Introduction: Pulmonary arterial hypertension (PAH) is rare disease that is categorized as idiopathic (IPAH) when no underlying cause can be identified. The finding that the lungs of most patients with IPAH contain increased numbers of T cells and dendritic cells (DCs) suggests the involvement of the immune system in its pathophysiology. To date, a detailed characterization of circulating immune cells in IPAH is lacking.
Methods: We used flow cytometry to characterize peripheral blood DCs and T cells in treatment-naïve IPAH patients, compared with connective tissue disease–PAH (CTD-PAH) patients and healthy controls (HCs).
Results: At diagnosis, T-helper (Th) cells of IPAH patients were less capable of producing tumor necrosis factor-α, interferon-g, interleukin (IL)-4 and IL-17 compared with HCs. The T-cell compartment of IPAH patients showed an increase of Th2 cells and enhanced expression of the CTLA4 checkpoint molecule in both naïve and memory CD4+ and CD8+ T cells. Expression of the PD-1 checkpoint molecule or the activation marker ICOS was normal. In contrast, CTD-PAH patients showed increased expression of both CTLA4 and ICOS. Frequencies and surface marker expression of circulating DCs and monocyte subsets were essentially comparable between IPAH patients and HCs. Principal components analysis separated IPAH patients, but not CTD-PAH patients, from HCs, based on T-cell cytokine profiles. At 1-year follow-up, the frequencies of IL-17+ production by memory CD4+ T cells was increased in IPAH patients and was accompanied by an increase in the proportions of Th17 and Tc17 cells, as well as decreased CTLA4 expression. Principal components analysis separated IPAH patients, but not CTD-PAH patients, at diagnosis from patients at 1-year follow-up.
Conclusion: Treatment-naïve IPAH patients displayed a unique T-cell phenotype that was different from CTD-PAH patients and was characterized by a reduced cytokine-producing capacity. These findings point to involvement of adaptive immune responses in IPAH, which might have implications for development of therapeutic interventions.
Thomas Koudstaal*, Denise van Uden*, Jennifer A. C. van Hulst, Madelief Vink, Menno van Nimwegen, Leon M. van den Toorn, Prewesh P. Chandoesing, Department of Pulmonary Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands Annemien E. van den Bosch, Department of Cardiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands Mirjam Kool, Rudi W. Hendriks*, Karin A. Boomars*, Department of Pulmonary Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands