Endothelial injury in scleroderma.

Kahaleh, M. Bashar; Sherer, Glenn K.; LeRoy, E. Carwile

doi:10.1084/jem.149.6.1326

Cited by 269 publications

(67 citation statements)

References 20 publications

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“…Its alteration under pathologic conditions may result in abnormal growth of the vasculature or defective repair processes. Earlier reports have suggested the presence of antiendothelial activity in SSc, but its nature has not been defined (8)(9)(10).…”

mentioning

confidence: 98%

Antiangiogenic plasma activity in patients with systemic sclerosis

Mulligan-Kehoe¹,

Drinane²,

Mollmark³

et al. 2007

Arthritis & Rheumatism

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Objective. Systemic sclerosis (SSc; scleroderma) is a systemic connective tissue disease with an extensive vascular component that includes aberrant microvasculature and impaired wound healing. The aim of this study was to investigate the presence of antiangiogenic factors in patients with SSc.Methods. Plasma samples were obtained from 30 patients with SSc and from 10 control patients without SSc. The samples were analyzed for the ability of plasma to affect endothelial cell migration and vascular structure formation and for the presence of antiangiogenic activity.Results. Exposure of normal human microvascular dermal endothelial cells to plasma from patients with SSc resulted in decreased cell migration (mean ؎ SEM 52 ؎ 5%) and tube formation (34 ؎ 6%) compared with that in plasma from control patients (P < 0.001 for both). SSc plasma contained 2.9-fold more plasminogen kringle 1-3 fragments (angiostatin) than that in control plasma. The addition of angiostatin to control plasma resulted in inhibition of endothelial cell migration and proliferation similar to that observed in SSc plasma. In vitro studies demonstrated that granzyme B and other proteases contained in T cell granule content cleave plasminogen and plasmin into angiostatin fragments.Conclusion. Plasminogen conformation in patients with SSc enables granzyme B and granule content protease to limit the proangiogenic effects of plasmin and increase the levels of antiangiogenic angiostatin. This increase in angiostatin production may account for some of the vascular defects observed in patients with SSc.

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mentioning

confidence: 98%

Antiangiogenic plasma activity in patients with systemic sclerosis

Mulligan-Kehoe¹,

Drinane²,

Mollmark³

et al. 2007

Arthritis & Rheumatism

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“…The extent of abnormality correlated with the presence and course of the disease (9). Serum activity cytotoxic to endothelial cells (13), studied for the first time in familial scleroderma, was reproducibly present in 2 of 3 siblings with scleroderma, in the 2 siblings with Raynaud's phenomenon, and in 3 healthy relatives. This is the first observation of this activity in asymptomatic relatives of scleroderma subjects.…”

Section: Discussionmentioning

confidence: 91%

Three siblings with scleroderma (systemic sclerosis) and two with raynaud's phenomenon from a single kindred

Sheldon

Lurie

Maricq

et al. 1981

Arthritis & Rheumatism

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A kindred is reported which contains 3 siblings with scleroderma, 2 siblings with Raynaud's phenomenon, and 2 firstdegree relatives with histories suggestive of connective tissue syndromes. Studies of microvascular morphology and flow, serum endothelial cytotoxic activity, antinuclear antibodies, and HLA hap lotypes in 18 relatives and 6 spouses revealed that 4 of 5 affected siblings expressed the HLA-DRw4 antigen, which was also present in 2 of 3 asymptomatic relatives whose serum contained endothelial cytotoxic activity. The evidence for an inherited susceptibility to scleroderma is reviewed.

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“…A cytotoxic protease-like serum factor, quite distinct from IgG, has been described [34], but has been attributed by others to a storage artefact arising from the oxidation of lipoproteins [35]. While circulating immune complexes are a well recognized feature of the disease [4,5], deposition of IgG and complement components in diseased vessels and tissues is not well described.…”

Section: Discussionmentioning

confidence: 99%

Antibodies to membranes of endothelial cells and fibroblasts in scleroderma

Hill¹,

Phipps²,

Cartwright

et al. 1996

Clinical and Experimental Immunology

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SUMMARYAnti-endothelial and other cell membrane-reactive antibodies in scleroderma were characterized by immunoblotting sera with membrane and cytosol preparations of human umbilical vein endothelial cells (HUVEC), dermal fibroblasts and a T cell lymphoma HUT78. Antibodies reactive with HUVEC membranes were found in 17 of 20 patients with scleroderma (33 bands) in contrast to only two of 20 controls (two bands; P<0 . 01) and three of 11 patients with myocardial infarction (four bands). Eleven of the 20 patients possessed antibodies that were specific for HUVEC membrane and did not cross-react with other cell lines. Analysis of patient subgroups showed that HUVEC membrane antibodies were present in nine of 11 patients with systemic sclerosis and in all nine with the CREST syndrome, and were HUVEC-specific in five and six of these cases, respectively. Although considerable heterogeneity was seen, antibodies to an 18-19-kD membrane epitope were found in 11 of the 20 patients but in none of the controls (P<0 . 01). This antibody which reacted particularly with HUVEC (n 9) and HUT78 membranes (n 9) was associated with CREST syndrome rather than systemic sclerosis (9/9 versus 1/ 11; P<0 . 01), and after elution was shown to possess anticentromere activity. In addition, antibodies reactive with both fibroblast (n 11; 18 bands) and HUT78 membranes (n 18; 42 bands) were detected and were specific for either fibroblast or HUT78 membranes in nine and 14 patients, respectively. There was no significant difference in the incidence of these fibroblasts and HUT78 membrane antibodies in the two patient subgroups. These findings support the concept that membranereactive antibodies, including anticentromeric antibodies, may play a central role in the pathogenesis of scleroderma, through their ability to react with endothelial cells.

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Endothelial injury in scleroderma.

Cited by 269 publications

References 20 publications

Antiangiogenic plasma activity in patients with systemic sclerosis

Antiangiogenic plasma activity in patients with systemic sclerosis

Three siblings with scleroderma (systemic sclerosis) and two with raynaud's phenomenon from a single kindred

Antibodies to membranes of endothelial cells and fibroblasts in scleroderma

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