Antibodies to membranes of endothelial cells and fibroblasts in scleroderma

Abstract

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.

Classification of anti-endothelial cell antibodies into antibodies against microvascular and macrovascular endothelial cells: The pathogenic and diagnostic implications

“…Several studies found that the prevalence of AECA in systemic sclerosis varied from 20% to 80%, according to whether the disease was in its limited or diffuse form: 23% in primary Raynaud's phenomenon, 44% in limited scleroderma, and 84% in diffuse scleroderma (6,47,48). However, AECA in systemic sclerosis are not EC specific.…”

“…However, AECA in systemic sclerosis are not EC specific. Namely, AECA characterized by immunoblotting with membrane preparation of HUVEC exhibited a cross-reactivity with other cell types such as fibroblasts and a T cell lymphoma line (6). In addition, antibodies against a 19-kd protein, apparently associated with the CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias) syndrome, were shown to possess anticentromere activity (6).…”

“…IgG, IgM, and IgA isotypes of those antibodies have been reported. The EC target antigens for AECA have not yet been defined, but it is clear that there are likely to be multiple target antigens (4)(5)(6)(7). Accordingly, sera positive for AECA have been shown to display a broad reactivity against EC obtained from different human anatomic sources: from large arterial (aorta) or venous (umbilical cord vein, saphenous vein) vessels as well as from small vessels such as renal, skin, omental, and brain microvasculature (8)(9)(10).…”

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

“…In sera from SSc patients with lung involvement, the proteomic approach allowed the identification of new targets for anti-endothelial cell antibodies (AECA), which further support the role of EC damage as central event in the pathogenesis of the disease [30][31][32]. In particular, Negi et al [32] observed a significantly higher incidence of PAH in AECA positive patients.…”

A Novel Protein Highly Expressed in Testis Is Overexpressed in Systemic Sclerosis Fibroblasts and Targeted by Autoantibodies

“…A recent microarray analysis of SSc dermal fibroblasts found that SSc-related autoantigens, including centromeric protein B, fibrillarin, a largest subunit of RNAP II, and topo I, were up-regulated in SSc dermal fibroblasts obtained from affected skin compared with those from unaffected skin, suggesting a possible association between overexpression of SSc-specific autoantigens in the affected fibroblasts and the specific autoantibody responses (6). In contrast, autoantibodies reactive with dermal fibroblasts have been reported in sera from SSc patients (7)(8)(9)(10), but fibroblast-specific autoantigens have not been identified to date.…”