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Inhibitory and agonistic autoantibodies directed against the ß(2)-adrenergic receptor in pseudoexfoliation syndrome and glaucoma

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Title:Inhibitory and agonistic autoantibodies directed against the ß(2)-adrenergic receptor in pseudoexfoliation syndrome and glaucoma
Creators Name:Hohberger, B. and Schlötzer-Schrehard, U. and Mardin, C. and Lämmer, R. and Munoz, L. and Kunze, R. and Herrmann, M. and Wallukat, G.
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 ß(2)-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 ß(2)-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 ß(2)-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 ß(2)-agAAb–positive (0.2 ± 0.5 U). No ß(2)-agAAbs (0.2 ± 0.4 U), but inhibitory ß(2)-AAbs were observed in 80% of the patients that partially blocked the drug-induced ß(2)-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 ß(2)-AR as the target of the inhibitory ß(2)-AAbs, being of IgG3 subtype in PEXS patients. In contrast, patients with PEXG showed ß(2)-agAAbs (5.6 ± 0.9 U), but no inhibitory ones. The ß(2)-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 ß(2)-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 ß(2)-AAbs seem to be a part of this multifactorial interplay.
Keywords:Autoantibodies, Glaucoma, Imbalanced Autonomic Theory, Pseudoexfoliation, ß(2)-Adrenergic Receptor
Source:Frontiers in Neuroscience
Publisher:Frontiers Media SA
Page Range:676579
Date:6 August 2021
Official Publication:https://doi.org/10.3389/fnins.2021.676579
PubMed:View item in PubMed

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