Genetic and Potential Autoimmune Triggers of Primary Aldosteronism

Functionally active autoantibodies against G-protein– coupled receptors have been discovered in the sera of patients with many different cardiovascular disorders acting in several cases as pathogenic drivers. Some of these involve autoantibodies against AT1R that share a common theme in that they recognize epitopes in the second extracellular loop of the receptor as for the cognate ligand. However, the factor that elicits the production of AT1-AA is unknown. AT1R itself could plausibly be a trigger or, as has been described in some humoral-mediated autoimmune diseases, a defect associated with CD40 with its role in B-cell activation. Moreover, the molecular mechanisms whereby AT1-AA activate AT1R remain to be elucidated, and the signaling pathways elicited and their associated cellular responses still have to be characterized. Nonetheless, AT1-AA have a defined role in preeclampsia and realistic therapeutic strategies aimed at their removal by plasmapheresis or by abolishing AT1-AA function with an epitope-blocking peptide have been proposed. There is a striking link between AT1-AA and renal-allograft rejection with malignant hypertension, and these examples together with other autoimmune mechanisms involving the α1- and β1-adrenergic receptors that are associated with hypertensive disorders raise the fascinating concept of autoimmune mechanisms in hypertension. The role of autoantibodies in PA requires some clarification, but AT1-AA may yet be revealed as a missing piece of a puzzle that is being rapidly solved.