Single-cell transcriptomic analysis reveals distinct plasma cell populations in chronic thromboembolic pulmonary hypertension.

Background: Chronic thromboembolic pulmonary hypertension (CTEPH) presents challenges due to its complex pathobiology. Although numerous studies have reported heterogeneous cell types by single-cell RNA sequencing, the atlas and characteristics of plasma cells remain poorly understood.

Objectives: To identify the altered phenotype and differentiation patterns of plasma cells in CTEPH.

Methods: We performed single-cell RNA sequencing on pulmonary endarterectomy tissue from 5 patients and 6 normal pulmonary arteries. Serum immunoglobulins (Igs) were measured using protein electrophoresis among 273 CTEPH patients, 259 idiopathic pulmonary arterial hypertension (IPAH) patients, and 251 healthy controls.

Results: The percentage of plasma cells was significantly increased from less than 1% in healthy controls to 15% in CTEPH patients. We identified 1 B cell cluster and 5 distinct mature plasma cell clusters, including IGHG1, HSPA1A, AHNAK, IGLC3, and IGKV4. Notably, the AHNAK and IGLC3 subclusters are newly identified. GeneSwitches analysis indicated early activation of IGHG1 and early deactivation of HLA-DPA1. The trajectory of AHNAK cluster was earlier than that of IGLC3 cluster, with an enrichment for pathways responsive to lipopolysaccharide. The IGLC3 cluster revealed lower differentiation potential and was predominantly associated with Ig production. Furthermore, Igα2 levels in CTEPH patients were lower than in controls but higher than in IPAH patients. Significantly, Igγ levels were markedly elevated in CTEPH patients compared with IPAH patients and controls, better distinguishing CTEPH patients from controls and IPAH patients.

Conclusion: Plasma cells of CTEPH had a distinctive landscape and heterogeneity. The newly identified clusters represented excessive Ig production but lacked immune response function. These findings highlight that targeted plasma cells can be used to develop novel CTEPH treatments.