Abstract

Simultaneously occurring functional autoantibodies directed to angiotensin II type 1 receptor (AT₁R) and endothelin-1 type A receptor (ET_AR) are present in the majority of patients with systemic sclerosis (SSc). The levels of the antibodies correlate with each other suggesting a strong link of these antibodies in SSc. Presence of high anti-AT₁R/ET_AR Ab levels in sera of SSc patients reveal a 10-fold increased risk for development of lung fibrosis. In addition, there is a strong association of the antibodies with pulmonary arterial hypertension and other SSc features. Chronic stimulation of AT1R and ETAR may lead to several clinical symptoms found in SSc. Therefore, we hypothesize a causal role of the antibodies in disease pathogenesis of systemic sclerosis. AT1R and ETAR are present on endothelial cells, smooth muscle cells, fibroblasts, and immune cells. Therefore, in vitro as well as in vivo experiments are preformed to proof our concept.

At present, we use affinity-purified IgG from SSc patients and block all effects by the receptor blockers to proof the specificity of the observed effects. On endothelial cells, anti-AT1R- and anti-ETAR induce TGFβ, endothelial cell proliferation, but also reduced endothelial cell viability. They affect endothelial cell-mediated wound healing and induce adhesion molecules and several proinflammatory and profibrotic cytokines, especially IL-8, a strong chemo attractant for neutrophils. Antibody-mediated modulation of endothelial cell function increased migration of neutrophils in vitro and in vivo. In fibroblast, the antibodies induce collagen-I expression. Moreover, the antibodies have an impact on the innate immune system and via IL-8 and CCL18 activation, on the inflammatory process present in SSc. More convincing data come from in vivo studies: Adoptive transfer of the antibodies induce neutrophilic alveolitis in mice.

Therefore, there is a growing body of evidence showing a direct link between the presence of the antibodies and SSc pathogenesis. The simultaneous stimulation of AT1R and ETAR by these antibodies was blocked best by simultaneous blockade of the AT1R and ETAR-mediated pathways. Blockade of only one pathway may lead to receptor activation through the other pathway that would explain missing effects of single ETAR blockade on lung fibrosis. Combined blockade of both receptor pathways could be, therefore, of advantage in SSc patients. Unfortunately, the antibodies are very resistant to immunosuppressants including autologeous stem cell transplantation.

Taken together, anti-AT1R and -ETAR antibody-mediated pathology seem to contribute to SSc pathogenesis and can explain several clinical features found in SSc. Addressing the antibodies and their effects my provide novel therapeutic targets in SSc.