Mechanism of Serum-Mediated Endothelial Injury in Scleroderma: Identification of a Granular Enzyme in Scleroderma Skin and Sera

Kahaleh, M. Bashar; Fan, Pan-Sheng

doi:10.1006/clin.1996.4322

Cited by 61 publications

(40 citation statements)

References 31 publications

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“…Teff cells may exert cytolytic activities and produce high levels of cytokines with immunomodulatory potential and profibrotic activities. Indeed, inhibition of endothelial cell growth in SSc by vascular injury appears to be mediated by granzyme B and perforin (47). Interestingly, selfprotein fragments (47) generated by granzyme B are recognized by autoantibodies in a subset of SSc patients (48).…”

Section: Discussionmentioning

confidence: 99%

Effector CD8+ T cells in systemic sclerosis patients produce abnormally high levels of interleukin‐13 associated with increased skin fibrosis

Fuschiotti¹,

Medsger²,

Morel³

2009

Arthritis & Rheumatism

104

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Objective. T lymphocytes play an important role in systemic sclerosis (SSc), a connective tissue disease characterized by inflammation, fibrosis, and vascular damage. While their precise role and antigen specificity are unclear, T cell-derived cytokines likely contribute to the induction of fibrosis. The aim of this study was to establish the role of cytokine dysregulation by T cells in the pathogenesis of SSc.Methods. To identify relationships between a specific cytokine, T cell subset, and the disease course, we studied a large cohort of patients with diffuse cutaneous SSc (dcSSc) or limited cutaneous SSc (lcSSc). Using Luminex analysis and intracellular cytokine staining, we analyzed the intrinsic ability of CD4؉ and CD8؉ T cell subsets to produce cytokines following in vitro activation.Results. High levels of the profibrotic type 2 cytokine interleukin-13 (IL-13) were produced following activation of peripheral blood effector CD8؉ T cells from SSc patients as compared with normal controls or with patients with rheumatoid arthritis. In contrast, CD4؉ T cells showed a lower and more variable level of IL-13 production. This abnormality correlated with the extent of fibrosis and was more pronounced in dcSSc patients than in lcSSc patients. Conclusion. Dysregulated IL-13 production by effector CD8؉ T cells is important in the pathogenesis of SSc and is critical in the predisposition to more severe forms of cutaneous disease. Our study is the first to identify a specific T cell phenotype that correlates with disease severity in SSc and can be used as a marker of immune dysfunction in SSc and as a novel therapeutic target.

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Section: Discussionmentioning

confidence: 99%

Effector CD8+ T cells in systemic sclerosis patients produce abnormally high levels of interleukin‐13 associated with increased skin fibrosis

Fuschiotti¹,

Medsger²,

Morel³

2009

Arthritis & Rheumatism

104

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“…The relevance of a Th2/Tc2-polarized immune response in the pathogenesis and progression of SSc lung fibrosis is plausible, although it remains to be confirmed whether such bias is present within early inflammatory lung infiltrates during ILD initiation. With regard to SSc vasculopathy, previous studies have implicated both 1172 BOIN ET AL cellular and humoral immune effector pathways and have demonstrated that T cells can cause microvascular injury directly through cell-mediated cytotoxicity or by inducing proinflammatory molecules on the endothelial cell surface (36,37). Recently, new data have shown that the endothelium and inflammatory cells infiltrating vessel walls in lesional skin and lung biopsy specimens from patients with SSc exhibit up-regulation of IFN␥-inducible molecules that are implicated in vascular smooth muscle migration/proliferation as well as proinflammatory cytokine secretion (38).…”

Section: T Cell Polarization In Systemic Sclerosis 1171mentioning

confidence: 99%

T cell polarization identifies distinct clinical phenotypes in scleroderma lung disease

Boin¹,

Fanis²,

Bartlett³

et al. 2008

Arthritis & Rheumatism

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Objective. Lung involvement is the leading cause of morbidity and mortality in systemic sclerosis (SSc; scleroderma), and interstitial lung disease (ILD) is the most common pulmonary manifestation. An abnormal profibrotic Th2/Tc2-polarized T cell response is postulated to mediate tissue damage and fibrosis. The aim of this study was to investigate whether a polarized T cell phenotype in SSc is associated with lung disease or other clinical manifestations of SSc.Methods. Circulating T cells were characterized by flow cytometry in 62 patients with SSc and 36 healthy control subjects, using antibodies against CD3, CD4, CD8, chemokine receptor CCR5 (Th1/Tc1-specific), and prostaglandin D 2 receptor CRTH2 (Th2/Tc2-specific). The ratio between CCR5 and CRTH2 T cell frequencies was used to quantify type 1 (high-ratio) or type 2 (low-ratio) immune polarization.Results. Patients with SSc exhibited lower CCR5/ CRTH2 T cell ratios than those exhibited by control subjects (P < 0.0001), indicating a Th2/Tc2-polarized phenotype. Markedly reduced CCR5/CRTH2 T cell ratios were observed in SSc patients with ILD compared with SSc patients without ILD (P < 0.0001), particularly in patients with active ILD (P < 0.0001) compared with those with stable lung function. Lower CCR5/ CRTH2 ratios were strongly associated with a lower value for the percent predicted forced vital capacity (P < 0.0001). In patients with an estimated right ventricular systolic pressure >35 mm Hg, suggestive of pulmonary vascular disease, a lower value for the percent predicted diffusing capacity (DLCO) was associated with higher CCR5/CRTH2 T cell ratios (Th1/Tc1) (P ‫؍‬ 0.009), while in those with right ventricular systolic pressure <35 mm Hg, a lower value for the percent predicted DLCO correlated with lower ratios (Th2/Tc2) (P < 0.0001), as observed for ILD.

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“…Other proposed mechanisms contributing to endothelial cell injury in SSc involve the production of nitric oxiderelated free radicals 9 or granzyme. 10 Additional studies suggest that insufficient vascular repair due to impairment of vasculogenesis may also be a contributing factor. 11 Interestingly, analyses of the microvascular cells isolated from SSc skin suggest that endothelial cells themselves may be defective.…”

mentioning

confidence: 99%

Endothelial Fli1 Deficiency Impairs Vascular Homeostasis

Asano

Stawski

Hant

et al. 2010

The American Journal of Pathology

187

223

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Mechanism of Serum-Mediated Endothelial Injury in Scleroderma: Identification of a Granular Enzyme in Scleroderma Skin and Sera

Cited by 61 publications

References 31 publications

Effector CD8+ T cells in systemic sclerosis patients produce abnormally high levels of interleukin‐13 associated with increased skin fibrosis

Effector CD8+ T cells in systemic sclerosis patients produce abnormally high levels of interleukin‐13 associated with increased skin fibrosis

T cell polarization identifies distinct clinical phenotypes in scleroderma lung disease

Endothelial Fli1 Deficiency Impairs Vascular Homeostasis

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