Peripheral B cell dysregulation associated with post-COVID-19 pulmonary fibrosis characterized by multi-cohort single-cell transcriptomics

Hang, Wei, Wu, Shenggen, Lin, Hao, Wu, Yisong, Zhong, Wen, Fang, Jiabin, Wu, Junting, He, Yingqiu, Xiao, Yan, Ren, Lili, Xu, Nengluan, Lin, Rong, Zhou, You ORCID: https://orcid.org/0000-0002-1743-1291, Li, Hong and Li, Hongru 2026. Peripheral B cell dysregulation associated with post-COVID-19 pulmonary fibrosis characterized by multi-cohort single-cell transcriptomics. Journal of Translational Medicine 10.1186/s12967-026-08885-6

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Abstract

Background Post-COVID-19 pulmonary fibrosis represents a significant long-term complication affecting 10–30% of survivors, yet peripheral immune signatures predicting fibrotic progression remain poorly characterized. This study aimed to identify peripheral immune signatures of post-COVID-19 pulmonary fibrosis and determine their potential for risk stratification. Methods We integrated single-cell RNA sequencing data from 115 samples across multiple cohorts, including public acute-phase COVID-19 datasets stratified by estimated fibrosis risk (high fibrosis risk [n = 50]; low fibrosis risk [n = 52]) and an in-house Fujian cohort comprising 13 patients sampled at the two-week post-discharge timepoint (7 with CT-confirmed pulmonary fibrosis and 6 without). We performed comprehensive immune profiling, differential gene expression analysis, pathway enrichment, and survival analyses to identify candidate immune features associated with high fibrosis risk post-COVID states. Results Peripheral immune profiling revealed marked B cell dysregulation in severity-stratified public cohorts associated with higher fibrosis risk, characterized by depletion of naive B cells and expansion of activated B cells, plasmablasts, and plasma cells. These dysregulated B cell subsets exhibited distinct pathway signatures: plasma cells showed enrichment in TGF-β signaling, collagen metabolism, and extracellular matrix (ECM) remodeling pathways, while plasmablasts demonstrated enrichment in inflammasome-related, TNF signaling, and angiogenesis pathways. Elevated proportions of plasmablasts and FCRL5+ (Fc receptor-like 5) exhausted B cells, together with reduced proportions of naive B cells and memory B cells, were each associated with increased mortality (p < 0.05). Clinically, the high fibrosis risk grouping was associated with worse short-term survival (p < 0.001). Conclusions Peripheral B cell dysregulation, characterized by altered subset distribution and enrichment of fibrosis-related pathways, may represent candidate peripheral immune features associated with high fibrosis risk post-COVID states and adverse outcomes. These findings highlight candidate biological processes for further study and may inform future peripheral immune profiling strategies to identify COVID-19 survivors at elevated fibrosis risk.

Item Type:	Article
Date Type:	Publication
Status:	In Press
Schools:	Schools > Medicine
Publisher:	BioMed Central
ISSN:	1479-5876
Date of First Compliant Deposit:	14 September 2026
Date of Acceptance:	21 August 2026
Last Modified:	14 Sep 2026 15:30
URI:	https://orca.cardiff.ac.uk/id/eprint/189572

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