Autoimmunity and PAH
The self-tolerance is controlled in the periphery by a particular population of T-lymphocytes called regulatory T-lymphocytes (Treg). The breakdown of self-tolerance can lead to the development of an autoimmune response (i.e. directed against self antigens) that can finally give rise to an autoimmune disease. Huertas et al. [151] showed that circulating Treg number was comparable in idiopathic PAH and SSc-PAH patients. However the percentage of those expressing leptin receptors was higher in idiopathic PAH and SSc-PAH as compared to controls, and their function was reduced in idiopathic PAH and SSc-PAH patients as compared to controls in a leptin-dependent manner [151]. Work on chronic inflammatory disorders and autoimmune diseases suggest that pathogenic antibodies and T cells may be generated locally, in the targeted organ, in highly organized ectopic lymphoid follicles commonly called tertiary lymphoid tissues. Recently, Perros et al. [152] described the presence of highly organized perivascular follicles in idiopathic PAH lungs arguing for specific immune-adaptive mechanisms in the pathophysiology of the disease. One can propose that deregulated and unresolved pulmonary inflammation on the background of a genetic predisposition, could result in persisting vascular remodelling leading to PAH. An initial acute inflammation that is normally expected to resolve with return to homeostasis, could conduct the production of auto-antibodies against vascular wall components, and would shift to chronic persisting and chronic inflammation, endothelial barrier breakdown, infiltration by immune cells, local and chronic autoimmunity, and vascular remodeling culminating in PAH.