Renal Pathologic Features of Wegener's Granulomatosis: A Review

Weiss, Mark A.; Crissman, John D.

doi:10.1055/s-2007-1006162

Cited by 9 publications

(7 citation statements)

References 19 publications

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“…In our hands, the linear and granular staining along the glomerular basement membrane did not dissipate by 10 days. This model does not resemble the human form of ANCA-associated glomerulonephritis, which is a pauci-immunc necrotizing and crescentic glomeruionephritis and is characterized by a lack of immunoglobulin deposition at the time of fulminant glomerulonephritis [12,13].…”

Section: Discussionmentioning

confidence: 99%

Immune complex glomerulonephritis is induced in rats immunized with heterologous myeloperoxidase

Jia

Jennette

Falk

1994

Clinical and Experimental Immunology

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SUMMARY Anti‐neutrophil cytoplasmic antibodies (ANCA), including anti‐myeloperoxidase (MPO) antibodies, are associated with pauci‐immune necrotizing small vessel vasculitis or glomerulonephritis, 1n order to substantiate a pathogenic role for ANCA, an animal model of pauci‐immune ANCA‐induced glomerulonephritis or vasculitis is required. Brouwer et al. reported pauci‐immune glomerulonephritis in rats immunized with human MPO followed by perfusion of kidneys with lysosomal enzyme extract combined with H2O2, and suggested that this could serve as a model of ANCA‐induced disease. We repeated these studies in spontaneously hypertensive rats (SHR) and Brown Norway rats (BNR). We immunized rats with human MPO, When circulating anti‐MPO antibodies were detectable by indirect immunofluorescence microscopy and ELISA, blood pressure was measured, then perfusion of the left kidney of each rat was done via the renal artery in a closed, blood‐free circuit with either MPO + H2O;, MPO, H2O2 alone or MPO + H2O2 neutral protease. Rats were killed on day 4 or day 10 after perfusion, and specimens were examined by light and immunofluorescence microscopy. Pathological lesions and deposits of IgG. C3, and MPO were found in immunized rats perfused with MPO + H2O2 with or without neutral protease, or MPO alone, in both rat strains and on both day 4 and day 10, The degree of histologic injury was proportional in intensity to the amount of IgG immune deposits. Spontaneously hypertensive rats sustained more damage and higher blood pressure than Brown Norway rats. No lesion was observed in immunized rats perfused with H2O2 or in the non‐perfused right kidneys. Some of the non‐immunized rats perfused with MPO + H2O2 developed pathological lesions. In conclusion, these rat models are examples of immune complex‐mediated glomerulonephritis, and therefore are not similar to human ANCA‐associated disease.

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Section: Discussionmentioning

confidence: 99%

Immune complex glomerulonephritis is induced in rats immunized with heterologous myeloperoxidase

Jia

Jennette

Falk

1994

Clinical and Experimental Immunology

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“…Once the autoantigen PR3 is expressed, circulating ANCA may gain access to TEC from the basolateral side through vasculitic lesions found not only around glomeruli but also in the tubulo-interstitial compartment (3,4,64). Alternatively, in progressive states of renal failure, ANCA-IgG may gain access to tubules from the luminal side due to proteinuria.…”

Section: Discussionmentioning

confidence: 99%

“…The development of renal lesions represents a limiting factor for the course and prognosis of this disease (1,2). Morphologically, as assessed in renal biopsies, necrotizing, crescentic pauci-immune glomerulonephritis, and marked leukocyte influx into glomeruli and interstitium represent the predominant findings (3)(4)(5). Cells accumulating in the extracapillary space of the glomeruli and around tubuli include neutrophils, monocytes, lymphocytes, and epithelial cells.…”

Section: W Egener's Granulomatosis (Wg)mentioning

confidence: 99%

“…The macroscopically normal tissue was dissected and immediately transferred to ice-cold medium M199 (Seromed, Berlin, Germany) containing 10% FCS (Life Technologies, Eggenstein, Germany), 100 U/ml penicillin, 100 g/ml streptomycin, and 17 U/ml heparin (Seromed). The tissue was decapsulated, the cortex was discarded, and the outer medulla was cut into pieces of 2-3 mm 3 . After incubation with HBSS (Life Technologies) containing 0.1% collagenase type II (Seromed) for 30 min at 37°C with gentle shaking, the tissue was passed through a 120-m mesh.…”

Section: Isolation and Culture Of Tecmentioning

confidence: 99%

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Interaction of Antibodies to Proteinase 3 (Classic Anti-Neutrophil Cytoplasmic Antibody) with Human Renal Tubular Epithelial Cells: Impact on Signaling Events and Inflammatory Mediator Generation

Hattar¹,

Grandel²,

Bickenbach³

et al. 2002

The Journal of Immunology

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Among the anti-neutrophil cytoplasmic Abs (ANCA), those targeting proteinase 3 (PR3) have a high sensitivity and specificity for Wegener’s granulomatosis (WG). A pathogenetic role for these autoantibodies has been proposed due to their capacity of activating neutrophils in vitro. Recently, PR3 was also detected in human renal tubular epithelial cells (TEC). In the present study, the effect of murine monoclonal anti-PR3 Abs (anti-PR3) and purified c-ANCA targeting PR3 from WG serum on isolated human renal tubular cell signaling and inflammatory mediator release was characterized. Priming of TEC with TNF-α resulted in surface expression of PR3, as quantified in immunofluorescence studies and by flow cytometry. Moreover, PR3 was immunoprecipitated on surface-labeled TEC. Primed TEC responded to anti-PR3 with a dose- and time-dependent activation of phosphoinositide hydrolysis, resulting in a remarkable accumulation of inositolphosphates. Control IgG was entirely ineffective, whereas PR3-ANCA reproduced the phosphoinositide response. The signaling response was accompanied by a pronounced release of superoxidanion into the cell supernatant. Moreover, large amounts of PGE2 and, to a lesser extent, of thromboxane B2, the stable metabolite of TxA2, were secreted from anti-PR3-stimulated TEC. In parallel, a rise in intracellular cAMP levels was observed, which was blocked by the cyclooxygenase inhibitor indomethacin. We conclude that anti-PR3 Abs directly target renal TECs, thereby provoking pronounced activation of the phosphoinositide-related signal transduction pathway. Associated metabolic events such as the release of reactive oxygen species and lipid mediators may directly contribute to the development of renal lesions and loss of kidney function in WG.

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“…Renal lesions in WG are characterized by intraglomerular and interstitial infiltration of neutrophils, monocytes and lymphocytes [34]. The authors assume that VCAM-1 is involved in the recruitment of monocytes in WG.…”

Section: Discussionmentioning

confidence: 99%

Antibodies to proteinase 3 mediate expression of vascular cell adhesion molecule-1 (VCAM-1)

Mayet¹,

Schwarting²,

Orth³

et al. 1996

Clinical and Experimental Immunology

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VCAM‐1 was first identified as an adhesion molecule induced on human endothelial cells (HEC) by inflammatory cytokines such as IL‐1, tumour necrosis factor (TNF), and lipopolysaccharide (LPS). The molecule binds to a variety of leucocytes, including B cells, T cells, basophils, eosinophils and monocytes. Vascular expression of VCAM‐1 has been associated with a number of disease states, including rheumatoid arthritis and vasculitis. The detection of antineutrophil cytoplasmic antibodies (ANCA), especially to proteinase 3 (PR3), has become important in the diagnosis of Wegener’s granulomatosis (WG) and related vasculitides. Recently we were able to demonstrate a direct effect of anti‐PR3 antibodies on neutrophil–endothelial interactions (Blood 1993; 82:1221). Binding of anti‐PR3 antibodies to their antigen translocated into the membrane of HEC leads to an enhanced adhesion of neutrophils via induction of E‐selectin (Clin Exp Immunol 1993; 94:440). The aim of this study was to investigate the effect of anti‐PR3 antibodies on the expression of VCAM‐1. HEC was isolated from umbilical vein and cultured on microtitre plates. After preincubatiion with purified anti‐PR3 antibody, purified control antibodies (SS‐A, SS‐B, RNP) (IgG and F(ab′)2 fragments) or different cytokines (controls), VCAM‐1 was detected on the surface of unfixed HEC by cyto‐ELISA and polymerase chain reaction analysis. Incubation of HEC with anti‐PR3 antibodies led to a marked increase of endothelial VCAM‐1 expression with a peak after 8 h. Incubation with TNF‐α also led to maximal VCAM‐1 expression after 4–6 h (control). Increased adhesion of T lymphocytes to HEC after binding of anti‐PR3 antibodies to their antigen could be confirmed by performing adherence assays. This effect could be inhibited by antibodies to VLA‐4. In conclusion, we have been able to show that cytokine‐like effects of anti‐PR3 antibodies on HEC are not limited to induction of neutrophil adhesion. Anti‐PR3 antibodies may thus contribute to the regulation of T lymphocyte migration from the blood by HEC in ANCA‐related vasculitides.

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Renal Pathologic Features of Wegener's Granulomatosis: A Review

Cited by 9 publications

References 19 publications

Immune complex glomerulonephritis is induced in rats immunized with heterologous myeloperoxidase

Immune complex glomerulonephritis is induced in rats immunized with heterologous myeloperoxidase

Interaction of Antibodies to Proteinase 3 (Classic Anti-Neutrophil Cytoplasmic Antibody) with Human Renal Tubular Epithelial Cells: Impact on Signaling Events and Inflammatory Mediator Generation

Antibodies to proteinase 3 mediate expression of vascular cell adhesion molecule-1 (VCAM-1)

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