Endothelial cell apoptosis in systemic sclerosis is induced by antibody-dependent cell-mediated cytotoxicity via CD95

Sgonc, Roswitha; Gruschwitz, Matthias S.; Boeck, Guenther; Sepp, Norbert; Gruber, Johann; Wick, Georg

doi:10.1002/1529-0131(200011)43:11<2550::aid-anr24>3.0.co;2-h

Cited by 209 publications

(116 citation statements)

References 56 publications

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“…NK cells (47) and gd cells (48) were reported as the mediators of the cytotoxicity; however, it remains unclear whether CD8 + T cells are involved in endothelial cell injury. On this point, we observed that the cytotoxic capacity of CD8 + T cells against endothelial cells was upregulated in SSc patients.…”

Section: Discussionmentioning

confidence: 99%

Increased CD226 Expression on CD8+ T Cells Is Associated with Upregulated Cytokine Production and Endothelial Cell Injury in Patients with Systemic Sclerosis

Ayano

Tsukamoto

Kohno

et al. 2015

The Journal of Immunology

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Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular damage and fibrosis of the skin and internal organs. Because activated and oligoclonally expanded CD8+ T cells can be detected in peripheral blood and lungs of SSc patients, effector memory CD8+ T cells may play a critical role for organ involvement in SSc; however, the pathogenic functions of effector memory CD8+ T cells remain incompletely understood. In this study, we performed DNA microarray analysis of the sort-purified effector memory CD8+ T cells from SSc patients and healthy controls, and showed that the expression of genes related to immune response and cell adhesion, including CD226 (also known as DNAX accessory molecule-1 [DNAM-1]), was significantly altered. Moreover, detailed analysis of CD226 revealed that CD226highCD8+ T cells were increased in SSc patients (mean, 50.7%) compared with healthy controls (32.9%) and were appreciably associated with the severity of skin sclerosis and interstitial lung disease. Furthermore, CD226+CD8+ T cells produced higher amount of various cytokines than CD226− ones, and CD226highCD8+ T cells from SSc patients showed upregulated IL-13 production and positive correlation with the cytotoxic capacity of CD8+ T cells against HUVECs. Finally, the neutralization of CD226 in CD8+ T cells impaired costimulation, cytokine productions, and cytolysis against HUVECs. These findings indicate that upregulated CD226 expression on CD8+ T cells reflects disease severity and is involved in SSc pathogenesis via the production of various cytokines, including profibrotic IL-13 and endothelial cell injury, and that CD226 may be a useful target in the treatment of SSc.

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Section: Discussionmentioning

confidence: 99%

Increased CD226 Expression on CD8+ T Cells Is Associated with Upregulated Cytokine Production and Endothelial Cell Injury in Patients with Systemic Sclerosis

Ayano

Tsukamoto

Kohno

et al. 2015

The Journal of Immunology

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“…Intriguingly, and as opposed to myofibroblasts, increased EC apoptosis has been reported to play a primary pathogenic role in various fibrotic diseases such as chronic rejection of solid organ transplants, graft-versus-host disease and systemic sclerosis. 4,5,25 The fibrogenic pathways elicited by EC apoptosis are still poorly defined. Here, we aimed at evaluating whether paracrine mediators produced by apoptotic ECs could activate fibrogenic pathways in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…1,3 Endothelial cell (EC) apoptosis is increasingly recognized as an early pathogenic event in fibrosis. A wide array of fibrogenic conditions, such as systemic sclerosis, 4,5 graftversus-host disease 6,7 and chronic rejection of solid allografts, 8,9 has been associated with increased EC apoptosis. Pathophysiological pathways linking endothelial apoptosis to fibrogenesis are still poorly defined.…”

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confidence: 99%

Caspase-3-mediated secretion of connective tissue growth factor by apoptotic endothelial cells promotes fibrosis

et al. 2009

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Apoptosis of endothelial cells (ECs) is an early pathogenic event in various fibrotic diseases. In this study, we evaluated whether paracrine mediators produced by apoptotic ECs play direct roles in fibrogenesis. C3H mice injected subcutaneously with serumfree medium conditioned by apoptotic ECs (SSC) showed increased skin thickness and heightened protein levels of a-smoothmuscle actin (aSMA), vimentin and collagen I as compared with mice injected with medium conditioned by non-apoptotic ECs. Fibroblasts exposed to SSC in vitro showed cardinal features of myofibroblast differentiation with increased stress fiber formation and expression of aSMA. Caspase-3 silencing in ECs prevented the release of mediators favoring myofibroblast differentiation. To identify the fibrogenic factor(s) released by ECs, the protein contents of media conditioned by either apoptotic or non-apoptotic ECs were compared using SDS-PAGE-liquid chromatography (LC)-tandem mass spectrometry (MS/MS) and two-dimensional LC-MS/MS. Connective tissue growth factor (CTGF) was the only fibrogenic protein found increased in SSC. Pan-caspase inhibition with ZVAD-FMK or caspase-3 silencing in ECs confirmed that CTGF was released downstream of caspase-3 activation. The fibrogenic signaling signatures of SSC and CTGF on fibroblasts in vitro were similarly Pyk2-, Src-family kinases-and PI3K dependent, but TGF-b-independent. CTGF-immunodepleted SSC failed to induce myofibroblast differentiation in vitro and skin fibrosis in vivo. These results identify caspase-3 activation in ECs as a novel inducer of CTGF release and fibrogenesis.

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“…The basic science studies, integrated with clinical evaluation of SSc patients, are direct to identify either new biological disease marker(s) suitable for clinical practice or new signaling pathways involved in the pathogenesis of SSc disease [5,7].…”

Section: Introductionmentioning

confidence: 99%

Progress in Understanding the Pathogenesis of Systemic Sclerosis with Lung Involvement: The Contribution of Proteomic Studies

Scambi

Franceschi²,

Bosello³

et al. 2012

Rheumatology

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Systemic sclerosis (SSc) is a chronic inflammatory disease involving the skin and various internal organs. SSc is characterized by microvascular dysfunction, activation of the immune system and tissue fibrosis. Endothelial cell damage seems to be the initiating factor, but the precise triggering events that underlie the development of the disease remain unclear.Lung involvement is a frequent complication, which causes increased morbidity and mortality in patients with SSc. In particular, pulmonary arterial hypertension and interstitial lung disease are the two major clinical diseases that affect SSc patients, but the current treatments appear to have no satisfying effects on these pulmonary complications, until yet.Recently researches using innovative technologies have highlighted several peptides that might contribute to better understand the underlying pathogenic mechanisms of pulmonary injury and could promote more effective therapeutic strategies for SSc patients. Here, we focus on the major proteomic studies on biological fluid from patients with SSc.

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Endothelial cell apoptosis in systemic sclerosis is induced by antibody-dependent cell-mediated cytotoxicity via CD95

Abstract: The results suggest that endothelial cell apoptosis in SSc is induced by antibody-dependent cell-mediated cytotoxicity via the Fas pathway. These data not only provide insight into the pathogenesis of SSc, but also may open new ways to rational therapy for this disease.

Cited by 209 publications

References 56 publications

Increased CD226 Expression on CD8+ T Cells Is Associated with Upregulated Cytokine Production and Endothelial Cell Injury in Patients with Systemic Sclerosis

Increased CD226 Expression on CD8+ T Cells Is Associated with Upregulated Cytokine Production and Endothelial Cell Injury in Patients with Systemic Sclerosis

Caspase-3-mediated secretion of connective tissue growth factor by apoptotic endothelial cells promotes fibrosis

Progress in Understanding the Pathogenesis of Systemic Sclerosis with Lung Involvement: The Contribution of Proteomic Studies

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