Fibrosis and immune dysregulation in systemic sclerosis

Autoimmun Rev. 2011 Mar;10(5):276-81. doi: 10.1016/j.autrev.2010.09.016. Epub 2010 Sep 21.


Autoimmune and inflammatory phenomena are characteristically present in systemic sclerosis (SSc) and impact on dysregulated fibroblast extracellular matrix deposition, hallmark of the disease in conjunction with fibroproliferative vasculopathy. Oligoclonal T helper 2-like cells are present in the skin and peripheral blood in early diffuse disease. Type 2 cytokines synergize with profibrotic cytokines including transforming growth factor beta, favoring collagen deposition and metalloproteinase inhibition by fibroblasts. Furthermore, chemokine with pro-fibrotic and pro-angiogenic properties are preferentially produced by fibroblasts under the influence of Th2-like cells. The profibrotic monocyte chemotactic protein 1 is also produced by fibroblasts, partially in response to Toll-like receptor 4 (TLR4) recognition, when autoantibodies (autoAb) bind to fibroblast surface. In addition, immune-complex formed by autoAb and ubiquitous antigens including topoisomerase-1 favor the production of interferon-alpha (IFN-α) possibly by interacting with intravesicular TLRs. Consistent with this findings, unbiased gene screening has revealed that SSc peripheral blood cells express genes induced by IFN-α, a characteristic shared with systemic lupus erythematosus and other autoimmune disorders. These findings highlight the complex relationship between adaptive and acquired immune responses, which may participate to the pathogenesis of SSc in manners until now unsuspected, which may help in identifying novel therapeutic targets.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adaptive Immunity
  • Animals
  • Antigen-Antibody Complex / metabolism
  • Autoantibodies / immunology
  • Autoantibodies / metabolism
  • Chemokine CCL2 / genetics
  • Chemokine CCL2 / metabolism
  • Collagen / biosynthesis
  • Extracellular Matrix / metabolism
  • Extracellular Matrix / pathology
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Fibrosis
  • Gene Expression
  • Humans
  • Inflammation
  • Interferon-alpha / genetics
  • Interferon-alpha / metabolism
  • Mice
  • Scleroderma, Systemic / immunology*
  • Scleroderma, Systemic / metabolism*
  • Scleroderma, Systemic / pathology
  • Signal Transduction / immunology
  • Skin / metabolism
  • Skin / pathology
  • Th1-Th2 Balance
  • Th2 Cells / immunology
  • Th2 Cells / metabolism
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism


  • Antigen-Antibody Complex
  • Autoantibodies
  • Chemokine CCL2
  • Interferon-alpha
  • TLR4 protein, human
  • Toll-Like Receptor 4
  • Transforming Growth Factor beta
  • Collagen