Endothelial cell apoptosis is a primary pathogenetic event underlying skin lesions in avian and human scleroderma.

Sgonc, Roswitha; Gruschwitz, Matthias S.; Dietrich, Hermann; Recheis, Heidrun; Gershwin, M. Eric; Wick, Georg

doi:10.1172/jci118851

Cited by 345 publications

(226 citation statements)

References 21 publications

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“…Furthermore, topo II is clustered and concentrated in the surface blebs (apoptotic bodies) of apoptotic cells, which may result in antigen presentation of the cryptic epitopes. In addition, apoptosis is detected in endothelial cells of early inflammatory lesions from patients with localized scleroderma (14). Collectively, these results indicate that anti-topo II␣ antibody may be secondarily produced by modification of topo II␣ during endothelial apoptosis in localized scleroderma.…”

Section: Discussionmentioning

confidence: 71%

“…Collectively, these results indicate that anti-topo II␣ antibody may be secondarily produced by modification of topo II␣ during endothelial apoptosis in localized scleroderma. However, similar modification of topo I during apoptosis and endothelial apoptosis is also observed in SSc (13,14); it remains unknown why localized scleroderma was associated with the production of anti-topo II␣ antibody but not anti- topo I antibody, and why SSc did not have the high prevalence of anti-topo II␣ antibody.…”

Section: Discussionmentioning

confidence: 92%

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Anti‐DNA topoisomerase IIα autoantibodies in localized scleroderma

Hayakawa¹,

Hasegawa²,

Takehara³

et al. 2004

Arthritis & Rheumatism

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Objective. To determine the prevalence and clinical correlation of anti-DNA topoisomerase II␣ (antitopo II␣) antibody in patients with localized scleroderma.Methods. Anti-topo II␣ antibodies or anti-DNA topoisomerase I (topo I) antibodies were determined by enzyme-linked immunosorbent assay (ELISA) and immunoblotting. Inhibition of topo II␣ enzymatic activity by the antibodies was evaluated by decatenation assays using kinetoplast DNA as a substrate. Results. IgG or IgM anti-topo II␣ antibody was detected in 76% ( Conclusion.The results of the present study indicate that anti-topo II␣ is a major autoantibody in localized scleroderma, and is distinct from anti-topo I antibody in SSc.

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Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 92%

Anti‐DNA topoisomerase IIα autoantibodies in localized scleroderma

Hayakawa¹,

Hasegawa²,

Takehara³

et al. 2004

Arthritis & Rheumatism

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“…Apoptosis of ECs is the initiating step in the vascular pathogenesis of SSc, and the number of microparticles from apoptotic ECs is strongly increased in the blood of patients with SSc (1,22). To analyze whether microparticles derived from apoptotic ECs affect the number of CACs, CACs from patients with SSc and healthy volunteers were coincubated with microparticles for 4 days.…”

Section: Resultsmentioning

confidence: 99%

Induction of apoptosis in circulating angiogenic cells by microparticles

Distler

Akhmetshina

Dees

et al. 2011

Arthritis & Rheumatism

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“…Endothelial vascular damage is an early event in SSc (1,4) and leads to activation of the immune response with release of various cytokines, autoantibody production, fibroblast activation, and enhanced collagen synthesis (5). In this process, various types of immune cells, such as T cells, B cells, and macrophages, play important roles.…”

mentioning

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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Endothelial cell apoptosis is a primary pathogenetic event underlying skin lesions in avian and human scleroderma.

Abstract: The mechanism that may cause degenerative fibrotic skin lesions was studied in situ using skin biopsies from patients with systemic sclerosis (

Cited by 345 publications

References 21 publications

Anti‐DNA topoisomerase IIα autoantibodies in localized scleroderma

Anti‐DNA topoisomerase IIα autoantibodies in localized scleroderma

Induction of apoptosis in circulating angiogenic cells by microparticles

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

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