Physicians treating patients with pulmonary vascular diseases must account for a wide spectrum of etiologies and presentations that are associated with the syndrome, including HIV/AIDS, connective tissue diseases, chronic obstructive pulmonary disease, and eosinophilic granuloma, all of which have an inflammatory disease component. In addition, idiopathic pulmonary arterial hypertension (PAH) has long been recognized to overlap with collagen vascular disease–associated PAH (1). Patients with idiopathic PAH can present with autoimmune features including Raynaud’s symptoms, antinuclear antibodies, and anti-fibroblast and anti–endothelial cell antibodies (2–4). It is now more than 20 years since the seminal publication by Marc Humbert and colleagues, which documented significantly elevated levels of IL-1 and IL-6 in the blood of patients with severe PAH (5). More recently both retrospective (6) and prospective (7) analyses have found that high levels of inflammatory mediators were predictive of a worse outcome. Against this backdrop, and in light of more recent reports and reviews (8, 9), the field now stands at the threshold of putting targeted immunotherapy to the test. A National Institutes of Health (NIH) workshop document summarized the priorities in pulmonary vascular research in 2010 (10). Inflammation was acknowledged in the article as an area of emerging interest, with a notation about “the critical contributions of the immune system in terms of immune surveillance of the vascular milieu.” However, relatively little has been done to move the field forward since then, possibly because of the ongoing question about whether inflammation is the cause of the pulmonary vascular disease or is merely the consequence of a biotoxic high-pressure microenvironment. Another consideration possibly limiting enthusiasm in the past was that, although the pathophysiology of PAH may begin with significant inflammation, by the time the condition comes to medical attention it has become refractory to immunotherapy; most diseases, after all, exhibit an inflammatory component. Understandable skepticism has affected this field of research, given the number of patients who fail to respond to broad immunosuppressive approaches, such as corticosteroids.

In this Perspective, we highlight a growing knowledge of immune pathways associated with PAH, which provides further argument about the usefulness of tailored immunotherapy for PAH. Our view can be integrated with other recent reviews in the Journal, which also cite emerging scientific discoveries to urge new therapeutic advancements (11–14). To begin to close the translational gap, which is considerable, it is important to carefully define these pathways more clearly, delineating unique signaling events for different forms of PAH. We already have examples for individualized antiinflammatory treatments. Patients with lupus erythematosus–associated PAH can respond to steroids (15), patients with HIV/AIDS-associated PAH to antiviral