Spatial Transcriptomics Resolve an Emphysema-Specific Lymphoid Follicle B Cell Signature in Chronic Obstructive Pulmonary Disease

• Published in: American journal of respiratory and critical care medicine Vol. 209; no. 1; pp. 48 - 58
• Main Authors: Rojas-Quintero, Joselyn, Ochsner, Scott A., New, Felicia, Divakar, Prajan, Yang, Chen Xi, Wu, Tianshi David, Robinson, Jerid, Chandrashekar, Darshan Shimoga, Banovich, Nicholas E., Rosas, Ivan O., Sauler, Maor, Kheradmand, Farrah, Gaggar, Amit, Margaroli, Camilla, San Jose Estepar, Raul, McKenna, Neil J., Polverino, Francesca
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 01.01.2024
• Subjects: Chronic obstructive pulmonary disease; Emphysema; Gene expression; Gene Expression Profiling; Humans; Inflammation; Lung diseases; Lymphadenopathy; Proteomics; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema - diagnostic imaging; Pulmonary Emphysema - genetics; switch-class recombination; centrilobular emphysema; lymphoid follicles; autoimmunity; metabolic reprogramming
• ISSN: 1073-449X; 1535-4970; 1535-4970
• DOI: 10.1164/rccm.202303-0507LE

Within chronic obstructive pulmonary disease (COPD), emphysema is characterized by a significant yet partially understood B cell immune component. To characterize the transcriptomic signatures from lymphoid follicles (LFs) in ever-smokers without COPD and patients with COPD with varying degrees of emphysema. Lung sections from 40 patients with COPD and ever-smokers were used for LF proteomic and transcriptomic spatial profiling. Formalin- and O.C.T.-fixed lung samples obtained from biopsies or lung explants were assessed for LF presence. Emphysema measurements were obtained from clinical chest computed tomographic scans. High-confidence transcriptional target intersection analyses were conducted to resolve emphysema-induced transcriptional networks. Overall, 115 LFs from ever-smokers and Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1-2 and GOLD 3-4 patients were analyzed. No LFs were found in never-smokers. Differential gene expression analysis revealed significantly increased expression of LF assembly and B cell marker genes in subjects with severe emphysema. High-confidence transcriptional analysis revealed activation of an abnormal B cell activity signature in LFs ( -value = 2.56E-111). LFs from patients with GOLD 1-2 COPD with emphysema showed significantly increased expression of genes associated with antigen presentation, inflammation, and B cell activation and proliferation. LFs from patients with GOLD 1-2 COPD without emphysema showed an antiinflammatory profile. The extent of centrilobular emphysema was significantly associated with genes involved in B cell maturation and antibody production. Protein-RNA network analysis showed that LFs in emphysema have a unique signature skewed toward chronic B cell activation. An off-targeted B cell activation within LFs is associated with autoimmune-mediated emphysema pathogenesis.