Impaired survival of regulatory T cells in pulmonary sarcoidosis

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.

Infliximab therapy balances regulatory T cells, tumour necrosis factor receptor 2 (TNFR2) expression and soluble TNFR2 in sarcoidosis

“…In addition to enhanced TNF-TNFR2 stimulation, which we suggest here, there might be additional mechanisms accounting for the observed elevation in T reg levels. One of these mechanisms include an apoptosis defect, as described recently by Broos et al [7].…”

“…In cross-over experiments, however, it was shown subsequently that these T regs are incompetent and cannot inhibit the secretion of interferon (IFN)-g and TNF by T effs [5,6]. Furthermore, it was shown that sarcoidosis T regs showed impaired survival compared to healthy controls [7].…”

Etiology and Immunopathogenesis of Sarcoidosis: Novel Insights

“…Furthermore, Tregs obtained from pulmonary sarcoidosis patients suffered from impaired survival and increased apoptosis. 67 Moreover, restoration of Treg function was associated with disease remission. 48 Taflin and colleagues have suggested that Tregs may be able to prevent sarcoidosis development, but cannot reverse the granuloma process.…”

Pediatric Sarcoidosis: A Review with Emphasis on Early Onset and High-Risk Sarcoidosis and Diagnostic Challenges

“…B lymphocytes may also be involved in sarcoidal granuloma formation, as Lofgren syndrome patients exhibit higher levels of Proprionibacterium acnes-specific IgA antibodies [77]. In chronic diseases, sarcoid T-reg fails to efficiently suppress proliferation and cytokine production by T helper cells [78], and with accumulation of Th1/Th17 cells, further support stabilization of granulomas and chronic disease progression [35]. In contrast, highly plastic and qualified effector T-cells aiming at clearance of the antigens from the granulomas leads to recovery [35,76].…”