Bronchoalveolar Lavage Fluid IFN-γ+Th17 Cells and Regulatory T Cells in Pulmonary Sarcoidosis

Abstract

In sarcoidosis, increased Th17 cell fractions have been reported in bronchoalveolar lavage fluid, and elevated numbers of Th17 cells producing IFN-γ have been observed in peripheral blood. The balance between Th1, Th17, and FoxP3+ CD4+ T cell subsets in sarcoidosis remains unclear. Bronchoalveolar lavage fluid cells, from 30 patients with sarcoidosis, 18 patients with other diffuse parenchymal lung diseases, and 15 healthy controls, were investigated with flow cytometry for intracellular expression of FoxP3. In a subset of the patients, expression of the cytokines IL17A and IFN-γ was investigated. The fractions of FoxP3+ CD4+ T cells and Th17 cells were both lower in sarcoidosis compared to controls (P = 0.017 and P = 0.011, resp.). The proportion of Th17 cells positive for IFN-γ was greater in sarcoidosis than controls (median 72.4% versus 31%, P = 0.0005) and increased with radiologic stage (N = 23, rho = 0.45, and P = 0.03). IFN-γ + Th17 cells were highly correlated with Th1 cells (N = 23, rho = 0.64, and P = 0.001), and the ratio of IFN-γ + Th17/FoxP3+ CD4+ T cells was prominently increased in sarcoidosis. IFN-γ + Th17 cells may represent a pathogenic subset of Th17 cells, yet their expression of IFN-γ could be a consequence of a Th1-polarized cytokine milieu. Our results indicate a possible immune cell imbalance in sarcoidosis.

Sarcoidosis and T-Helper Cells. Th1, Th17, or Th17.1?

“…Deconditioning and frailty, specifically sarcopenia, are cogent confounding factors in this regard. It was once hoped that pretransplant cardiopulmonary exercise testing would be a critical tool to help determine the balance between heart and lung dysfunction, but in practice, the ability to fully test the pulmonary component may be limited by the severity of the heart failure, causing reduced alveolar-capillary membrane diffusing capacity (14).…”

“…1281-1291) used multiparameter flow cytometry to analyze bronchoalveolar lavage (BAL) T cells and report that a subset of Th17 cells that coexpress IFN-g is particularly enriched in the lung in sarcoidosis (12). IFN-g-producing Th17 cells (termed Th17.1 or Th17/Th1 cells) were previously detected in mouse and man, including in human subjects with sarcoidosis or Crohn's disease (13)(14)(15). Ramstein and colleagues identified Th17.1 cells by their coexpression of the chemokine receptors CCR6 and CXCR3, which had been previously linked with Th17 and Th1 cells, respectively (12).…”

Positive fungal quantitative PCR and Th17 cytokine detection in bronchoalveolar lavage fluids: Complementary biomarkers of hypersensitivity pneumonitis?

“…HP and sarcoidosis are generally considered as Th1 diseases (Mroz et al, 2008;Ye et al, 2009;Tondell et al, 2014) but recent studies showed for both of them that a Th17 response was also part of the immunopathology (Joshi et al, 2009;Simonian et al, 2009;Facco et al, 2011). These diseases have in common to lead ultimately to formation of granulomas and a fibrotic phase (Girard et al, 2009;Facco et al, 2011).…”

“…A panel of 10 key cytokines/chemokines were selected for testing, based on the scientific literature concerning ILD immunopathology (Mroz et al, 2008;Ye et al, 2009;Joshi et al, 2009;Simonian et al, 2009;Andrews et al, 2016;Tondell et al, 2014;Facco et al, 2011;Schupp et al, 2015;Oruqaj et al, 2015): IL-8, IL-6, TNFα, IFNγ, IL-1β (Th1 response), IL-4 (Th2 response) and IL-17, IL-21 and IL-23 (Th17 response). The TSLP, unexplored up to now, was also measured in patient's BALF (Kuethe et al, 2014).…”

“…An imbalance in the production of cytokines/chemokines, with a shift to the Th1 profile, has also been identified as a key feature of sarcoidosis, a multisystem inflammatory disease of unknown etiology characterized by the formation of epithelioid granulomas, with the accumulation of CD4 + Th1 lymphocytes and macrophages (Tondell et al, 2014). Recent data demonstrated that Th17 cells were also involved and actively participated in sarcoidosis progression (Facco et al, 2011).…”