Date of Award
Fall 2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Genetics
First Advisor
Kaminski, Naftali
Abstract
Fibrotic lung diseases constitute a heterogeneous group of disorders that cause scarring of the lung parenchyma, making breathing difficult for patients, and affect an estimated 300,000 people in the United States alone. These diseases may have either “intrinsic” or “extrinsic” immune etiologies. A subset of these fibrotic lung diseases, like Idiopathic Pulmonary Fibrosis (IPF; intrinsic) and Fibrotic Hypersensitivity Pneumonitis (FHP; extrinsic), can often be difficult to distinguish due to their similar symptoms, pulmonary function tests, and radiographic and histologic findings. However, their immune drivers, prognoses, and treatments are distinct; thus, accurate diagnosis of the fibrotic lung disease subtype is essential for patient care. Patients’ immune cell signatures can guide accurate diagnoses. To elucidate shared and distinct immune signatures in fibrotic lung diseases, we applied single-cell RNA-sequencing to peripheral blood and bronchoalveolar lavage samples collected from patients with IPF and FHP and healthy controls. The goals of this dissertation are three-fold: 1) to characterize the shared immune signatures in both FHP and IPF, 2) to establish disease-specific immune signatures that reflect “extrinsic” or “intrinsic” immune drivers, and 3) to gain an understanding of potential antigens that may be contributing to disease. Overall, we found both etiology-specific and shared peripheral immune signatures in IPF and FHP. Transcriptional changes in monocytes and macrophages were shared between IPF and FHP compared to controls, whereas T lymphocytes of FHP patients exhibited disease-specific gene expression profiles. Moreover, aberrant cell-to-cell signaling was observed in both FHP and IPF compared to healthy controls and each other. Finally, T cell and B cell receptor repertoires suggested that the adaptive immune drivers in FHP are distinct compared to IPF and controls. Therefore, this dissertation research uncovered immune cell aberrations that may drive fibrotic lung disease, and this work can hopefully advance diagnoses and therapeutics for patients with these debilitating diseases.
Recommended Citation
Zhao, Amy, "Peripheral Immune Signatures of Fibrotic Lung Diseases" (2023). Yale Graduate School of Arts and Sciences Dissertations. 1216.
https://elischolar.library.yale.edu/gsas_dissertations/1216
