Artikel
Anti-AT1R and anti-ETAR autoantibodies from patients with SSc and their agonistic effects
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Autoren
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Angela Kill
- Charité - Universitätsmedizin Berlin, Medizinische Klinik mit Schwerpunkt Rheumatologie und klinische Immunologie, Berlin
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Christoph Tabeling
- Charité - Universitätsmedizin Berlin, Medizinische Klinik mit Schwerpunkt Infektiologie und Pneumologie, Berlin
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Anja A. Kühl
- Charité - Universitätsmedizin Berlin, Gastroenterology, Infectiology and Rheumatology and Research Center ImmunoScience (RCIS), Berlin
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Jeannine Günther
- Deutsches Rheuma-Forschungszentrum (DRFZ), Berlin
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Mike Becker
- Charité - Universitätsmedizin Berlin, Medizinische Klinik mit Schwerpunkt Rheumatologie und klinische Immunologie, Berlin
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Harald Heidecke
- CellTrend GmbH, Luckenwalde, Germany, CellTrend GmbH, Luckenwalde
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Duska Dragun
- Charité - Universitätsmedizin Berlin, Medizinische Klinik mit Schwerpunkt Nephrologie und internistische Intensivmedizin, Berlin
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Gerd-Rüdiger Burmester
- Charité - Universitätsmedizin Berlin, Medizinische Klinik mit Schwerpunkt Rheumatologie und klinische Immunologie, Berlin
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Gabriela Riemekasten
- Charité - Universitätsmedizin Berlin, Medizinische Klinik mit Schwerpunkt Rheumatologie und klinische Immunologie, Berlin
| Veröffentlicht: | 12. September 2014 |
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Gliederung
Text
Background: Agonistic autoantibodies to angiotensin II type 1 receptor (AT1R) and endothelin 1 type A receptor (ETAR) are found in elevated levels in systemic sclerosis (SSc). Furthermore, these autoantibodies show distinct associations to increased risk of SSc-related manifestations and reduced cumulative survival, thus indicating their value as biologic markers and their impact on disease pathogenesis. Here, functional effects of these autoantibodies (anti-AT1R and anti-ETAR autoantibodies) were studied in vitro and in vivo to understand the influence of anti-AT1R and anti-ETAR autoantibodies on inflammation and fibrotic reactions on the cellular and systemic level.
Methods: In vitro, autoantibody-mediated effects were studied on human microdermal endothelial cells-1 (HMEC-1), on healthy donor dermal fibroblasts and in healthy donor neutrophils. In vivo, autoantibody-mediated effects were studied by passive autoantibody-transfer treatment into healthy C57Bl/6J mice. For each setting anti-AT1R and anti-ETAR autoantibody-positive IgG of SSc patients was used and IgG of healthy donors as a control. Angiotensin and endothelin receptor inhibitors were used in vitro to analyze receptor-mediated effects.
Results: Treatment with anti-AT1R and anti-ETAR autoantibody-positive IgG of SSc patients resulted in several effects, both in vitro and in vivo. Endothelial cells showed an activation reflected by enhanced expression of adhesion molecule VCAM-1, of IL-8, reduced wound repair and an increased neutrophil trans-endothelial migration.
Fibroblasts showed increased type I collagen expression. Effects were induced in an autoantibody-level dependent manner. BALF neutrophil counts were elevated in treated mice accompanied by increased chemokine KC plasma levels and a correlation between KC levels and neutrophil counts. Repeated transfer led to marked structural alterations in the lung architecture.
Conclusion: Our current findings demonstrate the potential of anti-AT1R and anti-ETAR autoantibodies to induce inflammatory and fibrotic events on cellular and systemic levels. In vitro data indicate direct receptor activation by anti-AT1R and anti-ETAR autoantibody-positive SSc-IgG. Activation of the angiotensin and endothelin receptors by these autoantibodies could account in part for effects seen here in in vivo animal experiments. These findings additionally stress the autoimmunity aspect in pathogenesis of systemic sclerosis. Therefore, receptor inactivation studies are currently performed to assess a deeper knowledge of the autoantibody-mediated effects and to improve our current understanding of SSc pathogenesis.
