Identifying Disease-Specific Immune Cell Shifts in Chronic Fibrotic Interstitial Lung Diseases with Single-Cell RNA Sequencing

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Project Summary/Abstract: Identifying Disease-Specific Immune Cell Shifts in Chronic Fibrotic Interstitial Lung Diseases with Single-Cell RNA Sequencing Description: Interstitial lung diseases (ILDs) are a heterogeneous group of lung disorders that cause scarring of the lung parenchyma and affect an estimated 300,000 people in the United States alone. These diseases can be categorized as having “intrinsic,” “extrinsic,” or “auto-immune” etiologies. A particular subset of chronic fibrotic ILDs – idiopathic pulmonary fibrosis (intrinsic), chronic hypersensitivity pneumonitis (extrinsic), and connective tissue-associated ILD (auto-immune) – can present with usual interstitial pneumonia (UIP) patterns on imaging and have similar symptoms and pulmonary function tests. However, their prognoses and treatments are distinct. Among them, idiopathic pulmonary fibrosis is associated with the highest mortality in patients and confers a median survival time after diagnosis of three to five years. Moreover, incorrect diagnosis and administration of immunosuppressive treatments to patients with idiopathic pulmonary fibrosis can significantly worsen their disease. Therefore, it is critical to accurately diagnose these patients in a minimally invasive manner, such as through peripheral blood draws. Obtaining peripheral blood mononuclear cells poses little risk to patients and provides a window into their health; previous work by the application’s sponsor, Dr. Naftali Kaminski, and his group demonstrated that PBMC cell-type composition and gene expression signatures can distinguish idiopathic pulmonary fibrosis disease severity. Leveraging single-cell RNA- sequencing (scRNA-seq) technology, we hope to elucidate the disease-specific immune mechanisms of ILDs with UIP patterns (UIP ILDs) captured in the peripheral blood. In particular, Aim 1 will determine whether disease-specific immune aberrations can be captured by peripheral blood cell-type composition and gene expression signatures in idiopathic pulmonary fibrosis, chronic hypersensitivity pneumonitis, and connective tissue disease-associated ILD. Aim 2 will ascertain whether there are distinct antigens that drive disease in UIP ILD patients and will characterize the adaptive immune landscape in these diseases through B and T cell receptor profiling. The goals of this study are three-fold: 1) to characterize disease-specific peripheral blood biomarkers, 2) to create a clinical decision model that would diagnose a UIP ILD subtype given gene expression, cell composition, T and B cell receptor repertoires, and patient clinical information, and 3) to gain insight into UIP ILD disease mechanisms to advance patient therapeutics. In summary, the proposed research will hopefully inform clinical diagnostics and treatments for patients with similarly presenting UIP ILDs. The fellowship also includes a training plan with valuable learning experiences for the applicant’s development as a physician-scientist.