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Zhao, A.* ; Rojas, J.J.* ; Cao, C.* ; Zhang, Y.* ; Semenova, A. ; Schiller, H. ; Estépar, R.S.J.* ; Bhattacharya, D.* ; Sauler, M.* ; Polverino, F.*

Lung Marginal Zone-like B Cells: A Novel Pathogenic Immune Cell Population in Chronic Obstructive Pulmonary Disease.

Am. J. Respir. Crit. Care Med. 211, A5246 - A5246 (2025)
DOI
Rationale: Inflammation often persists even after smoking cessation, suggesting a self-sustaining pathogenic process similar to autoimmune diseases. However, the specific role of B cells in COPD onset and progression remains underexplored. Methods: We analyzed lung and peripheral blood samples from 61 COPD patients and healthy controls using single-cell transcriptomics to characterize B cell subpopulations and their association with emphysema severity. High emphysema was defined as greater than 5% lobar emphysema and greater than 15% total emphysema. B cell receptor (BCR) sequencing and clonal analysis assessed mutational frequency, clonal expansion, variable gene usage, and CDR3 region diversity. Autoantigen microarrays evaluated autoantibodies in the blood and the lung associated with different clinical characteristics. In contrast, mass spectrometry-based differential antigen capture assays evaluated plasma proteins reactive to lung self-antigens. Analyses were conducted in R, and statistical tests were corrected for multiple-hypothesis testing. Results: Lung B cells were significantly enriched in patients with high emphysema, with quantitative correlations observed between B cell abundance, emphysema severity, and pulmonary function tests (p< 0.05; Figure 1A-D). Within B cell subpopulations, MZ-like cells - defined as highly expressing IGHM and NR4A with enrichment in TNFα-NFκB and STAT3 pathways - were enriched in patients with increased emphysema (p=7.7e-11; Figure 1C-E). Spatial transcriptomics demonstrated these MZ-like cells were increased in lung follicles and airways. Furthermore, immunofluorescence and flow cytometry confirm the presence of this cell type in patients' lung tissue. B cell receptor sequencing analysis indicated a higher mutational frequency in IGHM isotypes (p=2.9e-6) and shorter CDR3 regions (p=0.0089) among patients with severe emphysema. Clonally expanded cells in patients with emphysema were more common in MZ-like cells (p=2.0e-8), with expanded clones shared in both the lungs and blood (Figure 1F-I). Similar CDR3 motifs were also shared across patients with clonally expanded MZ-like cells. Additionally, patients with high emphysema demonstrated recurrent usage of specific variable genes, including IGHV1-69 and IGHV4-34 (Figure 1J). Autoantigen microarrays revealed that patients with elevated lung MZ-like cell counts also had IGHM-predominant autoantibodies in the lungs and blood (p<0.05; Figure 1K-L). Patients' sera were also autoreactive to lung IGHM in patients with increased MZ-like cells. Conclusions: This study identifies a novel immune cell population - MZ-like B cells - enriched in severe emphysema. These cells may drive local and systemic autoantibody production, reminiscent of autoimmune diseases. Targeting MZ-like B cells or modulating IGHM autoantibody production presents a promising therapeutic avenue for addressing B cell-mediated mechanisms in COPD.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Meeting abstract
Korrespondenzautor
ISSN (print) / ISBN 1073-449X
e-ISSN 1535-4970
Zeitschrift American Journal of Respiratory and Critical Care Medicine
Quellenangaben Band: 211, Heft: Abstracts, Seiten: A5246 - A5246 Artikelnummer: , Supplement: ,
Verlag American Thoracic Society
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Lung Health and Immunity (LHI)