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>

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Published
2025-03-20
DOI
https://doi.org/10.1183/23120541.lsc-2025.tp215
Primary Topic
Systemic Sclerosis and Related Diseases
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article
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article

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

Nataliia Artysh, Jonas C. Schupp, Christoph Wrede, Jens Gottlieb et al.
Systemic Sclerosis and Related Diseases
article

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

Nataliia Artysh, Jonas C. Schupp, Christoph Wrede, Jens Gottlieb, Vincent de Montpréville, Jan C. Kamp, Lavinia Neubert, Jens Michael Hohlfeld, Antje Prasse, Jean‐François Bernaudin, A. Justet, Christine S. Falk, Ben Seeliger, Edith Plucinski, Aurélie Cazes, Mark Greer, Tobias Welte, Lars Knudsen, Danny Jonigk, Jan Hegermann, Pierre Mordant, Hervé Mal, Naftali Kaminski, Jannik Ruwisch, B. Crestani, Linus Langer, Lena Maureen Leiber, Hande Yilmaz, Leonard Christian, Raphael Brorie
article en

Abstract

<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>

Université Claude Bernard Lyon 1 (FR), Inserm (FR), Université Sorbonne Nouvelle (FR), University Hospital of Basel (CH), Yale University (US), Medizinische Hochschule Hannover (DE), Sorbonne Université (FR), Centre d'Économie de la Sorbonne (FR), Assistance Publique – Hôpitaux de Paris (FR), Hôpital Marie Lannelongue (FR), Hôpital Bichat-Claude-Bernard (FR), Physiopathologie et Epidémiologie des Maladies Respiratoires (FR), Université Paris 1 Panthéon-Sorbonne (FR), RWTH Aachen University (DE)
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Systemic Sclerosis and Related Diseases
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