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

Joselyn Rojas-Quintero, Scott A. Ochsner, Felicia New, Prajan Divakar, Chen Xi Yang, Tianshi David Wu, Jerid Robinson, Darshan Shimoga Chandrashekar, Nicholas E. Banovich, Ivan O. Rosas, Maor Sauler, Farrah Kheradmand, Amit Gaggar, Camilla Margaroli, Raul San Jose Estepar, Neil J. McKenna, Francesca Polverino

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Rationale: Within chronic obstructive pulmonary disease (COPD), emphysema is characterized by a significant yet partially understood B cell immune component. Objectives: To characterize the transcriptomic signatures from lymphoid follicles (LFs) in ever-smokers without COPD and patients with COPD with varying degrees of emphysema. Methods: 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. Measurements and Main Results: 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 (q-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. Conclusions: An off-targeted B cell activation within LFs is associated with autoimmune-mediated emphysema pathogenesis.

Original languageEnglish (US)
Pages (from-to)48-58
Number of pages11
JournalAmerican journal of respiratory and critical care medicine
Volume209
Issue number1
DOIs
StatePublished - Jan 1 2024
Externally publishedYes

Keywords

  • autoimmunity
  • centrilobular emphysema
  • lymphoid follicles
  • metabolic reprogramming
  • switch-class recombination

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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