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The role of the immune system in the pathogenesis of systemic sclerosis (SSc) is still unclear. Chronic allograft rejection and sclerodermoid graft-versus-host disease (Scl-GVHD) show a tissue pathology similar to SSc providing a indirect evidence of this role. We have shown that allograft inflammatory factor-1 (AIF-1) and caveolin-1 (cav-1) play an important role in the pathogenesis of SSc [Arthritis and Rheumatism, 2006, 54: 2616–25; Arthritis and Rheumatism, 2007, 56: 3478–88; Arthritis and Rheumatism, 2008, 58: 2854–65]. Nevertheless their role in different aspects of SSc pathogenesis is unclear and hard to investigate in vivo because of the coexistence of tissue infiltrate, fibroproliferative vasculopathy and tissue fibrosis.
Scl-GVHD and non-Scl-GVHD offer a valuable model of different tissue phenotypes in the presence of the same immune trigger. Here we analysed relative tissue expression of AIF-1 and cav-1 in SSc, Scl-GVHD and non-Scl-GVHD.
Full-thickness skin biopsies were obtained from eight patients with Scl-GVHD, three non-Scl-GVHD and seven diffuse SSc patients. Histopathology and immunofluorescence studies were conducted and quantitative analysis of fluorescence was determined by Image J software.
Average onset of chronic graft-versus-host disease (cGVHD)was 8.2±4 months in Scl-GVHD and 6.7±4 in non-Scl-cGVHD. Average Modified Rodnan Skin Score was 8.2 in Scl-GVHD, 12 in SSc and 0 in non-Scl-GVHD. Histopathological analysis of Scl-GVHD confirmed full thickness skin fibrosis in the presence of a more dense tissue infiltrate and the absence of the fibroproliferative vasculopathy and vessel rarefication peculiar of SSc. On the contrary non-Scl-GVHD showed intense tissue infiltrate and neither tissue fibrosis nor fibroproliferative vasculopathy. AIF-1 expression was significantly increased in both Scl- and non-Scl-cGVHD. The pattern of expression was mostly in perivascular and tissue infiltrating mononuclear cells, whereas microvascular endothelial cells (MVECs) did not show any AIF-1 expression despite what has been previously shown in SSc. Cav-1 expression was profoundly decreased in both SSc and Scl-GVHD whereas it was conserved in non-Scl-GVHD.
AIF-1 expression in infiltrating cells is independent of tissue fibrosis in GVHD, whereas its overexpression in MVECs is associated with the presence of fibroproliferative vasculopathy in SSc. The decreased expression of cav-1 is peculiar and specific of skin fibrosis regardless of its origin and therefore a good marker of tissue fibrosis. Transcriptome analysis of the same skin biopsies is ongoing to dissect the specific pathways associated with the different phenotypes.