to the cell surface upon neutrophil stimulation, PR3 can also be detected on the surface of non-stimulated neutrophils (membrane PR3 or mPR3), with an interindividual variability in percentages of mPR3 Ϫ -positive cells and level of mPR3 expression. This study began with the hypothesis that the presence of PR3 on the surface of non-stimulated neutrophils enables interaction with PR3-ANCA and influences clinical manifestations of the disease. It analyzed mPR3 expression on neutrophils of 89 WG patients in complete remission and 72 healthy controls to
ANCA antigens, proteinase 3 and myeloperoxidase, are not expressed in endothelial cells
Kidney international, 2000
One hypothesis for the pathogenesis of vasculitis associated with antineutrophil cytoplasmic autoantibodies (ANCAs) proposes that ANCAs bind to ANCA antigens, such as proteinase 3 (PR3) or myeloperoxidase (MPO), which are produced by endothelial cells and expressed on their surfaces. There are conflicting reports, however, on whether endothelial cells express the ANCA antigen PR3, and there are no reports on endothelial expression of MPO. The aim of this study was to determine the presence or absence of PR3 and MPO mRNA in both venous and arterial endothelial cells, employing standard reverse transcription-polymerase chain reaction (RT-PCR) techniques and also the quantitative and highly specific method, TaqMan PCR. RT-PCR (with 3 primer sets) and TaqMan PCR, a method for detecting low copy transcripts, were used to probe for PR3 and MPO transcripts in human endothelial cells from umbilical vein (HUVEC) and artery (HUAEC) and from lung microvascular (HLMVEC). Cells were treated with...
Proteinase 3 and Neutrophil Apoptosis in ANCA-Associated Systemic Vasculitis
Lund University Faculty of Medicine Doctoral Dissertation Series, 2010
the Crafoord foundation, the renal foundation, the Greta and Johan Kock foundation, The kungliga fysiografiska sällskapet, the Thelma Zoéga foundation, the Magnus Bergvalls foundation, The Åke Wibergs foundation and the Alfred Österlund foundation.