Defining the Prototype of Immune Cell Driven Fibrotic Tissue Organization in Restrictive Allograft Syndrome and Pleuroparenchymal Fibroelastosis

<bold>Background:</bold> Restrictive allograft syndrome (RAS) and pleuroparenchymal fibroelastosis (PPFE) are progressive fibrotic lung diseases characterized by alveolar fibroelastosis (AFE). Despite poor prognosis, effective treatments remain unavailable, and their pathophysiologies are elusive. <bold>Aim:</bold> To uncover common cellularly resolved transcriptomic and histologic features of human RAS and PPFE lungs to identify novel therapeutic targets. <bold>Methods:</bold> Peripheral lung tissues from 15 RAS, 32 PPFE, and 16 control lungs were analyzed using snRNA-seq. Results were validated and extended using e.g., immunofluorescence and RNA in situ hybridization. <bold>Results:</bold> Our data revealed a shared fibrotic niche in RAS and PPFE at the edge of AFE remodeling. Key findings are: (A) aberrant basaloid cells, overlaying AFE lesions; (B) expansion of <italic>CTHRC1+</italic> fibrotic fibroblasts within AFE areas; (C) partial replacement of the physiologic <italic>PRX+</italic> alveolar endothelium by ectopic <italic>COL15A1+</italic> endothelial cells; and (D) elevated T- and B-cell fractions in PPFE, suggesting immune-mediated repair failure. <bold>Conclusions:</bold> RAS and PPFE depict cellular hallmarks of fibrotic tissue organization first described in IPF. Remarkably, our data suggests an underlying immune-mediated process in contrast to the pathogenesis of IPF. These shared cell types, essential to fibrogenesis, might be prime therapeutic targets. <fig><object-id>erjor;11/suppl_15/TP215/F1</object-id><object-id>F1</object-id><object-id>F1</object-id><graphic></graphic></fig>