Inflammation in Pulmonary Hypertension: How Immunobiology Provides the Missing Link Between These Conditions

Pulmonary Arterial Hypertension: Inflammation, Immunodeficiency, and Autoimmunity

Plexiform lesions in PAH lungs are often accompanied by an inflammatory cellular exudate consisting of macrophages, mast cells, and lymphocytes (Figure 1).2–4 Additionally, the presence of antibody-complement deposits have been described in several conditions associated with PAH.56 The presence of known systemic autoimmunity in PAH-associated conditions suggests that this inflammation could also impact lung circulation. It has been recognized for more than 40 years that there are associations between autoimmune conditions, such as systemic lupus erythematosus, and severe PAH.

View Figure

• Download as Powerpoint
• Download Figure

In addition to this well-recognized association with autoimmune disorders, there is a link between viral infections, immune insufficiency, and PAH (Table 1). For example, patients who are HIV positive and patients with AIDS are at a higher risk for developing PAH. As with HIV infection, most conditions associated with PAH are associated with a defect in the CD4 T cell compartment, meaning that these conditions are characterized by an absolute deficiency of CD4 cells, a decreased CD4/CD8 ratio, and/or a diminished relative percentage of CD4⁺CD25⁺ cells, the putative regulatory T cell (T_reg) subset. Furthermore, PAH has been described following splenectomy.7 Additionally, it was recently reported that a patient with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), which is caused by a mutation leading to the loss of function of the autoimmune regulator (AIRE) protein, died with fatal idiopathic PAH (IPAH).8 The AIRE gene is of central importance in the development of thymus-dependent self-tolerance.

Table 1. Viral and Connective Tissue Diseases Associated With PAH

View Fullscreen

Our group has also recently noted that athymic nude rats, which lack T cells, have significantly worse PAH in response to vascular epithelial growth factor receptor antagonism treatment than do euthymic nude rats that have a normal complement of T cells.9 In this setting of T-cell immunodeficiency, animals develop severe PAH under Denver altitude conditions (ie, chronic severe hypoxia is not required to develop PAH).

It is estimated that 30% to 40% of the patients with IPAH are antinuclear antibody positive, 23% anti-Ku antibody positive, and another 10% to 15% of those patients may express antiphospholipid antibodies.10–12 A unifying hypothesis that addresses these cumulative findings is that in the setting of relative or absolute immunodeficiency, immune dysregulation likely occurs and may lead to the activation of pathogenic autoreactive B cells and T cells.

Immune Dysregulation in PAH: Lymphocytes, Antibodies, and Mast Cells

Whether injury incurred by T cells or B cells in PAH is important in disease development is currently unknown. However, it is well established, as a general immunologic principle, that in the absence of regulation exerted by a population of regulatory T cells over B cells, autoantibodies will arise and autoimmune disease can develop.13 With absent or diminished T_reg activity, other cells (such as mast cells) presumably provide stimulatory signals to relevant self-reactive B cells, rescue them from apoptosis, and stimulate them to form pathogenic antibodies.14 Antibodies directed against the vascular endothelium could certainly promote endothelial apoptosis, and antiendothelial antibodies (AECAs) are present in autoimmune disorders associated with PAH including systemic lupus erythematosus,15 mixed connective tissue disease,16 and scleroderma.17 In lupus and Sjögren syndrome, antibody and complement deposits have been localized in the walls of pulmonary arteries of patients with PAH.56

Scleroderma and the antiphospholipid antibody syndrome (APS) are 2 syndromes that may demonstrate how dysregulated immunity can potentially contribute to the development of PAH. Not only are absolute lymphocyte counts reduced in scleroderma,1819 but patients with scleroderma also have relatively fewer CD4⁺CD25⁺ cells in the peripheral circulation compared to healthy controls.20 Similarly, patients with APS have altered peripheral T cell subsets; most notably in a significantly reduced CD4⁺CD25⁺ population.21 Both conditions are associated with AECAs capable of inducing endothelial cell apoptosis,22–24 which may be the first event implicated in systemic disease development.25 An instigating injury to endothelial cells in scleroderma and APS that can trigger autoantibody formation may be a viral infection that leads to immunomodulatory effects.26–28 In this setting of T_reg activity, a dysregulation of B cells is also observed.29 Plexiform lesions found in the arterial walls of patients with sclerodermal PAH include an inflammatory infiltrate30 consisting of macrophages, T cells, B cells, and mast cells3132; whereas APS can be associated with pulmonary capillaritis.33 In summary, scleroderma and APS are disorders characterized by perivascular inflammation associated with possible viral infection, endothelial damage, diminished peripheral CD4⁺CD25⁺ cells, dysregulated B cells, and AECAs. Figure 2 presents a putative model of this process.

View Figure

• Download as Powerpoint
• Download Figure

Inflammatory Chemokines and Cytokines in PAH

Inflammatory mediators in patients with PAH are readily detected in the circulation. For example, patients with the syndrome plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, M protein and skin changes (POEMS) associated with PAH, exhibit increased levels of TNF-α, soluble TNF-receptor type I, IL-2, soluble IL-2 receptor, IL-6, and interferon-Á.34 Similarly, IPAH patients exhibit markedly elevated IL-1 and IL-6 serum levels.35 FKN/CX3CL1 is a chemokine which is upregulated in CD4+ and CD8⁺ cells in PAH.36 Regulated on Activation, Normal T Expressed and Secreted (RANTES, also known as CCL5) is a key cytokine member of the interleukin-8 superfamily of cytokines that is upregulated in the inflammatory milieu of PAH lungs.37 RANTES is a selective attractant for memory T cells and monocytes that also stimulates endothelin converting enzyme-1 and endothelin-1, a potent vasoconstrictor that may also contribute to increased vascular resistance in PAH.38 Thus, these cytokines and chemokines in PAH patients may act to further target immune cells to lung circulation.

By focusing on the phenomena of inflammation in PAH, and by incorporating what is known from clinical disease and from experimental models, there should be increasing understanding of how the immune system contributes to this lethal disease. It is conceptually possible that appropriately targeted immunotherapies initiated in a timely fashion will have the potential to attenuate or even reverse this frequently relentless condition.