Same Immune Cell Dysfunction, But Not Its Cause, Found in All Types of PAH

Researchers found that key immune cells, called regulatory T lymphocytes (Treg), are dysfunctional in all forms of pulmonary arterial hypertension (PAH), but the nature of the alterations differ among subtypes of the disease. Specifically, Treg dysfunction is leptin-dependent in idiopathic PAH (iPAH) and connective tissue disease-associated PAH, and leptin-independent in heritable PAH.

Their study, “Regulatory T cell dysfunction in idiopathic, heritable and connective tissue-associated pulmonary arterial hypertension,” published in the journal Chest, helps to further understanding of the development and progression of the different forms of the disease.

PAH is a group of conditions with distinct causes, part of the larger “pulmonary hypertension” group of diseases. Immune system dysregulation is a known common factor of all types of PAH, contributing to disease susceptibility and progression. Research has shown that Tregs are dysfunctional in iPAH, a subgroup without a clear cause. Such dysfunction is also known to be leptin-dependent, meaning that the overproduction of the hormone leptin participates in the pathways that lead to the immune cell dysfunction and vascular remodeling. It is not known, however, if these pathological abnormalities are common to other types of PAH or specific to iPAH.

Researchers investigated if Treg dysfunction is also present in heritable (hPAH) and connective tissue disease-associated PAH (CTD-PAH), if the defective leptin-dependent signaling pathway contributes to Treg dysregulation in these PAH types, and if modulation of the leptin pathway could preserve Treg normal function. Moreover, researchers also investigated if restoring Treg activity in an animal model of the disease could reverse or limit pulmonary hypertension caused by chronic hypoxia (lack of oxygen).

The study included 62 patients with PAH (30 iPAH, 18 hPAH, and 14 CTD-PAH), 10 CTD patients without PAH, and 20 healthy controls.

Tregs were found to be dysfunctional in all types of PAH, and also in CTD without PAH. Leptin signaling was confirmed as crucial to Treg dysfunction in iPAH, and also to CTD with or without PAH. Leptin levels, however, had no influence on the Treg dysfunction observed in hPAH, leading researchers to believe that in this type of PAH, Tregs are altered in a leptin- independent manner.

In a rat model that was exposed to chronic hypoxia, researchers also observed that animals without the leptin receptor (ObR) developed less severe pulmonary hypertension and had normal Treg function, whereas rats with functional leptin receptors had clearly dysfunctional Treg cells.

“Taken altogether, our results suggest that Treg dysfunction is common to all forms of PAH and may contribute to the development and/or the progression of the disease,” the researchers concluded in their article.