Agonistic Autoantibodies to the β2-Adrenergic Receptor Involved in the Pathogenesis of Open-Angle Glaucoma

Abstract

Glaucoma is a frequent ocular disease that may lead to blindness. Primary open-angle glaucoma (POAG) and ocular hypertension (OHT) are common diseases with increased intraocular pressure (IOP), which are mainly responsible for these disorders. Their pathogenesis is widely unknown. We screened the sera of patients with POAG and OHT for the prevalence of autoantibodies (AAb) against G protein-coupled receptors (GPCRs) in comparison to controls. Employing frequency modulation of spontaneously contracting neonatal rat cardiomyocytes in vitro, agonistic GPCR AAb were to be detected in roughly 75% of the patients with POAG and OHT, however, not in controls. Using inhibitory peptides the AAb’ target was identified as β2 adrenergic receptor (β2AR). The AAb interact with the second extracellular loop of β2AR. The peptides 181–187 and 186–192 were identified as binding sites of the AAb within the extracellular loop II. The binding of the AAb to β2ARs was verified by surface-plasmon-resonance analysis. The isotype of the AAb was (immunoglobulin) IgG3. In an additional pilot principal-of-proof study, including four patients with POAG, the removal of the AAb against the β2AR and other immunoglobulins G by immunoadsorption resulted in a transient reduction of IOP. These findings might indicate a possible role of agonistic AAb directed against β2ARs in the dynamics of aqueous humor and might support a contribution of adaptive autoimmunity in the etiopathogenesis of POAG and OHT.

Autoantibodies Activating the β2-Adrenergic Receptor Characterize Patients With Primary and Secondary Glaucoma

“…As shown in a previous study, pathophysiology of glaucoma is multifactorial and includes immunological components (1). Agonistic β2-agAAb were to be observed in sera of patients with OHT and POAG.…”

“…The β2-agAAb, observed in patients with POAG or OHT, were directed against the second extracellular loop of β2AR (peptides 181–187 and 186–192); the major subclass was IgG3. In a principal-of-proof study IOP decreased transiently after unspecific removal by immunoadsorption of IgG, including the potentially pathogenic β2-agAAb (1). These observations lead us to postulate the hypothesis of an involvement of agonistic β2-agAAb in the pathogenesis of glaucoma.…”

“…Recently, agonistic autoantibodies (agAAb) activating the β2-adrenergic receptor were detected in primary open-angle glaucoma (POAG) or ocular hypertension (OHT) patients and were linked to intraocular pressure (IOP) (1). The aim of the present study was to quantify β2-agAAb in the sera of glaucoma suspects and patients with primary and secondary glaucoma.…”

Neuroimmunological Aspects in Glaucoma

“…Spezifische Autoantikörper gegen den adrenergen β2-Rezeptor ließen sich im Serum von Patienten mit okulärer Hypertension (OHT), primärem (pOWG) und sekundärem Offenwinkelglaukom (sOWG) zu einem hohen Prozentsatz nachweisen [26,27]. Diese Autoantikörper gegen den β2-adrenergen Rezeptor (β2-AAb) führen zu einer Aktivierung desselbigen, dieim Unterschied zu Timololzu einer langanhaltenden Überstimulation des Rezeptors führt.…”

“…Daten aus einer klinischen Pilotstudie stützen diese Hypothese. Eine Immunapherese konnte die agonistischen β2-AAb "auswaschen" und zeigte zudem begleitend, dass sich hierbei auch der IOD bei den Patienten reduzierte [26]. Über die β2-AAb ist zudem eine Verbindung des erhöhten IODs und der vaskulären Dysregulation denkbar.…”