Background/Purpose:

Autoimmunity, vasculopathy and fibrosis are features of systemic sclerosis (SSc). The functional link between these three pathophysiological components is still missing. Research suggests an involvement of endothelin-1 and angiotensin II, and of the activation of their receptors by the natural ligands as well as by agonistic autoantibodies against these receptors in SSc–associated vasculopathy and fibrosis [1]. Autoantibodies against the angiotensin receptor type 1 (AT1R) and the endothelin receptor type A (ETAR) are present in the majority of SSc patients and high levels of the antibodies are associated with severe organ manifestations [1]. AT1R and ETAR are expressed in various cell types such as endothelial cells, fibroblasts, as well as cells of the adaptive and innate immune system. The aim of the present study was to identify the effects of these antibodies on those effector cells and establish a link to SSc pathogenesis.

Methods:

Human microvascular endothelial cells, fibroblast, and peripheral blood mononuclear cells (PBMCs) from healthy donors were stimulated in vitro by affinity-purified IgG from sera of SSc patients containing anti-AT1R and anti-ETAR antibodies as well as by affinity-purified IgG from sera of healthy donors. Effects of the antibodies were measured by ELISA, migration assay, and PCR. To To prove that the IgG effects are specifically due to AT1R and ETAR activation, specific receptor blockers were used. Cytokine expression was correlated with clinical data from the IgG donors.

Results:

In endothelial cells, anti-AT1R and anti-ETAR ab induced adhesion molecules and IL-8 expression as well as further pro-fibrotic and inflammatory cytokines. IL-8 levels in the supernatants correlated with the antibody levels in the IgG fractions. In fibroblasts, collagen-I expression was induced. At a molecular level, c-Jun expression, known to play a role in SSc, was upregulated. The antibodies increased the migration of neutrophils as well as of PBMC. Stimulation of PBMCs by IgG from SSc patients resulted in a significantly increased expression and secretion of IL-8 and, in most cultures, of CCL18 compared to the stimulation by IgG of healthy donors. All the effects were significantly reduced or completely blocked by commercial AT1R and ETAR antagonists. Correlation analyses with clinical data of the SSc IgG donors revealed correlations between cytokine expression, induced by the antibodies, and clinical findings.

Conclusion:

As shown in vitro, anti-AT1R and anti-ETAR antibodies exhibit effects on inflammation, immune regulation, migration of cells, and on fibrosis. Based on the broad expression of the receptors on various effector cell types, the antibodies may link the adaptive and innate immune system as well as resident cells in order to produce the typical features vasculopathy, fibrosis, and autoimmunity.

Reference:

[1] Riemekasten et al., 2011. Involvement of functional autoantibodies against vascular receptors in systemic sclerosis, Ann Rheum Dis. 2011 Mar;70(3):530-6, PMID: 21081526

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/systemic-sclerosis-effects-of-agonistic-autoantibodies-directed-against-the-angiotensin-receptor-type-1-and-the-endothelin-receptor-type-a-on-effector-cells/