Systemic Sclerosis (Scleroderma): Specific Autoantigen Genes Are Selectively Overexpressed in Scleroderma Fibroblasts

Abstract

The pathogenesis of systemic sclerosis (SSc) involves complex interactions between activated fibroblasts eventually leading to fibrosis, and impaired immune tolerance characterized by a variety of circulating SSc-specific autoantibodies. The expression of autoantigens in fibroblasts, a key target tissue in SSc, may play an important role in this process. To obtain a global view of this process, we examined gene expression profiles of SSc dermal fibroblasts using cDNA microarrays. The results show that dermal fibroblasts from SSc patients obtained from either affected or unaffected skin displayed a characteristic pattern of increased SSc autoantigen gene expression compared with that from normal controls. In particular, fibrillarin (p = 0.028), centromeric protein B (p = 0.01), centromeric autoantigen P27 (p = 0.042), and RNA polymerase II (220 kDa; p = 0.02) were significantly overexpressed in SSc fibroblasts. Quantitative RT-PCR confirmed overexpression of these autoantigens and also revealed increased levels of DNA topoisomerase I transcripts in SSc fibroblasts compared with normal control fibroblasts (p = 0.0318). The polymyositis/scleroderma autoantigen gene was overexpressed in some SSc patients (p = 0.09). To examine the specificity of these overexpressed autoantigen genes for SSc and its tissue specificity for fibroblasts, cDNA microarrays of dermal fibroblasts from patients with eosinophilic fasciitis and scleromyxedema were studied as well as PBMC and muscle biopsies from SSc patients. None of these tissues showed significant alterations in gene expression of SSc-specific autoantigens. Therefore, SSc-associated autoantigen genes are selectively overexpressed in SSc dermal fibroblasts, a major tissue involved in disease pathogenesis.

Postnatal induction of transforming growth factor β signaling in fibroblasts of mice recapitulates clinical, histologic, and biochemical features of scleroderma

“…Our results are consistent with a central role of TGF␤ in disease pathogenesis (8,9), and they identify the fibroblast as a critical target cell (11)(12)(13). A logical implication of this view is that other pathogenic processes such as immunologic activation or endothelial cell dysfunction, both of which are observed early in scleroderma, lead to TGF␤-mediated activation of fibroblasts in vivo.…”

“…Thus, elevated levels of TGF␤ have been reported in SSc, and elevated expression of TGF␤ protein or messenger RNA in the skin and lung has been reported (10). In addition, the altered profile of gene and protein expression characteristic of SSc fibroblasts is reminiscent of that of normal fibroblasts activated by TGF␤ (11)(12)(13). It has therefore been hypothesized that TGF␤ released from a variety of cell types activates fibroblasts in SSc.…”

Association of novel polymorphisms with the expression of SPARC in normal fibroblasts and with susceptibility to scleroderma

“…There was no altered expression of the genes for growth factors which might be involved in the pathogenesis of SSc, such as transforming growth factor ␤ (TGF␤), plateletderived growth factor, and vascular endothelial growth factor. A more comprehensive report of these microarray results has been published elsewhere (19).…”

“…While examining gene expression profiles in SSc fibroblasts using complementary DNA (cDNA) microarrays, we noted consistent overexpression of the SPARC gene in SSc fibroblasts compared with normal fibroblasts (19). Thus, SPARC gene expression in SSc fibroblasts was further examined and found to parallel that of other ECM component genes known to be abnormally regulated in this disease, including collagens and MMPs.…”

Comprehensive gene expression profiles reveal pathways related to the pathogenesis of chronic obstructive pulmonary disease

“…Mice lung fibroblasts were cultured from lung tissue of EGR1 null (Ϫ/Ϫ) or control littermates. Fibroblast cell culture was carried out as described (15). Human fetal lung fibroblasts (MRC-5) were obtained from the American Type Culture Collection.…”