Crosstalk between memory B cells and fibroblasts contributes to COPD pathogenesis

Abstract

Adaptive immune responses, reflected by resident memory B cells and lymphoid follicles have been described in lungs of COPD patients. Furthermore, pulmonary fibroblasts were recently defined as key regulators of local immune responses. Therefore, we postulate a role for a crosstalk between memory B cells and fibroblasts in COPD pathogenesis.

Immunohistochemical co-staining for memory B cells (CD20+CD27+) and stromal cell markers (KiM4 and ER-TR7) was performed on human lung tissue. Next, memory B cells and control naive B cells were sorted from peripheral blood mononuclear cells of 6 never smokers, 6 smokers without airflow limitation and 7 patients with COPD (GOLD stage II-III) by flow cytometry. Memory (and naive B cells) were co-cultured with normal lung fibroblasts with or without cigarette-smoke extract. After 48 hours, both cell types were harvested separately and transcriptomic changes were determined by RNA sequencing.

Histological analyses demonstrated co-localization of memory B and stromal cells in lung parenchyma and lymphoid follicles of patients with COPD. Genes related to enhanced survival and responsiveness to stimuli were differentially expressed in memory compared to naïve B cells. Co-culture with fibroblasts induced genes involved in inflammation and lymphoid follicle formation in the B cell transcriptome, and downregulated genes involved in dampening of oxidative stress. Strikingly, fibroblasts co-cultured with memory B cells from COPD patients demonstrated a significant dysregulation of various genes and pathways involved in inflammation, emphysema, airway remodeling and lung cancer.

These results support a role for memory B cell-fibroblast crosstalk in COPD pathogenesis.