IgG4⁺ plasma cell enrichment and {lambda}-chain-biased BCR remodeling drive low-grade autoimmunity in chronic obstructive pulmonary disease

BackgroundThis study aimed to elucidate B cell subset pathology in COPD, a poorly characterized area, with a focus on its similarities to and differences from classical autoimmune disorders. MethodsThe single-cell RNA-sequencing (scRNA-seq) data from COPD and autoimmune diseases were obtained from Gene Expression Omnibus (GEO) for comparative analyses of B cell subsets and functions via differentially expressed genes (DEGs), KEGG, protein-protein interaction (PPI), and cell-cell communication analyses. Serum IgG4 was measured by ELISA and correlated with clinical parameters. The peripheral blood B cells were sorted by flow cytometry for single-cell B cell receptor (BCR) sequencing. A v-Abl/Bcl2 pro-B cell line was stimulated with cigarette smoke extract (CSE) to assess abnormal development in vitro. ResultsIn lung tissue, IgG4+ plasma cells were enriched and expressed BCR activation/inflammatory genes and TNF/NF-{kappa}B/MAPK pathways. Serum IgG4 concentrations correlated negatively with pre-and post-bronchodilator FEV1/FVC. B cell interacted with monocytes, macrophages, fibroblasts and endothelial cells via IL-1{beta}/IL-6, integrin and chemokine signalling, contributing to chronic inflammation and remodelling. In peripheral blood, transitional T1 B cells were increased, accompanied by {lambda}-chain enrichment and increased IGLV1-47 usage, as well as enrichment of autoimmune pathways. In the bone marrow, the numbers of pre-B I cells were increased while those of small pre-B III cells were reduced, with altered expression of BCR development genes. CSE stimulation of the pro-B cell line reduced {lambda}5 expression in a concentration-dependent manner. ConclusionsThe autoimmune abnormalities in COPD appear more restricted, although IgG4 antibody generation may contribute to immune-mediated lung damage.