Oxidation-Specific Epitope IgA in Pulmonary Fibrosis

The pathophysiology of idiopathic pulmonary fibrosis (IPF) remains poorly understood, and elucidation of the molecular mechanisms of IPF pathogenesis is key to the development of new therapeutics. There is evidence of adaptive immune dysfunction in IPF, as evidenced by aggregates of T and B lymphocytes within IPF lungs and the development of autoantibodies, particularly IgA. The specific epitopes however are largely unknown. Therefore, evaluating links between B cells, IgA, and fibrosis in IPF may provide insight into disease pathogenesis and novel therapeutic opportunities. Oxidation-specific epitopes (OSEs) are found on oxidized lipids and apoptotic cells. OSEs are generated during lung injury and promote fibrosis. Antibodies to OSEs, primarily IgM as well as IgG, have been shown to play a role in a variety of inflammatory disease processes. However, nothing is known about the antibody response to OSEs in humans with IPF or the role it may play in disease pathogenesis, and these are the subject of this proposal. In supporting preliminary data for this proposal, we identify novel circulating IgA against OSE (IgAOSE) which are significantly elevated in patients with IPF and positively correlate with disease severity. Using high-dimensional immunophenotyping by mass cytometry (CyTOF) we identify a novel B cell subset which correlates with IgAOSE levels. Interestingly, this subset resembles double negative 2 (DN2) B cells and bears markers indicative of lung homing (CXCR3) and autoreactivity (IL21r). We also show that the key fibrosis-related cytokine TGFb promotes IgAOSE secretion, providing a mechanistic link to IPF disease pathogenesis. Additionally, we show that the same IgAOSE is present in mice and increased in the lung during injury. Our overall hypothesis is that lung injury drives local secretion of IgAOSE through TGFb and that this propagates fibrosis through a positive feedback cycle. We will test this hypothesis through three specific aims. In Aim 1, using multiple independent cohorts: the Prospective tReatment EffiCacy in IPF uSIng genOtype for Nac Selection (PRECISIONS) clinical trial (NCT04300920), the UVA ILD Natural History Cohort, and two external validation cohorts (University of Chicago, University of Michigan), we will test the hypothesis that elevated circulating IgAOSE mark a unique molecular endotype in IPF. In Aim 2 we will test the hypothesis that IgA+ DN2 B cells are spatially related to fibrosis and TGFb in human lungs using our novel Quantitative Remodeling Scorer (QRS) to resolve fibroproliferative injury at cellular scales. We will also perform BCR repertoire sequencing of sorted lung B cells. In Aim 3, using gain- and loss-of-function murine models, we will test mechanistically the connections between lung TGFb, IgAOSE, and fibrosis. The mechanistic insights from these studies will provide a novel area for potential rapid development of first-in-class therapeutics for IPF and potentially other fibrotic lung diseases, including new monoclonal antibodies or an anti-fibrosis vaccine. Project Number: 1R01HL179312-01 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Jeffrey Sturek | Institution: UNIVERSITY OF VIRGINIA, CHARLOTTESVILLE, VA | Award Amount: $806,901 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 RCCS-B (81)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HL17931201