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Integrin-modulating therapy prevents fibrosis and autoimmunity in mouse models of scleroderma

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Abstract

In systemic sclerosis (SSc), a common and aetiologically mysterious form of scleroderma (defined as pathological fibrosis of the skin), previously healthy adults acquire fibrosis of the skin and viscera in association with autoantibodies1. Familial recurrence is extremely rare and causal genes have not been identified. Although the onset of fibrosis in SSc typically correlates with the production of autoantibodies, whether they contribute to disease pathogenesis or simply serve as a marker of disease remains controversial and the mechanism for their induction is largely unknown2. The study of SSc is hindered by a lack of animal models that recapitulate the aetiology of this complex disease. To gain a foothold in the pathogenesis of pathological skin fibrosis, we studied stiff skin syndrome (SSS), a rare but tractable Mendelian disorder leading to childhood onset of diffuse skin fibrosis with autosomal dominant inheritance and complete penetrance. We showed previously that SSS is caused by heterozygous missense mutations in the gene (FBN1) encoding fibrillin-1, the main constituent of extracellular microfibrils3. SSS mutations all localize to the only domain in fibrillin-1 that harbours an Arg-Gly-Asp (RGD) motif needed to mediate cell–matrix interactions by binding to cell-surface integrins3. Here we show that mouse lines harbouring analogous amino acid substitutions in fibrillin-1 recapitulate aggressive skin fibrosis that is prevented by integrin-modulating therapies and reversed by antagonism of the pro-fibrotic cytokine transforming growth factor β (TGF-β). Mutant mice show skin infiltration of pro-inflammatory immune cells including plasmacytoid dendritic cells, T helper cells and plasma cells, and also autoantibody production; these findings are normalized by integrin-modulating therapies or TGF-β antagonism. These results show that alterations in cell–matrix interactions are sufficient to initiate and sustain inflammatory and pro-fibrotic programmes and highlight new therapeutic strategies.

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Figure 1: SSS mouse models show skin fibrosis.
Figure 2: Integrin-modulating interventions prevent skin fibrosis.
Figure 3: A panspecific TGF-β-neutralizing antibody reverses established skin fibrosis.
Figure 4: Immunological abnormalities in SSS mice are prevented by integrin-modulating therapies.

Change history

  • 06 November 2012

    Figure 4a was corrected.

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Acknowledgements

We thank those who contributed skin biopsies to this study and those who provided reagents for this study, including S. Shattil, K. Flanders, C. J. Thomas, S. Patnaik and J. J. Marugan. This work was supported by grants to H.C.D. from the Scleroderma Research Foundation, the National Institutes of Health (RO1-AR41135 and PO1-AR049698), the National Marfan Foundation, the Smilow Center for Marfan Syndrome Research, and the Howard Hughes Medical Institute.

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Contributions

E.E.G., E.M.G. and H.C.D. designed experiments and interpreted the data. E.M.G. performed enzyme-linked immunosorbent assays. F.M.W. obtained skin samples from patients (the Scleroderma Center of Johns Hopkins University School of Medicine) and provided guidance and clinical expertise. S.C.F. assisted in drug trials in vivo and in the collection of mouse sera. E.C.D. performed electron microscopy. E.E.G. generated mouse models and performed all other experiments. D.L.H. aided in complete blood count analysis, mouse surgery, and histopathology. E.E.G. and H.C.D. wrote the paper.

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Correspondence to Harry C. Dietz.

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The authors declare no competing financial interests.

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Gerber, E., Gallo, E., Fontana, S. et al. Integrin-modulating therapy prevents fibrosis and autoimmunity in mouse models of scleroderma. Nature 503, 126–130 (2013). https://doi.org/10.1038/nature12614

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