Alex Pizzini1, Hannes Bacher1, Magdalena Aichner1, Alexander Franchi1, Kathrin Watzinger1, Ivan Tancevski1, Thomas Sonnweber1, Birgit Mosheimer-Feistritzer1, Christina Duftner1, Bettina Zelger2, Johannes Pallua2, Susanne Sprung2, Thomas Weichhart3, Bernhard Zelger4, Günter Weiss5, Judith Löffler-Ragg6. 1. Medical University of Innsbruck, Department of Internal Medicine II, Anichstraße 35, 6020, Innsbruck, Austria. 2. Medical University of Innsbruck, Department of Pathology, General Pathology Division, Anichstraße 35, 6020, Innsbruck, Austria. 3. Medical University of Vienna, Institute of Medical Genetics, Währinger Straße 10, 1090, Vienna, Austria. 4. Medical University of Innsbruck, Department of Dermatology and Venereology, Anichstraße 35, 6020, Innsbruck, Austria. 5. Medical University of Innsbruck, Department of Internal Medicine II, Anichstraße 35, 6020, Innsbruck, Austria. Electronic address: Guenter.Weiss@i-med.ac.at. 6. Medical University of Innsbruck, Department of Internal Medicine II, Anichstraße 35, 6020, Innsbruck, Austria. Electronic address: Judith.Loeffler@i-med.ac.at.
Abstract
INTRODUCTION: Sarcoidosis is a systemic granulomatous disease with a variable clinical presentation and disease course. There is still no reliable biomarker available, which assists in the diagnosis or prediction of the clinical course. According to a murine model, the expression level of the metabolic checkpoint kinase mechanistic target of Rapamycin complex 1 (mTORC1) in granulomas of sarcoidosis patients may be used as a clinical biomarker. MATERIAL AND METHODS: This is a retrospective analysis of 58 patients with histologically confirmed sarcoidosis. Immunohistochemical staining of granulomas from tissue samples was evaluated for the expression of activated mTORC1 signaling, including phosphorylated mTOR, its downstream effectors S6K1, 4EBP1 and the proliferation marker Ki-67. Patients were categorized according to different clinical phenotypes, serum biomarkers, and immunomodulatory therapy. RESULTS: All patients showed activated mTORC1 signaling in granulomas, which correlated with its downstream effectors S6K1 and 4EBP1 but was not related to Ki-67 expression. The mTORC1 activity revealed an association neither to disease severity nor the necessity of treatment; however, p-mTOR inversely correlated with cumulative corticosteroid dosage. CONCLUSION: Our data confirm activation of the mTORC1 pathway in sarcoidosis, supporting the hypothesis that mTOR is a significant driver in granuloma formation. However, we could not find a relationship between the degree of mTOR activation and disease severity or the need for therapy.
INTRODUCTION:Sarcoidosis is a systemic granulomatous disease with a variable clinical presentation and disease course. There is still no reliable biomarker available, which assists in the diagnosis or prediction of the clinical course. According to a murine model, the expression level of the metabolic checkpoint kinase mechanistic target of Rapamycin complex 1 (mTORC1) in granulomas of sarcoidosispatients may be used as a clinical biomarker. MATERIAL AND METHODS: This is a retrospective analysis of 58 patients with histologically confirmed sarcoidosis. Immunohistochemical staining of granulomas from tissue samples was evaluated for the expression of activated mTORC1 signaling, including phosphorylated mTOR, its downstream effectors S6K1, 4EBP1 and the proliferation marker Ki-67. Patients were categorized according to different clinical phenotypes, serum biomarkers, and immunomodulatory therapy. RESULTS: All patients showed activated mTORC1 signaling in granulomas, which correlated with its downstream effectors S6K1 and 4EBP1 but was not related to Ki-67 expression. The mTORC1 activity revealed an association neither to disease severity nor the necessity of treatment; however, p-mTOR inversely correlated with cumulative corticosteroid dosage. CONCLUSION: Our data confirm activation of the mTORC1 pathway in sarcoidosis, supporting the hypothesis that mTOR is a significant driver in granuloma formation. However, we could not find a relationship between the degree of mTOR activation and disease severity or the need for therapy.
Authors: Raisa Kraaijvanger; Kees Seldenrijk; Els Beijer; Jan Damen; Jayne Louise Wilson; Thomas Weichhart; Jan C Grutters; Marcel Veltkamp Journal: Cells Date: 2021-12-15 Impact factor: 6.600