Sarcoidosis is a granulomatous disease of unknown etiology with striking disparities in clinical outcome. Approximately 60% of sarcoidosis patients will spontaneously resolve their disease, while the remaining subjects experience a gradual loss of lung function, from with ~15- 20% ultimately die. We previously reported that the strength of the adaptive immune response is an important factor in sarcoidosis clinical outcome. Prior investigations demonstrate increased Programmed Death-1 (PD-1) expression on CD4+ T cells in sarcoidosis patients experiencing disease progression. Our recent publication in Science Translational Medicine demonstrates that PD-1+CD4+ T cells have augmented IL-6 expression that induces pSTAT3 transcription, leading to increased expression of the pathogenic cytokines, IL-17A and TGF-?1. These cells upon co-culture with human lung fibroblasts induce collagen-1 production. The percentage of PD-1+CD4+ T cells is significantly higher in female sarcoidosis subjects, compared to males. These observations support the hypothesis that estrogen-mediated alteration in PD-1 pathway/IL-6/pSTAT3 signaling drive the female predominance in sarcoidosis loss of lung function. This proposal will delineate if the effects of estrogen on Th17 cell development are directly or indirectly mediated through PD-1 pathway signaling. We will also conduct in vivo investigations of the efficacy of currently FDA-approved therapeutics against PD-L1, PD-1, IL-6, pSTAT3 and IL-17A on reduction of collagen production. These analyses will serve as proof-of-concept investigations, thus laying the foundation for design of innovative clinical trials of effective therapeutics against pulmonary sarcoidosis progression according to sex.
Sarcoidosis is a granulomatous disease of unknown etiology in which females experience significantly greater morbidity and mortality compared to males. We recently reported that the PD-1 signaling pathway contributes to loss of lung function in sarcoidosis subjects (Science Translational Medicine 2018, 2018 Sep 26;10(460). Building upon the observation of significantly higher PD-1+CD4+ T cells in female sarcoidosis subjects, this proposal will define the relevant mechanisms by which estrogen regulates the PD-1 pathway and Th17 cell development, as well as investigate the in vivo effects of PD-L1, IL-6, STAT3 and IL-17A inhibition on pulmonary sarcoidosis progression.