Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
Epithelial Cells Undergoing Epithelial Mesenchymal Transition (EMT) in Systemic Sclerosis Lack Caveolin-1 and Modulate WNT Signaling in the Dermis by Secreting SFRP4.
Tinazzi, Ilaria, Gillespie, Justin, Abignano, Giuseppina, Colato, Chiara, Biasi, Domenico, Emery, Paul, Del Galdo, Francesco
Systemic Sclerosis is a chronic fibrotic disease highly heterogeneous in clinical outcome, involving autoimmune activation, fibroproliferative vasculopathy and tissue fibrosis of skin and multiple internal organs. The mechanisms linking immune activation and tissue fibrosis are still not fully characterized. A widely accepted model of immune mediated skin fibrosis is chronic Sclerodermatous Graft versus Host Disease (SclGVHD), a form of chronic GVHD with a prevalence of approximately 310% in patients receiving allogenic bone marrow transplant. Recent histopathologic studies of cGVHD skin biopsies confirmed the presence of both fibroproliferative vasculopathy and tissue fibrosis in Scl-GVHD.
To identify which of the genes differentially expressed in SSc skin biopsies are similarly expressed in the transcriptome of cGVHD skin biopsies and therefore of potential importance in linking the immune activation and the skin fibrosis.
Metanalysis of the microarray data published in the literature identified a set of 86 genes whose differential expression is highly reproduced in SSc skin biopsies that we defined the SSc signature. The mRNA expression level of these genes was measured in 8 Scl-GVHD, three cGVHD skin biopsies and compared to normal skin mRNA and to their differential expression in SSc. All the genes found to be significantly differentially expressed (p < 0.05) in univariate analysis were tested in multivariate analysis. Immunofluorescence studies on skin biopsies were conducted to validate the mRNA findings
46 genes were differentially expressed in cGVHD biopsies and 34 remained peculiar of Scleroderma. 78.3% of the differentially expressed genes had a similar pattern of regulation in SSc. 25% were similarly expressed in both cGVHD variants, whereas 16.6% were specific of Scl GVHD. Remarkably, this analysis allowed to identify specific chemokines (CCL5, CXCL91011) involved specifically in the fibrotic versus non fibrotic response in GVHD and an increased expression of SFRP4 a potent angiogenesis inhibitor in SSc and SCL-GVHD. Double IF studies followed by confocal laser scanning microscopy allowed to identify as the source of increased SFRP4 expression, cells in the basal layer of the epidermis which lost E-cadherin expression, co-expressed Vimentin and specifically lacked caveolin-1 expression.
About 50% of SSc signature genes presented an altered expression in cGVHD. The further caracterization of the cells that play a role both in the fibrotic process, by undergoing EMT, and in the vasculopathy, by inhibiting angiogenesis through WNT inhibition, may pave the way to understand the link between these two processes in SSc.
To cite this abstract, please use the following information:
Tinazzi, Ilaria, Gillespie, Justin, Abignano, Giuseppina, Colato, Chiara, Biasi, Domenico, Emery, Paul, et al; Epithelial Cells Undergoing Epithelial Mesenchymal Transition (EMT) in Systemic Sclerosis Lack Caveolin-1 and Modulate WNT Signaling in the Dermis by Secreting SFRP4. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :671