High expression of mTOR signaling in granulomatous lesions is not predictive for the clinical course of sarcoidosis

Alex Pizzini; Hannes Bacher; Magdalena Aichner; Alexander Franchi; Kathrin Watzinger; Ivan Tancevski; Thomas Sonnweber; Birgit Mosheimer-Feistritzer; Christina Duftner; Bettina Zelger; Johannes Pallua; Susanne Sprung; Thomas Weichhart; Bernhard Zelger; Günter Weiss; Judith Löffler-Ragg

doi:10.1016/j.rmed.2020.106294

High expression of mTOR signaling in granulomatous lesions is not predictive for the clinical course of sarcoidosis

Respir Med. 2021 Feb:177:106294. doi: 10.1016/j.rmed.2020.106294. Epub 2021 Jan 5.

Authors

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

Affiliations

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.

PMID: 33485108
DOI: 10.1016/j.rmed.2020.106294

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.

Keywords: Biomarker; Clinical study; Prognosis; Sarcoidosis; mTOR.