Role of Natural Antibodies and B1 cells in Fibroproliferative Lung Disease - PROJECT SUMMARY Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease (ILD) of progressive scarring and no cure. Current pharmacologic interventions in IPF target canonical myofibroblast signaling, but at best slow disease progression, and median survival post diagnosis is 3-5 years. Dysregulated immunity of myeloid and lymphoid populations is party to the progression of fibrotic disease. Lung B cell frequency increases in human ILDs, and in both sterile and infectious animal models of fibroproliferative lung injury. The appearance of B cells in the alveolar spaces, a phenomena absent in healthy tissue, is characterized by both single lymphocytes and in larger, organized accumulations of lymphocytes termed tertiary lymphoid organs (TLOs). Our preliminary data show natural B cell immunity is protective in lung injury. Natural immunity is mediated B-1 cells, a type of T-cell independent B cell which produces natural antibodies (nAb). These nAb are largely IgM, and are protective in inflammatory and fibrotic pathologies. B-1 cells primarily reside in the serosal cavities, including millions of B-1 cells in close contact with the lung in the pleural cavity. We believe these pleural B-1 cells are a reservoir of nAb producing cells which are highly responsive to changes in soluble factor signaling from the lung. In supporting data for this proposal, we have found that increases in a B-1 secreted species of nAb against oxidized lipid is protective against bleomycin-induced lung injury in mice. The increase in lung B-1 cells and nAb after lung injury occurs concomitant with changes in chemokine receptor (CR) expression in the pleural B- 1 cell compartment. Our central hypothesis is that pleural B-1 cells traffic to the lung in a CR-dependent manner and protect from fibroproliferative injury via production of nAb. Our overarching goal is to understand the pleural B-1 cell response to lung injury, and elucidate the mechanisms by which nAb is protective in disease. To this end, we propose to test following aims: First, test the hypothesis that pleural B-1 cells traffic to the lung during lung injury in a CR-dependent manner. Second, test the hypothesis that secretion of nAb by B-1 cells is protective in fibrotic lung injury. These experiments will make use of extant transgenic mouse lines and established mechanistic approaches both in vivo and in vitro to dissect the B cell-Fibrosis axis in lung injury. It is novel in that it will answer mechanistic questions relating natural immunity in fibrosis, and identify new and potentially targetable signaling pathways in fibroproliferative disease – vital for the development of better treatments. The environment in which I will perform the proposed work could not be better suited; the University of Virginia is a world-class research university and we have assembled a world- class team to support this endeavor through intentional planning for both science and personal/professional development.
