Autoantibody activation of beta-adrenergic and muscarinic receptors contributes to an “autoimmune” orthostatic hypotension

Abstract

Background Orthostatic hypotension (OH) is characterized by an abnormal autonomic response to upright posture. Activating autoantibodies to β1/2-adrenergic (AAβ1/2AR) and M2/3 muscarinic receptors (AAM2/3R) produce vasodilative changes in the vasculature that may contribute to OH. Methods and Results IgG from 6 patients with idiopathic OH harboring autoantibodies and from 10 healthy control subjects were examined for: 1) β1AR and M2R activity with a perfused Purkinje fiber assay and PKA assay in H9c2 cells, and 2) vasodilator β2AR and M3R activity using a pressurized cremaster resistance arteriole assay. Changes of IgG activity with and without propranolol, atropine, and L-NAME were used to estimate AAβAR, AAM2R and AAM3R activation of their respective functions. All 6 patients had elevated ELISA titers to at least one of the receptors compared to controls. βAR-mediated contractility activity and M2R activity were increased in 5 of the 6 patients. IgG from all 6 patients produced a direct vasodilator effect upon cremaster arterioles. βAR and nitric oxide synthase blockade led to near normalization of IgG-induced vasodilation. Conclusion Aβ1/2AR and AAM2/3R are present in some patients with idiopathic OH compatible with an in vivo effect. These autoantibodies and their cardiovascular effects provide new mechanistic insights into the pathophysiology of OH.

Implications of a Vasodilatory Human Monoclonal Autoantibody in Postural Hypotension

“…More importantly, C5F2 perfusion of resistance arterioles produced a potent vasodilatation, which could also be inhibited by the ␤ 2 AR blocker and ␤ 2 AR ECL2 peptide, indicating that antibody activation of vascular ␤ 2 AR may contribute to systemic vasodilatation. The functional activity of C5F2 was consistent with that of serum IgG polyclonal autoantibodies from the patient and of serum anti-␤ 2 AR autoantibodies harbored in a subgroup of postural hypotension patients (21,22). ␤ 2 AR-mediated vasodilatation in resistance arteries involves two different mechanisms: direct vasodilatation via activation of cAMP/PKA-mediated dephosphorylation of the smooth muscle myosin (37) and endothelial nitric oxidemediated vasodilatation (38).…”

“…We recently reported the association of vasodilatory polyclonal autoantibodies to the ␤ 2 -adrenergic receptor (␤ 2 AR) and/or M3 muscarinic receptor in postural hypotension patients (21,22). These autoantibodies possess sufficient bioactivity to alter the postural vascular response, thus contributing to the pathophysiology of postural hypotension, especially the "idiopathic" type, i.e.…”

Agonistic Autoantibodies as Vasodilators in Orthostatic Hypotension

“…4, 13 We have recently reported for the first time the association of agonistic autoantibodies in 6 patients with demonstrable orthostasis. 14 This mechanistic study demonstrated significant vasodilatory activity associated with autoantibodies directed toward the β2-adrenergic receptor (β2AR) and M3 muscarinic receptor (M3R). Although the IgG purified from these patients demonstrated marked vasodilatory activity, the combination of potentially opposing effects from other agonistic autoantibodies and their diverse presentation within the small number of patients made it difficult to develop an impression of the autoantibody frequency and physiological role in patients subject to orthostatic symptomatology.…”

State of the art paper The role of G protein coupled receptor kinases in neurocardiovascular pathophysiology

“…Several features of idiopathic orthostatic hypotension have been attributed to hypoactive or hyperactive states of adrenergic receptors of the sympathetic nervous system. Recent data indicate that autoimmune lesions of the β-AR signaling pathway could be one of the contributing factors to orthostatic intolerance [47,48], but still there are no available data about the contribution of GRK to this syndrome.…”