Regulatory immune cells compromised in PAH

By Eleanor McDermid

Research suggests that regulatory T cells (Treg cells) may play a part in all subtypes of pulmonary arterial hypertension (PAH).

However, Alice Huertas (Hôpital Marie Lannelongue, Paris, France) and study co-authors found different mechanisms underlying Treg cell dysfunction in the different forms of PAH. Treg dysfunction was associated with elevated leptin in patients with idiopathic PAH and PAH related to systemic sclerosis (SSc-PAH), but not in those with heritable PAH.

The 30 study participants with idiopathic PAH and the 14 with SSc-PAH had similar Treg cell numbers to those in seven SSc patients without PAH and 20 healthy controls. However, the PAH patients' Treg cells had significant reductions in phosphorylation of STAT3, indicating reduced Treg activity in these patients.

In a previous study, the team showed that leptin production contributes to vascular remodelling in PAH. In this study, they found that leptin levels were significantly increased in patients with idiopathic PAH and SSc-PAH and that Treg cells from these patients had significantly increased levels of the leptin receptor.

The researchers explored this relationship further in an animal model of PAH. When PAH was induced in rats via chronic hypoxia, the function of their Treg cells significantly decreased. But when rats lacking the leptin receptor were exposed to chronic hypoxia, their Treg cell function remained normal.

The study also included 18 patients with heritable PAH (due to BMPR2 mutations). These patients had marked Treg cell dysfunction; however, their leptin levels were normal, as was the expression of the leptin receptor on their Treg cells.

"[O]ur results indicate that in [idiopathic] PAH and SSc-PAH patients, the leptin axis is crucial in Treg dysfunction whereas in [heritable] PAH, Treg cells are altered independently of the leptin signaling system", the researchers write in CHEST.

They note that Treg cells are involved in regulation of the immune system, including maintaining immune tolerance to self-antigens. They also reportedly limit inflammation and guard against vascular remodelling.

"Taken together, our results support the concept that in the absence of appropriate Treg activity, pulmonary vascular injury may lead to progressive elevations of pulmonary artery pressure and [pulmonary hypertension]", the team concludes.

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