Implications of a vasodilatory human monoclonal autoantibody in postural hypotension

Functional autoantibodies to the autonomic receptors are increasingly recognized in the pathophysiology of cardiovascular diseases. To date, no human activating monoclonal autoantibodies to these receptors have been available. In this study, we describe for the first time a β2-adrenergic receptor (β2AR)-activating monoclonal autoantibody (C5F2) produced from the lymphocytes of a patient with idiopathic postural hypotension. C5F2, an IgG3 isotype, recognizes an epitope in the N terminus of the second extracellular loop (ECL2) of β2AR. Surface plasmon resonance analysis revealed high binding affinity for the β2AR ECL2 peptide. Immunoblotting and immunofluorescence demonstrated specific binding to β2AR in H9c2 cardiomyocytes, CHO cells expressing human β2AR, and rat aorta. C5F2 stimulated cyclic AMP production in β2AR-transfected CHO cells and induced potent dilation of isolated rat cremaster arterioles, both of which were specifically blocked by the β2AR-selective antagonist ICI-118551 and by the β2AR ECL2 peptide. This monoclonal antibody demonstrated sufficient activity to produce postural hypotension in its host. Its availability provides a unique opportunity to identify previously unrecognized causes and new pharmacological management of postural hypotension and other cardiovascular diseases.