Immune Reaction Gone Awry Causes Pulmonary Arterial Hypertension

by Adrienne Mueller, PhD
October 7, 2022

Pulmonary arterial hypertension (PAH) is a serious and ultimately fatal disorder. It occurs when the arteries that transport blood from the heart through the lungs become occluded. Ultimately, the strain this puts on the right sided pumping chamber of the heart causes it to fail. Current therapies act by trying to reduce the contractile state  of the pulmonary arteries; but this approach does not treat the cause of the disease.

Recent studies have identified a relationship between PAH and a protein called elastase – an enzyme that degrades elastin. Elastin makes tissue, in this case blood vessel walls, elastic and also controls the ability of smooth muscle cells to divide and expand. In PAH therefore, the heightened elastase activity in vessel walls degrades elastin, and the walls become stiffer and the smooth muscle cell mass expands and occludes the lumen . We also know that across several different subtypes of PAH, the increased release of elastase is originating specifically from immune cells called neutrophils. Why is there an excess of elastase? That is the question a team of investigators led by Marlene Rabinovitch, MD recently sought to answer by collaborating on a study that examined the specific differences between the activity of neutrophils of PAH patients and healthy individuals. Their study, co-first-authored by Shalina Taylor, PhD, and Sarasa Isobe, MD, PhD, was recently published in the American Journal of Respiratory and Critical Care Medicine.

Patients with PAH neutrophils have a higher expression of a retrovirus protein (HERV-K envelope protein) than healthy controls.

The investigators identified differences in activity between PAH and control neutrophils: the PAH patient neutrophils had more elastase, reduced migration, and stronger adhesion. Intriguingly, these changes resemble an antiviral response. In exploring this connection, the investigators found elevated levels of a human endogenous retrovirus in PAH patient  neutrophils compared to healthy controls. This finding suggests that elevated levels of a retrovirus are causing an elastase-based immune response in neutrophils. This aberrant immune response could therefore be the source of the problematic excess elastase found in PAH patients. Consistent with this possibility, when the investigators transfected a neutrophil cell line with a retrovirus, they saw the same effects – an increase in elastase.

This novel antiviral response in PAH neutrophils suggests that a healthy immune response to a virus has gone awry and is now causing PAH in these patients. The results of this study not only help explain the mechanism underlying PAH, but also point to potential new therapies to treat PAH that target either elastase itself or the underlying increased presence of retroviral elements.

Additional Stanford Cardiovascular Institute-affiliated authors who contributed to this study include Aiqin Cao, Kévin Contrepois, Lihua Jiang, Lingli Wang, Stavros Melemenidis, Mehmet O. Ozen, Shoichiro Otsuki, Tsutomu Shinohara, Andrew J. Sweatt, Jordan Kaplan, Jan-Renier Moonen, David P. Marciano, Mingxia Gu, Kazuya Miyagawa, Brandon Hayes, Raymond G. Sierra, Christopher J. Kupitz, Patricia A. Del Rosario, Andrew Hsi, A. A. Roger Thompson, Utkan Demirci, Roham T. Zamanian, Francois Haddad, Mark R. Nicolls, and Michael P. Snyder.

Shalina Taylor, PhD

Sarasa Isobe, MD, PhD

Marlene Rabinovitch, MD