Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement
The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.
Autoimmune-Driven Skin Fibrosis: The Critical Requirement for IFNAR1 in An Experimental Model of Systemic Sclerosis
Delaney1, Tracy, Morehouse1, Christopher, Brohawn2, Philip, Yao1, Yihong, Chen1, Cindy, Cibotti1, Ricardo, Connor1, Jane
Diffuse systemic sclerosis (dSSc) is an autoimmune disorder featuring progressive fibrosis in skin and in visceral organs such as lung and kidney. Type I interferons (IFNs) have been associated with autoimmunity, but their role in dSSc pathogenesis remains unclear. To determine whether Type I IFNs contribute to autoimmune-driven fibrosis, mice deficient in their shared receptor IFNAR1-/- were compared to wild type (WT) in an experimental model of dSSc.
IFNAR1-/- and WT mice were immunized with human collagen V on days 0 and 21 and monitored by dipstick for signs of proteinuria for an additional 4 weeks. On day 50 animals were assessed for target tissue inflammation, fibrosis, and serum autoantibodies. qPCR analysis of lung, skin, and kidneys was performed by Fluidigm array, and autoantibody titers by ELISA. Fibrosis was evaluated by trichrome staining and Sircol assay.
Human collagen V immunization induced a sustained elevation in proteinuria between day 35 and day 50 in both WT and IFNAR1-/- mice. Inflammation and fibrosis in kidneys and lungs of WT and IFNAR1-/- mice were equivocal by histological analysis on day 50. By contrast, skin inflammation and fibrosis scores were markedly reduced in the immunized IFNAR1-/- group compared to WT; these differences were confirmed by Sircol assay for collagen. Overexpression of pro-inflammatory cytokines, leukocyte surface markers, and pro-fibrosis genes was highly significant in WT SSc skin compared to control skin, whereas little upregulation was detected in IFNAR1-/- SSc skin. Elevated serum titers of autoantibodies against the SSA, SSB, and the a and b subunits of the PDGF receptor were similar in both immunized WT and IFNAR1-/- mice.
Type I IFN signaling through IFNAR1 is required to drive skin fibrosis, but not lung or kidney fibrosis, in experimental dSSc. These data implicate Type I IFNs in an as yet unidentified key pathway that supercedes the production of pathogenic autoantibodies in importance in skin involvement in this model.
To cite this abstract, please use the following information:
Delaney, Tracy, Morehouse, Christopher, Brohawn, Philip, Yao, Yihong, Chen, Cindy, Cibotti, Ricardo, et al; Autoimmune-Driven Skin Fibrosis: The Critical Requirement for IFNAR1 in An Experimental Model of Systemic Sclerosis [abstract]. Arthritis Rheum 2009;60 Suppl 10 :1067