Abstract
Several reports have highlighted a potential role of autoreactive B-cells and autoantibodies that correlates with increased disease severity in patients with idiopathic pulmonary fibrosis (IPF). Here we show that patients with IPF have an altered B-cell phenotype and that those subjects who have autoantibodies against the intermediate filament protein periplakin (PPL) have a significantly worse outcome in terms of progression-free survival. Using a mouse model of lung fibrosis, we demonstrate that introducing antibodies targeting the endogenous protein PPL (mimicking naturally occurring autoantibodies seen in patients) directly in the lung increases lung injury, inflammation, collagen and fibronectin expression through direct activation of follicular dendritic cells, which in turn activates and drives proliferation of fibroblasts. This fibrocyte population was also observed in fibrotic foci of patients with IPF and was increased in peripheral blood of IPF patients compared to aged-matched controls. This study reiterates the complex and heterogeneous nature of IPF, identifying new pathways that may prove suitable for therapeutic intervention.
Abstract
Antiperiplakin antibodies accelerate the lung fibrotic process https://bit.ly/3ZnZbE8
Footnotes
Conflict of interest: C. Taillé reports grants from GSK, Sanofi and AstraZeneca, advisory board participation and consulting fees from GSK, Sanofi, AstraZeneca and Novartis, lecture honoraria from GSK, Sanofi, AstraZeneca, Stallergenes and Novartis, and travel support from GSK and AstraZeneca, outside the submitted work. D. Valeyre reports travel support from ERS, ATS and CPLF, and advisory board participation with Roche and Boehringer Ingelheim, outside the submitted work. H. Nunes reports consulting fees, lecture honoraria and travel support from Boehringer Ingelheim and Roche/Genentech, and advisory board participation with Galapagos, outside the submitted work. W.K. Lim reports options and stock as part of employee compensation from Regeneron Pharmaceuticals, outside the submitted work. V. Cottin reports grants from Boehringer Ingelheim, consulting fees from Boehringer Ingelheim and Roche/Promedior, lecture honoraria from Boehringer Ingelheim, Roche/Promedior, Sanofi and AstraZeneca, travel support from Boehringer Ingelheim, Roche/Promedior and AstraZeneca, and advisory board participation with Actelion, Bayer/MSD, Roche/Promedior, Sanofi, Celgene/BMS, Galapagos, Galecto, Shionogi, Fibrogen, RedX and PureTech, outside the submitted work. D. Corkill reports support for the present manuscript from AstraZeneca/MedImmune, as a full-time employee. T. Mustelin reports grants from NIH, and consulting fees from Miro Bio, Kiniksa, Cugene, QiLu and ROME, outside the submitted work. M.A. Sleeman reports support for the present manuscript from MedImmune/AstraZeneca, and during the research was a full-time employee of MedImmune/AstraZeneca. B. Crestani reports support for the present manuscript from MedImmune/AstraZeneca; B. Crestani also reports grants from Boehringer Ingelheim, Roche, BMS and Translate Bio, consulting fees from Apellis, Boehringer Ingelheim, Roche, BMS, Translate Bio, Sanofi and Novartis, lecture honoraria from AstraZeneca, Boehringer Ingelheim, Roche, BMS and Sanofi, travel support from AstraZeneca, BMS, Boehringer Ingelheim, Roche and Novartis, and is the Vice President of the Fondation du Souffle, outside the submitted work. All other authors have nothing to disclose.
This article has an editorial commentary: https://doi.org/10.1183/13993003.00653-2023
Support statement: Part of this study was supported by grants from the Programme Hospitalier de Recherche Clinique AOR 07076 (D. Valeyre) and AOR 10114 (C. Taillé), by the Contrat de Recherche Clinique CRC08 (C. Taillé) and by the Chancellerie des Universités de Paris-Legs Poix. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received September 1, 2021.
- Accepted January 5, 2023.
- Copyright ©The authors 2023. For reproduction rights and permissions contact permissions{at}ersnet.org