We have recently discovered in two separate cohorts that the most prevalent immune cells producing interferon? (IFN?) in pulmonary sarcoidosis lung lavage are not Th1 cells but another cell which has been identified as a highly pathogenic subset of Th17 cells, called Th17.1, due to their enhanced ability to produce IFN? among other functions. These findings challenge the Th1 paradigm that has held sway in sarcoidosis since the invention of research bronchoscopy. But more importantly, our findings have the ability to shift the research focus to these Th17.1 cells, about which we know little of their pathogenic traits and functional differences compared to Th17 cells in sarcoidosis. The literature suggests that Th17.1 cells appear to be derived from classically polarized Th17 cells which are highly ?plastic? and can be stimulated to turn on Th1-related signaling pathways by proinflammatory cytokines such as IL-12. Th17.1 cells in sarcoidosis do not appear to share proliferative defects as documented for Th17 cells. We also know from Crohn's disease that Th17.1 cells exhibit corticosteroid resistance. In our data, we found a trend in correlation between worsening lung function (FEV1 % predicted) with increasing percentage of Th17.1 cells. This suggests that Th17.1 cells in sarcoidosis may contribute to disease severity but cellular mechanisms have not been explored. In addition, another distinct subset of Th17 linage cells have been identified in published studies and are called ?Th17- derived Th1 cells?. These cells are thought to be even more polarized towards a Th1 phenotype than Th17.1 cells due to their loss of IL-17A secretion and marked production of IFN?. Thus, our finding of high frequencies of Th17.1 cells in sarcoidosis raises the question of whether the cells we have long termed ?Th1? in sarcoidosis could actually instead belong to this Th17-derived Th1 subset. Therefore, we hypothesize that Th17 cells are plastic and their biologic phenotype exists in a continuum from Th17?Th17.1?Th17-derived Th1 cells in the milieu of polarizing cytokines IL-12 and IFN? found in sarcoidosis. These polarized Th17 cells have pathogenic potential to promote sarcoidal inflammation and cause progressive disease. Thus, we propose to interrogate the proliferative capacity and related functions of Th17 vs Th17.1 cells in sarcoidosis compared healthy controls and asthmatics. We will also use flow cytometry and CyTOF methods to measure the range of Th17 subsets and their ability to resist corticosteroid effects.
The studies to examine the phenotypes and functions of newly identified immune cell subsets in sarcoidosis have the potential to impact the disease by re-directing the focus of research and identifying new targets for treatment, which may be applicable to other Th17.1 inflammatory diseases. This proposal will use state-of-the-art technology to accomplish its goals and could discover new relationships between Th17 subsets. Findings from the proposed studies could reveal how these Th17 cell subsets contribute to disease mechanisms in sarcoidosis. Finally, results from this study may further confirm the large impact that these cell types have on the inflammatory process in sarcoidosis and possibly other diseases.
