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Objective: Systemic sclerosis (SSc) is a rare but severe autoimmune disease characterized by immune dysregulation, fibrosis, and vasculopathy. While previous studies have highlighted the presence of functional autoantibodies targeting the angiotensin II type 1 receptor (ATR) and endothelin-1 type A receptor (ETR), leading to autoantibody-mediated receptor stimulation and subsequent activation of endothelial cells (ECs), a comprehensive understanding of the direct interaction between these autoantibodies and their receptors is currently lacking. Moreover, existing data confirming the presence of these autoantibodies in SSc often rely on similar methodologies and assays. Our aim was to replicate previous findings and to investigate the functional effects of SSc patient-derived IgG (SSc IgG) on ATR- and ETR signaling, the downstream EC response, as well as presence of ATR-binding autoantibodies in circulation.
Methods: Quantitative PCR (qPCR) and cytokine ELISA, alongside a real-time cell analyzer, were utilized to assess receptor-specific functional characteristics of purified IgG from SSc patients (n=18). Additionally, a novel protein capture assay using solubilized epitope-tagged ATR was developed to detect ATR-binding autoantibodies in plasma samples from SSc patients (n=28) and healthy donors (n=14).
Results: No evidence for EC activation in an ATR- or ETR-dependent manner was revealed. Furthermore, stimulation with SSc IgG did not induce receptor activation nor alter GPCR signaling upon agonist stimulation in a model with receptor overexpression. Lastly, no ATR-binding autoantibodies were detected in plasma from SSc patients when using epitope-tagged solubilized ATR.
Conclusion: Overall, our study did not provide evidence to support the presence of ATR- or ETR-activating autoantibodies in purified SSc IgG, nor ATR-binding autoantibodies in circulation of SSc patients.
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| http://dx.doi.org/10.1002/art.43099 | DOI Listing |
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