Cartilage Destruction in Granulomatosis with Polyangiitis (Wegener's Granulomatosis) Is Mediated by Human Fibroblasts after Transplantation into Immunodeficient Mice

Kesel, N.; Köhler, Dorothee; Herich, Lena; Laudien, Martin; Holl‐Ulrich, Konstanze; Jüngel, Astrid; Neidhart, Michel; Gay, Steffen; Gay, Renate E.; Csernok, Elena; Lamprecht, Peter; Gross, Wolfgang L.; Schumacher, Udo; Ullrich, Sebastian

doi:10.1016/j.ajpath.2012.01.021

Cited by 27 publications

(21 citation statements)

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“…Stainings for CD marker, PNAd, APRIL, TACI, and RANKL were carried out by applying a peroxidase-based protocol [6]. CXCL13 and CCL21 were stained with goat anti-CXCL13 and goat anti-CCL21 (R&D Systems), respectively, by using an avidin/biotinylated enzyme complex-based protocol [4]. Double stainings for secreted APRIL and goat anti-human IgG F(abʹ) 2 fragment (Dianova, Hamburg, Germany), as well as for CD138 and BCMA, were performed by using the Envision Doublestain kit (Dako) according to the manufacturer’s instructions, with the exception of using donkey anti-goat-HRP-conjugated antibody (Dianova) for IgG detection.…”

Section: Methodsmentioning

confidence: 99%

“…Anti-neutrophilic cytoplasmic antibodies (ANCA) with specificity for proteinase 3 are a defining feature of this disease, but other autoantibodies are found as well [1,2]. Clinical symptoms are often due to necrotizing granulomatous inflammation, predominantly in the respiratory tract, leading to fibroblast-mediated cartilage/bone destruction and to vasculitis, probably autoantibody mediated [1,3,4]. Inflamed tissue within nasal mucosa displays the pathognomonic triad consisting of ill-defined granuloma, geographic necrosis, and vasculitis [5], accompanied by prominent neutrophil infiltration (microabscess) and lymphoplasmocytic aggregates [3,5,6].…”

Section: Introductionmentioning

confidence: 99%

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Plasma cells within granulomatous inflammation display signs pointing to autoreactivity and destruction in granulomatosis with polyangiitis

et al. 2014

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IntroductionPlasma cells residing in inflamed tissues produce antibodies in chronic inflammatory and systemic autoimmune diseases. This study examined if plasma cells, located within inflamed nasal tissue in granulomatosis with polyangiitis (GPA), express features potentially associated with the autoimmune and destructive character of this disease.MethodsIg gene mutation patterns of individual tissue-derived plasma cells from GPA (n = 5) were analyzed, by using laser-assisted microdissection followed by semi-nested polymerase chain reaction (PCR). Signs of B-lymphocyte maturation (ectopic lymphoid structures, ELS) and survival (a proliferation-inducing ligand, APRIL; B-cell maturation antigen, BCMA; transmembrane-activator and calcium modulator and cyclophilin interactor, TACI; receptor activator of nuclear factor κB ligand, RANKL) were examined in nasal tissues or serum, respectively, by using immunohistochemistry/fluorescence and enzyme-linked immunosorbent assay, ELISA.ResultsPlasma-cell derived Ig genes (light- and heavy-chain pairs, n = 4; heavy chains, n = 33) resembled mutation patterns seen in other autoimmune diseases, predominantly displaying selection against replacement mutations within the framework region of Ig genes (10 of 15), which is responsible for structural integrity. Ectopic lymphoid structures were similar between GPA and a disease control (that is, unspecific chronic rhinosinusitis. However, histomorphologic features distinguishing GPA from rhinosinusitis (that is, neutrophilic microabscess and granuloma) expressed considerable amounts of membrane-associated and secreted APRIL, respectively. The latter was co-localized with CD138 and found in close proximity to cells expressing IgG, TACI, and BCMA. Interestingly, plasma cells strongly expressed receptor activator of nuclear factor κB ligand (RANKL), apart from fibroblast-like cells.ConclusionsPlasma cells within granulomatous inflammation appear to display features that might be required for autoreactivity and, possibly, RANKL-mediated destruction in GPA.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Plasma cells within granulomatous inflammation display signs pointing to autoreactivity and destruction in granulomatosis with polyangiitis

et al. 2014

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“…They observed a similar rate of cartilage destruction after subcutaneous cotransplantation of human healthy cartilage together with synovial fibroblasts from patients with rheumatoid arthritis compared to isolated cartilage transplant . Interestingly, fibroblasts have also been described as causing cartilage destruction in granulomatosis with polyangiitis . Hence, a common pathophysiological mechanism might be responsible for this destruction in several disease entities.…”

Section: Discussionmentioning

confidence: 91%

Orthotopic tracheal transplantation using human bronchus: an original xenotransplant model of obliterative airway disorder

et al. 2016

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Bronchiolitis obliterans syndrome (BOS) is a main cause of allograft dysfunction and mortality after lung transplantation (LTx). A better understanding of BOS pathogenesis is needed to overcome this treatment-refractory complication. Orthotopic tracheal transplantation using human bronchus was performed in Brown Norway (BN) and nude (RNU) rats. Allografts were recovered in both strains at Day 7 (BN , n = 6; RNU , n = 7) or Day 28 (BN , n = 6; RNU , n = 6). Immune response of the host against the bronchial graft was assessed. Human samples from BOS patients were used to compare with the histological features of the animal model. Obstruction of the allograft lumen associated with significant infiltration of CD3+ and CD68+ cells was observed in the BN group on Day 28. Immune response from type 1 T-helper cells against the tracheal xenograft was higher in BN animals compared to nude animals on Days 7 and 28 (P < 0.001 and P = 0.035). Xenoreactive antibodies were significantly higher at Day 7 (IgM) and Day 28 (IgG) in the BN group compared to RNU (respectively, 37.6 ± 6.5 vs. 5.8 ± 0.7 mean fluorescence, P = 0.039; and 22.4 ± 3.8 vs. 6.9 ± 1.6 mean fluorescence, P = 0.011). Immunocompetent animals showed a higher infiltration of S100A4+ cells inside the bronchial wall after 28 days, associated with cartilage damage ranging from invasion to complete destruction. In vitro expression of S100A4 by human fibroblasts was higher when stimulated by mononuclear cells (MNCs) from BN rats than from RNU (2.9 ± 0.1 vs. 2.4 ± 0.1 mean fluorescence intensity, P = 0.005). Similarly, S100A4 was highly expressed in response to human MNCs compared to stimulation by T-cell-depleted human MNCs (4.3 ± 0.2 vs. 2.7 ± 0.1 mean fluorescence intensity, P < 0.001). Obliterative bronchiolitis has been induced in a new xenotransplant model in which chronic airway obstruction was associated with immune activation against the xenograft. Cartilage infiltration by S100A4+ cells might be stimulated by T cells.

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“…Recently, the pathogenic mechanisms of tissue damage in GPA, resulting in saddle nose deformity and orbital destruction, have been further elucidated [ 38 , 70 ]. Fibroblasts lining bone and cartilage have been acknowledged to play the role of activated effector cells of tissue destruction in GPA.…”

Section: Pathophysiologymentioning

confidence: 99%

Pauci-Immune Crescentic Glomerulonephritis: An ANCA-Associated Vasculitis

Syed

Rehman

Valecha

et al. 2015

BioMed Research International

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Rapidly progressive glomerulonephritis (RPGN) is a syndrome signified by a precipitous loss of renal function, with features of glomerulonephritis including dysmorphic erythrocyturia and glomerular proteinuria. RPGN is associated with extensive crescent formation, and, thus, the clinical term RPGN is often used interchangeably with the pathologic term crescentic glomerulonephritis (CGN). From an immunopathologic standpoint, primary RPGN is divided into pauci-immune GN (PICG), anti-GBM GN, and immune complex GN. PICG, the most common etiology of primary RPGN, refers to a necrotizing glomerulonephritis with few or no immune deposits by immunofluorescence (IF) or electron microscopy (EM). In most patients, pauci-immune CGN is a component of a systemic small vessel vasculitis such as granulomatosis with polyangiitis (GPA). Approximately 90% of patients with PICG have circulating ANCA antibodies, leading to the nomenclature ANCA-associated vasculitis (AAV). Recent research has identified several other antibodies associated with PICG, which is now understood to be a complex spectrum of disease with considerable overlap in terms of clinical phenotype and outcomes. In addition, several genetic and environmental factors have recently been implicated in the pathogenesis of this disorder. With new prognostic classifications, enhanced understanding of immunopathologic mechanisms, and novel treatment paradigms, clinical and experimental interest in PICG remains high.

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Cartilage Destruction in Granulomatosis with Polyangiitis (Wegener's Granulomatosis) Is Mediated by Human Fibroblasts after Transplantation into Immunodeficient Mice

Cited by 27 publications

References 29 publications

Plasma cells within granulomatous inflammation display signs pointing to autoreactivity and destruction in granulomatosis with polyangiitis

Plasma cells within granulomatous inflammation display signs pointing to autoreactivity and destruction in granulomatosis with polyangiitis

Orthotopic tracheal transplantation using human bronchus: an original xenotransplant model of obliterative airway disorder

Pauci-Immune Crescentic Glomerulonephritis: An ANCA-Associated Vasculitis

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