Abstract 6163: Potential Pathogenetic Involvement of Agonistic Autoantibodies Against Alpha-1 Adrenergic and Endothelin-1 Receptors in Pulmonary Arterial Hypertension
Background Pulmonary arterial α1-adrenergic receptors (α1-AR) show particularly high sensitivity for noradrenaline (NA) and NA plasma levels and are elevated in patients with pulmonary arterial hypertension (PAH). Experimental data suggest that vasodilative and antiproliferative effects of calcium-channel blockers, prostacyclin and adenosin are mainly based on their ability to antagonize intracellular signals caused by α1-AR stimulation. In PAH patients production of endothelin-1 is increased and their elevated plasma levels correlate with PAH severity. After repeated detection of agonistic antibodies against the endothelin-1 A receptor (ETA) and the α1-AR in PAH patients’ sera we assessed their properties and prevalence.
Methods Using spontaneously beating rat neonatal cardiomyocytes as bioassay we analyzed sera of PAH patients for the presence of functional autoantibodies (AABs) aganst G-protein coupled receptors. AABs were purified by affinity chromatography.
Results Of 54 tested PAH patients, 51 (94%) tested positive for AABs against α1-AR and/or ETA and only 3 (6%) showed no evidence of these AABs. Among the 51 positive patients, 38 (75%) showed AABs against both α1-AR and ETA and 13 (25%) had AABs only against α1-ARs. AABs against α1-ARs exerted agonistic dose-dependent positive chronotropic effects which were blocked by the α1-AR blocker prazosine. AABs against ETA exerted agonistic negative chronotropic effects, which were blocked by the ETA antagonist BQ610. Both AAB types induced permanent stimulation without desensitization of the receptor mediated signal cascade. Our first attempts to eliminate by immunoadsorption these AABs against α1-AR and ETA (which appeared to belong to the IgG3 and IgG2 subclass, respectively) in PAH patients showed encouraging short-term results.
Conclusions The vast majority of PAH patients tested positive for functional serum AABs against ETA and α1-AR. These AABs activate the receptors, like the corresponding agonists, but prevent the desensitization of the receptor-mediated signal cascade normally seen with ongoing receptor stimulation. Our results suggest that these AABs are involved in PAH pathogenesis. AAB removal by immunoadsorption might be a possible new therapeutic approach.