Abstract
BackgroundImpaired regulatory T cell (Treg) function is thought to contribute to ongoing inflammatory responses in sarcoidosis, but underlying mechanisms remain unclear. Moreover, it is not known if increased apoptotic susceptibility of Tregs may contribute to an impaired immunosuppressive function in sarcoidosis. Therefore, the aim of this study is to analyze proportions, phenotype, survival, and apoptotic susceptibility of Tregs in sarcoidosis.MethodsPatients with pulmonary sarcoidosis (n = 58) were included at time of diagnosis. Tregs were analyzed in broncho-alveolar lavage fluid and peripheral blood of patients and healthy controls (HC).ResultsIn sarcoidosis patients no evidence was found for a relative deficit of Tregs, neither locally nor systemically. Rather, increased proportions of circulating Tregs were observed, most prominently in patients developing chronic disease. Sarcoidosis circulating Tregs displayed adequate expression of FoxP3, CD25 and CTLA4. Remarkably, in sarcoidosis enhanced CD95 expression on circulating activated CD45RO+ Tregs was observed compared with HC, and proportions of these cells were significantly increased. Specifically sarcoidosis Tregs - but not Th cells - showed impaired survival compared with HC. Finally, CD95L-mediated apoptosis was enhanced in sarcoidosis Tregs.ConclusionIn untreated patients with active pulmonary sarcoidosis, Tregs show impaired survival and enhanced apoptotic susceptibility towards CD95L. Increased apoptosis likely contributes to the insufficient immunosuppressive function of sarcoidosis Tregs. Further research into this field will help determine whether improvement of Treg survival holds a promising new therapeutic approach for chronic sarcoidosis patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-015-0265-8) contains supplementary material, which is available to authorized users.
Highlights
Impaired regulatory T cell (Treg) function is thought to contribute to ongoing inflammatory responses in sarcoidosis, but underlying mechanisms remain unclear
Since a relative deficit of Tregs has been suggested to contribute to a persisting granulomatous response in chronic sarcoidosis [19, 22], we first quantified CD25int-highFoxP3high Tregs in bronchoalveolar lavage fluid (BALF) and peripheral blood (PB) of active sarcoidosis patients and healthy controls by flow cytometry
No evidence was found for a relative deficit of Tregs in BALF of untreated patients with active sarcoidosis compared with healthy control BALF (Additional file 2: Figure S1), suggesting an intact migration of Tregs towards site of inflammation
Summary
Impaired regulatory T cell (Treg) function is thought to contribute to ongoing inflammatory responses in sarcoidosis, but underlying mechanisms remain unclear. It is not known if increased apoptotic susceptibility of Tregs may contribute to an impaired immunosuppressive function in sarcoidosis. The aim of this study is to analyze proportions, phenotype, survival, and apoptotic susceptibility of Tregs in sarcoidosis. The disease is characterized by an exaggerated T helper (Th)1/Th17 response upon exposure to one or several antigens in genetically susceptible individuals [2, 3]. The majority of the patients undergo spontaneous resolution, a substantial proportion develops chronic, progressive disease with need for therapy [1]. Factors that determine granuloma fate remain to be elucidated [1, 3].
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