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.

中文翻译：

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mTOR 信号在肉芽肿性病变中的高表达并不能预测结节病的临床病程

介绍

结节病是一种全身性肉芽肿性疾病，具有不同的临床表现和病程。目前还没有可靠的生物标志物可以帮助诊断或预测临床病程。根据小鼠模型，结节病患者肉芽肿中代谢检查点激酶机制靶点雷帕霉素复合物 1 (mTORC1) 的表达水平可用作临床生物标志物。

材料与方法

这是对 58 名经组织学证实的结节病患者的回顾性分析。对组织样本肉芽肿进行免疫组织化学染色，评估激活的 mTORC1 信号传导的表达，包括磷酸化 mTOR、其下游效应子 S6K1、4EBP1 和增殖标记物 Ki-67。根据不同的临床表型、血清生物标志物和免疫调节治疗对患者进行分类。

结果

所有患者的肉芽肿中均表现出激活的 mTORC1 信号传导，与其下游效应器 S6K1 和 4EBP1 相关，但与 Ki-67 表达无关。mTORC1 活性显示与疾病严重程度和治疗必要性均无关。然而，p-mTOR 与累积皮质类固醇剂量呈负相关。

结论

我们的数据证实了 mTORC1 通路在结节病中的激活，支持了 mTOR 是肉芽肿形成的重要驱动因素的假设。然而，我们无法找到 mTOR 激活程度与疾病严重程度或治疗需求之间的关系。