Inhibitory and Agonistic Autoantibodies Directed Against the β2-Adrenergic Receptor in Pseudoexfoliation Syndrome and Glaucoma

Abstract

Pseudoexfoliation syndrome (PEXS) and glaucoma (PEXG) are assumed to be caused by a generalized elastosis leading to the accumulation of PEX material in ocular as well as in extraocular tissues. The exact pathophysiology of PEXS is still elusive. PEXG, the most common type of secondary open-angle glaucoma (OAG), is characterized by large peaks of intraocular pressure (IOP) with a progressive loss of the visual field. Agonistic autoantibodies (agAAbs) against the β2-adrenergic receptor (AR) have been shown to be present in sera of patients with primary and secondary OAG and ocular hypertension and are seemingly linked to IOP. In the present study, we investigated the autoantibodies directed against the β2-AR in sera of patients with PEXS and PEXG. We recruited 15, 10, and 15 patients with PEXG, PEXS, and primary OAG, respectively. Ten healthy individuals served as controls. All patients underwent standard ophthalmological examination with Octopus G1 perimetry. agAAbs prepared from serum samples were analyzed in a rat cardiomyocyte–based bioassay for the presence of agAAbs. We identified the interacting loop of the β2-AR and the immunoglobulin G (IgG) subclasses using synthetic peptides corresponding to the extracellular loops of the receptors and enzyme-linked immunosorbent assay, respectively. None of the controls were β2-agAAb–positive (0.2 ± 0.5 U). No β2-agAAbs (0.2 ± 0.4 U), but inhibitory β2-AAbs were observed in 80% of the patients that partially blocked the drug-induced β2-adrenergic stimulation; 5.8 ± 1.7 U vs. 11.1 ± 0.9 U for clenbuterol in the absence and the presence of sera from patients with PEXS, respectively. Epitope analyses identified the third extracellular loop of the β2-AR as the target of the inhibitory β2-AAbs, being of IgG3 subtype in PEXS patients. In contrast, patients with PEXG showed β2-agAAbs (5.6 ± 0.9 U), but no inhibitory ones. The β2-agAAbs levels of patients with PEXG and primary OAG patients (3.9 ± 2.8 U; p > 0.05) were at a similar level. In two cases of PEXG, the β2-agAAbs exert synergistic effects with clenbuterol. The activity increased from 11.5 ± 0.3 (clenbuterol only) to 16.3 ± 0.9 U. As autoimmune mechanisms were reportedly involved in the pathogenesis of glaucoma, agonistic and inhibitory β2-AAbs seem to be a part of this multifactorial interplay.

Progress on Brain and Ocular Lymphatic System

“…Ocular Lymphatic System and Diseases. Glaucoma is the first irreversible and blinding eye disease in the world and its pathogenesis is unclear [57]. Recent studies suggest that the glymphatic system may be involved.…”

Small Nucleolar RNAs in Pseudoexfoliation Glaucoma

“…PEXG is the most common type of secondary glaucoma [ 10 ]. As with the other types of glaucoma, elevated intraocular pressure (IOP) is a major cause of retinal ganglion cell (RGC) apoptosis [ 11 ].…”

“…The ECM has the greatest share in the production of resistance to AH outflow, and the disturbance of its homeostasis leads to an increase in IOP [ 12 ]. In PEXG, IOP often reaches high maximum values, and the large coexisting fluctuations in IOP also accelerate the progression of optic nerve degeneration [ 10 , 13 ]. However, as indicated in the long-term observations of patients, PEX material in the eyes does not always lead to increased IOP and glaucoma, or glaucoma occurs despite normal IOP [ 14 , 15 ].…”