Integrin Modulating Therapies Prevent Fibrosis and Autoimmunity in Genetic Mouse Models of Scleroderma. E. E. Gerber1, E. M. Gallo1, S. C. Fontana1, E. C. Davis3, X. Zhong1, F. M. Wigley4, D. L. Huso5, H. C. Dietz1, 2 1) Institute for Genetic Medicine, Johns Hopkins University, Baltimore, MD; 2) Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; 3) McGill University, Montreal, Quebec H3A 2K6, Canada; 4) Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; 5) Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

   Systemic sclerosis (SSc), the most common form of scleroderma, affects up to 1 in 5,000 individuals and is characterized by the acquired predisposition for autoantibodies and progressive dermal and visceral fibrosis in young adults, culminating in death. The study of SSc is hindered by the absence of a defined genetic contribution and a lack of animal models that mechanistically recapitulate human disease. In an effort to overcome these barriers, we focused on the study of a rare but tractable childhood presentation of scleroderma called stiff skin syndrome (SSS) that is caused by heterozygous missense mutations in the gene (FBN1) encoding the extracellular matrix protein fibrillin-1. All SSS mutations localize to a single domain in fibrillin-1 that mediates cellular attachment via the binding of integrins to a specific Arg-Gly-Asp (RGD) sequence. We generated two mouse lines harboring either a heterozygous SSS-associated amino acid substitutions in fibrillin-1 (W1570C) or one that results in obligate loss of integrin-binding (RGD to RGE). Both mouse lines recapitulate fully penetrant dense dermal fibrosis by three months of age with the added predisposition for aggressive visceral fibrosis upon minimal environmental provocation. Mutant mice show tissue infiltration and activation of pro-inflammatory immune cells including plasmacytoid dendritic cells (pDCs), Th2 and Th17 T helper cell subsets, and plasma cells in association with high circulating levels of anti-nuclear antibodies and anti-topoisomerase I antibodies that are more characteristic of and specific for SSc. Activation of pDCs is associated with high expression of many pro-fibrotic cytokines including transforming growth factor (TGF), interleukin-6 (IL-6) and interferon (IFN). The combination of IL-6 and TGF is sufficient for Th17 skewing (with IL-17 production), while the combination of IL-6 and IFN is sufficient for plasma cell infiltration and activation with autoantibody production. Furthermore, na´ve pDCs show an enhanced propensity to attach and activate in culture when plated on the matrix elaborated by SSS cells, when compared to controls. All phenotypic abnormalities including fibrosis and autoimmunity are fully prevented by integrin-modulating therapies and reversed by TGF antagonism in both SSS mouse models. These data show that alterations in cell-matrix interactions are sufficient to fully phenocopy autoimmune scleroderma and highlight novel therapeutic strategies.

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