Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.
Anti-AT(1)R and Anti-ET(A)R Autoantibodies in Systemic Sclerosis: Indication of Possible Involvement in Disease Pathology.
Kill1, Angela, Becker2, Mike O., Guenther1, Jeannine, Heidecke3, Harald, Dragun2, Duska, Riemekasten1, Gabriela
Recently identified functional autoantibodies simultaneously targeting the angiotensin-II type-1 receptor (AT1R-Abs) and the endothelin-1 receptor type A (ETAR-Abs) were linked with vascular and fibrotic complications in patients with systemic sclerosis (SSc). Presence of both autoantibodies moreover predicted mortality due to cardiopulmonary complications implicating their contribution in SSc pathogenesis. Here, different autoantibody- and ligand-mediated effects and their blockade by receptor inhibitors were studied.
HMEC-1 were treated with IgG from SSc patients containing anti-AT(1)R and anti-ET(A)R autoantibodies, with IgG from healthy donors, and with the natural receptor ligands. In parallel, cells were pre-treated with various receptor antagonists alone and in combination. The effect on different cytokines, growth factors, cell signaling molecues, and cell viability was measured by e.g. toxicity test, qRT-PCR, and ELISA.
Exposure of endothelial cells to SSc- IgG led to a strong upregulation of several mediators. In case of IL-8 mRNA and on protein expression levels, expression of mRNA was downregulated and partially reduced on the protein levels using pre-treatment with receptor inhibitors. There was a high variability in the response to the blockers exhibiting responders and non-responders. Interestingly, treatment with natural ligands did not result in IL-8 up-regulation.Treatment with SSc-IgG led also to a significantly reduced cell viability compared to N-IgG treatment. These effects were partially abolished by pre-treatment with AT(1)R- inhibitor, but completely abolished using by one but not by another ET inhibitor. MCP-1 was also up-regulated by IgG from SSc patients but not from controls, but was not blockable using receptor inhibitors.
Our results suggest an autoantibody-driven cytotoxicity and inflammatory activation of endothelial cells by angiotensin/endothelin-receptors in vitro. The data also suggest a heterogeneity of the antibody-mediated effects, the role of other possible autoantibodies, and different responses to inhibitors and the natural ligands. Whether these in vitro data could be used to identify responders or non-responsers to therapy, remain to be studied. In vivo experiments are underway to give better insight into the complex nature of the SSc-antibody-mediated effects.
To cite this abstract, please use the following information:
Kill, Angela, Becker, Mike O., Guenther, Jeannine, Heidecke, Harald, Dragun, Duska, Riemekasten, Gabriela; Anti-AT(1)R and Anti-ET(A)R Autoantibodies in Systemic Sclerosis: Indication of Possible Involvement in Disease Pathology. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :2312