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Background: Systemic sclerosis (SSc) belongs to the group of connective tissue diseases and is associated with the occurrence of disease-specific autoantibodies. Although it is still controversial whether these antibodies contribute to pathogenesis, there are new insights into the development of these specific antibodies and their possible pathophysiological properties. Interestingly, they are associated with specific clinical manifestations, but for some rarer antibodies this association is not fully clarified. The aim of this study is a comprehensive analysis of the serum autoantibody status in patients with SSc followed by correlation analyses of autoantibodies with the clinical course of the disease., Methods: Serum from SSc patients was analyzed using a line blot (EUROLINE, EUROIMMUN AG) for SSc-related autoantibodies. Autoantibodies to centromere, Topo-1, antimitochondrial antibodies (AMA) M2 subunit, angiotensin II type 1 receptors (AT 1 R) and endothelin-1 type-A-receptors (ET A R) were also determined by ELISA. We formed immunological clusters and used principal components analysis (PCA) to assign specific clinical characteristics to these clusters., Results: A total of 372 SSc patients were included. 95.3% of the patients were antinuclear antibody positive and in 333 patients at least one SSc specific antibody could be detected. Four immunological clusters could be found by PCA. Centromere, Topo-1 and RP3 all formed own clusters, which are associated with distinct clinical phenotypes. We found that patients with an inverted phenotype, such as limited cutaneous SSc patients within the Topo-1 cluster show an increased risk for interstital lung disease compared to ACA positive patients. Anti-AT 1 R and anti-ET A R autoantibodies were measured in 176 SSc patients; no association with SSc disease manifestation was found. SSc patients with AMA-M2 antibodies showed an increased risk of cardiovascular events., Conclusion: In our in large cluster analysis, which included an extended autoantibody profile, we were able to show that serologic status of SSc patients provides important clues to disease manifestation, co-morbidities and complications. Line blot was a reliable technique to detect autoantibodies in SSc and detected rarer autoantibodies in 42% of our patients., Competing Interests: CT received funding for research from Deutsche Gesellschaft für Pneumologie, Bayer HealthCare, Boehringer Ingelheim, and for lectures and advisory from Actelion Pharmaceuticals, Boehringer Ingelheim, GlaxoSmithKline, and for non-financial support from Actelion, ALK-Abelló, Bayer HealthCare, Boehringer Ingelheim and GlaxoSmithKline. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2023 Höppner, Tabeling, Casteleyn, Kedor, Windisch, Burmester, Huscher and Siegert.)

Introduction: Inflammation is a major pathological feature of pulmonary arterial hypertension (PAH), particularly in the context of inflammatory conditions such as systemic sclerosis (SSc). The endothelin system and anti-endothelin A receptor (ET A ) autoantibodies have been implicated in the pathogenesis of PAH, and endothelin receptor antagonists are routinely used treatments for PAH. However, immunological functions of the endothelin B receptor (ET B ) remain obscure., Methods: Serum levels of anti-ET B receptor autoantibodies were quantified in healthy donors and SSc patients with or without PAH. Age-dependent effects of overexpression of prepro-endothelin-1 or ET B deficiency on pulmonary inflammation and the cardiovascular system were studied in mice. Rescued ET B -deficient mice (ET B -/- ) were used to prevent congenital Hirschsprung disease. The effects of pulmonary T-helper type 2 (Th2) inflammation on PAH-associated pathologies were analyzed in ET B -/- mice. Pulmonary vascular hemodynamics were investigated in isolated perfused mouse lungs. Hearts were assessed for right ventricular hypertrophy. Pulmonary inflammation and collagen deposition were assessed via lung microscopy and bronchoalveolar lavage fluid analyses., Results: Anti-ET B autoantibody levels were elevated in patients with PAH secondary to SSc. Both overexpression of prepro-endothelin-1 and rescued ET B deficiency led to pulmonary hypertension, pulmonary vascular hyperresponsiveness, and right ventricular hypertrophy with accompanying lymphocytic alveolitis. Marked perivascular lymphocytic infiltrates were exclusively found in ET B -/- mice. Following induction of pulmonary Th2 inflammation, PAH-associated pathologies and perivascular collagen deposition were aggravated in ET B -/- mice., Conclusion: This study provides evidence for an anti-inflammatory role of ET B . ET B seems to have protective effects on Th2-evoked pathologies of the cardiovascular system. Anti-ET B autoantibodies may modulate ET B -mediated immune homeostasis., Competing Interests: CT received funding for research from Deutsche Gesellschaft für Pneumologie, Bayer HealthCare, Boehringer Ingelheim, and for lectures from Actelion Pharmaceuticals, Boehringer Ingelheim. HH is CEO of CellTrend GmbH, Luckenwalde, Germany. MW received funding for research from Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, Deutsche Gesellschaft für Pneumologie, European Respiratory Society, Marie Curie Foundation, Else Kröner Fresenius Stiftung, CAPNETZ STIFTUNG, International Max Planck Research School, Actelion, Bayer Health Care, Biotest AG, Boehringer Ingelheim, NOXXON Pharma, Pantherna, Quark Pharma, Silence Therapeutics, Vaxxilon, and for lectures and advisory from Actelion, Alexion, Aptarion, Astra Zeneca, Bayer Health Care, Berlin Chemie, Biotest, Boehringer Ingelheim, Chiesi, Glaxo Smith Kline, Insmed, Novartis, Teva and Vaxxilon. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tabeling, González Calera, Lienau, Höppner, Tschernig, Kershaw, Gutbier, Naujoks, Herbert, Opitz, Gruber, Hocher, Suttorp, Heidecke, Burmester, Riemekasten, Siegert, Kuebler and Witzenrath.)