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Abstract
Fibrotic interstitial lung disease (ILD) is a group of heterogeneous conditions characterizedby progressive respiratory decline and early death. Current understanding of the disease
mechanisms depends on etiological and morphological classification of ILD subtypes. A
prevailing paradigm is that immune cells play a pathogenic role in immune-associated
ILDs, whereas their role in idiopathic pulmonary fibrosis (IPF) is controversial. However,
patients with fibrotic ILDs commonly have enlarged lung-draining lymph nodes (LLN),
which correlate with mortality. Our study revealed converging adaptive immune landscapes
in LLNs of end-stage fibrotic ILD patients, characterized by the enrichment of germinal
centers (GC), antigen-stimulated T cells, and regulatory T cells with an aberrant
phenotype. The presence of GC B cells in LLNs was associated with worse respiratory
decline in patients. A proteome-wide screening identified 17 novel auto-antigens to which
circulating antibodies in ILD patients are reactive. Autoantibody responses to ABLIM1, a
protein highly expressed in fibrotic lungs, correlated with frequencies of follicular helper T
cells and regulatory T cells in patients’ LLNs. These findings suggest that antigen-driven
immune responses could be a key immunopathology that is common to end-stage fibrotic
ILDs, even in IPF. Furthermore, we demonstrated that subtle differences in the gut
microbiome compositions have a large impact in lung injury response of mice in specific
pathogen-free barrier facilities. Presence of Proteobacteria, including Helilcobacter
hepaticus and Desulfovibrio sp., in the gut was associated with increased weight loss and
mortality during lung injury responses in mice. These data support the gut-lung axis and
highlight the potential benefit of specific alterations to the gut microbiome compositions to
control lung injury outcomes. Together, my dissertation developed a comprehensive
understanding of the human immune responses and the effect of the host-microbiota
interaction during lung injury and fibrosis. This work will inform the development of
models for mechanistic studies and patient endotypes for effective therapeutic intervention.