Autoantibodies Which Bind to and Activate Keratinocytes in Systemic Sclerosis.

Systemic sclerosis (SSc) is a multisystem connective tissue disease characterised by pathological processes involving autoimmunity, vasculopathy and resultant extensive skin and organ fibrosis. Recent studies have demonstrated activation and aberrant wound healing responses in the epithelial layer of the skin in this disease, implicating the epithelial keratinocytes as a source of pro-fibrotic and inflammatory mediators. In this paper, we investigated the role of Immunoglobulin G (IgG) autoantibodies directed against epithelial cells, as potential initiators and propagators of pathological keratocyte activation and the ensuing SSc fibrotic cascade. A keratinocyte cell-based ELISA is used to evaluate the binding of SSc IgG. SSc skin biopsies were stained by immunofluorescence for the presence of IgG in the keratinocyte layer. Moreover, IgG purified from SSc sera was evaluated for the potential to activate keratinocytes in tissue culture and to induce TLR2 and 3 signalling in reporter cell lines. We demonstrate enhanced binding of SSc IgG to keratinocytes and the activation of these cells leading to the release of IL-1α, representing a potential initiating pathway in this disease.

Commentary on a recent article-"A prostacyclin analogue, Iloprost, protects from bleomycin-induced fibrosis in mice" Zhu Y et al. Respir Res. 2010 Mar 20;11(1):34.

Data from our laboratory show that in vitro fibroblasts are exquisitely responsive to prostacyclin and the prostacyclin derivative Iloprost, which block their activation by TGFß. A recent article by Zhu Y et al confirm these effects in vivo showing that Iloprost, given as a single intraperitoneal injection, blocks lung fibrosis in the bleomycin model of lung injury and fibrosis. These results are important because at present no effective clinical treatments are available to treat idiopathic lung fibrosis, which progresses and leads to respiratory failure. Limiting factors for the clinical use of prostacyclin derivatives as anti-fibrotics are failure to achieve therapeutic levels in the involved fibrotic tissues, and dose limiting side effects due to vasodilatation and binding to the IP receptor on vascular cells. Possible approaches include fibroblast directed gene therapies or amelioration of the vascular side effects.