PROJECT ABSTRACT Sarcoidosis is a systemic immune mediated disease that has an unknown etiology, no cure, and is currently treated with broadly acting immunosuppressants that can lead to significant toxicity. Approximately half of sarcoidosis patients experience self-limited disease that resolves on its own within 2-3 years, the remainder progress to chronic sarcoidosis, characterized by progressive loss of lung function leading to pulmonary fibrosis. Moreover, there are insufficient tools to guide clinical decision making on which patients will experience self- limited sarcoidosis, and thus do not require immunosuppressive therapy, versus those that will progress to more severe disease. We seek to identify immunological signatures associated with and predictive of sarcoidosis disease progression. Our preliminary results suggest PD-1+ CD4+ T cells have pathological role through production of profibrotic cytokines, such as IL-17A and TGF- β1. Additionally, estrogen augments pulmonary fibrosis through modulation of pSTAT3, IL17, and TGF- β. We aim to build on these results by examining the composite immune profile, while accounting for known non-immune risk factors. To accomplish this, we will determine the longitudinal phenotype of innate and adaptive immune compartments utilizing longitudinally acquired peripheral blood mononuclear cells with paired clinical characterization. Phenotyping will include markers for leukocyte differentiation, activation, and recruitment. We will align these observations with in vitro assays, wherein we aim to determine the functional capacity of the immune system using non-inflammatory stimuli (e.g., polyclonal stimulation of the T cell receptor via plate-bound anti-CD3 and soluble anti-CD28 antibodies), a panel of Toll like receptor ligands that mimic pathogenic challenge (lipopolysaccharide, Pam3CSK4, transfected poly(I:C), transfected poly(dA:dT)), mycobacterial antigens or live influenza A virus. To incorporate these data with known non-immune risk factors, we will utilize multivariate modeling to account for cellular populations, genetics, socioeconomic status, and demographic factors (age, sex). Outcome variables will be sarcoidosis outcome (progressor or resolver) and clinical quantitative metrics of lung function to identify cellular predictors of sarcoidosis disease progression and immunological signatures underlying clinical outcome, respectively. The integrative experimental and analytical approach will allow for quantitative comparisons of the magnitude of each contributing factor that can prioritize putative therapeutic targets. These data can ultimately be used to improve clinical decision making regarding appropriate use of therapeutics, identify optimum points of intervention for high-risk patients, and will set the foundation for follow-up studies on the development of targeted therapeutics that maximize treatment efficacy while minimizing detrimental side effects. Insight gained from these studies i...