Integrin-modulating Therapy Prevents Fibrosis and Autoimmunity in Mouse Models of Scleroderma

Nature. 2013 Nov 7;503(7474):126-30. doi: 10.1038/nature12614. Epub 2013 Oct 9.

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 autoantibodies. 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 unknown. 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 microfibrils. 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 integrins. 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs / genetics
  • Amino Acid Substitution / genetics
  • Animals
  • Antibodies, Antinuclear / immunology
  • Antibodies, Neutralizing / immunology
  • Antibodies, Neutralizing / pharmacology
  • Antibodies, Neutralizing / therapeutic use
  • Autoimmunity / drug effects*
  • Autoimmunity / immunology
  • Contracture / drug therapy*
  • Contracture / immunology
  • Contracture / pathology*
  • Contracture / prevention & control
  • Dendritic Cells / drug effects
  • Female
  • Fibrillin-1
  • Fibrillins
  • Fibrosis / drug therapy
  • Fibrosis / pathology
  • Fibrosis / prevention & control
  • Integrins / drug effects*
  • Integrins / metabolism*
  • Male
  • Mice
  • Microfilament Proteins / chemistry
  • Microfilament Proteins / genetics
  • Microfilament Proteins / metabolism
  • Mutation, Missense / genetics
  • Plasma Cells / drug effects
  • Scleroderma, Systemic / drug therapy*
  • Scleroderma, Systemic / immunology
  • Scleroderma, Systemic / pathology*
  • Scleroderma, Systemic / prevention & control
  • Skin Diseases, Genetic / drug therapy*
  • Skin Diseases, Genetic / immunology
  • Skin Diseases, Genetic / pathology*
  • Skin Diseases, Genetic / prevention & control
  • T-Lymphocytes, Helper-Inducer / drug effects
  • Transforming Growth Factor beta / antagonists & inhibitors
  • Transforming Growth Factor beta / immunology

Substances

  • Antibodies, Antinuclear
  • Antibodies, Neutralizing
  • Fbn1 protein, mouse
  • Fibrillin-1
  • Fibrillins
  • Integrins
  • Microfilament Proteins
  • Transforming Growth Factor beta

Supplementary concepts

  • Stiff Skin Syndrome