Review: More Research Needed on Immune System to Understand PAH Pathobiology

While research has examined the implications of the immune system and its contributions to pulmonary arterial hypertension, further research is required to understand the pathobiology of the condition.

While the relationship between the immune system, autoimmunity, and pulmonary arterial hypertension (PAH) has been studied for years, the pathobiology of PAH requires further investigation, according to a review published in Pulmonary Pharmacology & Therapeutics.

PAH causes narrowing of the lumen of small and medium pulmonary arteries and the development of occlusive cellular lesions in precapillary pulmonary arterioles, resulting in irreversible pulmonary arterial remodeling. The condition leads to increased infiltration of immune cells like monocytes, macrophages, mast cells, dendritic cells (DCs), CD4+ and CD8+ T cells and B cells.

Among the group of conditions that make up PAH, idiopathic PAH (IPAH) refers to PAH that is associated with no identifiable causes. Associated PAH (APAH) is associated with human immunodeficiency virus, congenital heart disease, exposure to toxins and drugs, rheumatoid arthritis, telangiectasia, Raynaud phenomenon, systemic sclerosis, systemic lupus erythematosus (SLE) and schistosomiasis. Heritable/familial PAH (HPAH) encompasses PAH brought on by mutations in the associated genes and includes patients with a family history of the conditions.

Regardless of cause and type of PAH, patients with exhibit significant inflammation with immune cell infiltration in their lungs. Raised levels of inflammatory markers, predominantly interleukin (IL)-6, IL-8, IL-10 and IL-12p70, found in the sera of patients with PAH are predictors of disease severity and patient survival.

Pulmonary vascular inflammation has also been observed in patients with SLE-associated PAH (PAH-SLE). Immunosuppressive therapy has yielded positive results for patients with PAH-SLE who experience inflammation, indicative of the inflammation and autoimmunity in these patients.

Recent preclinical studies investigating the significance of adaptive immunity in patients with PAH have found that natural killer cell numbers and their levels of function were reduced concomitant with a reduced expression of killer cell immunoglobin (Ig)-like receptors. Blood plasmablast numbers were found to rise in patients with IPAH over time, producing antibodies of the IgA isotype.

Infiltrating immune cells such as cytotoxic and helper T cells, B lymphocytes, neutrophiles, monocytes and macrophages, natural killer cells, DCs, and mast cells were observed in the lesions of pulmonary vessels of patients with PAH. Macrophage infiltration plays a key role in the pathogenesis of PAH by initiating inflammation, damaging endothelial cells, and secreting factors which induce arteriole muscularization, such as vascular endothelial growth factor and platelet-derived growth factor.

The presence of autoantibodies for pulmonary endothelial cells and fibroblasts highlights the role of B cells in patients with PAH. Elevated levels of plasmablasts and rates of production of IgA antibodies in patients with IPAH give rise to anti-endothelial cell IgA autoantibodies, indicating a role of autoimmunity and autoimmune damage in the pathogenesis of IPAH.

Effective treatment methods are critical for patients with PAH, as the condition can lead to heart failure and death in 2 to 3 years if not treated promptly. Current therapeutic approaches include cytokine treatments and the use of immunomodulating drugs.

Future methods of treatment for patients with PAH may involve pharmacogenomic approaches, which would assist in the identification of individuals who may benefit from therapy. One possible direction of therapeutic interest involves clinical trials on the combination pharmacotherapy of investigational targeted agents with traditional drugs.

Further research regarding the pathology of PAH, the pathogenesis, and the relationship between the 2, as well as implications on other conditions, is needed to develop targeted therapeutics, appropriate diagnostics, and prevention methods, the authors concluded.


Han Z, Li X, Cui X, Yuan H, and Wang H. The roles of immune system and autoimmunity in pulmonary arterial hypertension: a review. Pulm Pharmacol Ther. Published online November 2, 2021. doi:10.1016/j.pupt.2021.102094