Peripheral Blood T Cells of Patients with IPAH Have a Reduced Cytokine-Producing Capacity

Denise van Uden, Thomas Koudstaal, Jennifer A.C. van Hulst, Madelief Vink, Menno van Nimwegen, Leon M. van den Toorn, Prewesh P. Chandoesing, Annemien E. van den Bosch, Mirjam Kool, Rudi W. Hendriks*, Karin A. Boomars

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Pulmonary arterial hypertension (PAH) is rare disease that is categorized as idiopathic (IPAH) when no underlying cause can be identified. Lungs of most patients with IPAH contain increased numbers of T cells and dendritic cells (DCs), suggesting involvement of the immune system in its pathophysiology. However, our knowledge on circulating immune cells in IPAH is rather limited. We used flow cytometry to characterize peripheral blood DCs and T cells in treatment-naive IPAH patients, compared with connective-tissue disease-PAH (CTD-PAH) patients and healthy controls (HCs). At diagnosis, T-helper (Th) cells of IPAH patients were less capable of producing TNFα, IFNγ, IL-4 and IL-17 compared to HCs. IPAH patients showed a decreased frequency of Th2 cells and significantly enhanced expression of the CTLA4 checkpoint molecule in naive CD4+ T cells and both naive and memory CD8+ T cells. Frequencies and surface marker expression of circulating DCs and monocytes were essentially comparable between IPAH patients and HCs. Principal component analysis (PCA) 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 were increased in IPAH patients and accompanied by increased proportions of Th17 and Tc17 cells, as well as decreased CTLA4 expression. Treatment-naive IPAH patients displayed a unique T-cell phenotype that was different from CTD-PAH patients and was characterized by reduced cytokine-producing capacity. These findings point to involvement of adaptive immune responses in IPAH, which may have an implication for the development of therapeutic interventions.

Original languageEnglish
Article number6508
JournalInternational Journal of Molecular Sciences
Issue number12
Publication statusPublished - 10 Jun 2022

Bibliographical note

Funding Information:
Funding: This research was funded by the Dutch Heart Foundation under grant number 2016T052 (DvU/MK) and partially supported by an unrestricted grant from Ferrer pharmaceuticals, Actelion Pharmaceuticals and the Pulmonary Hypertension Patients Association (TK).

Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.


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