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.
Highlights
Pseudoexfoliation syndrome (PEXS) is an age-related disorder affecting the extracellular matrix of the whole body (Elhawy et al, 2012; Scharfenberg and Schlotzer-Schrehardt, 2012)
PEX material consists of fibrillar aggregates containing elastic fiber components such as elastin, fibrillin-1, fibulin, microfibrilassociated glycoprotein-1 (MAGP-1), latent transforming growth factor β (LTBP)1/2, and cross-linking enzymes such as lysyl oxidase-like 1 (LOXL1) (Schlotzer-Schrehardt et al, 2000; Krumbiegel et al, 2009; Lee et al, 2009; Zenkel and SchlotzerSchrehardt, 2014; Founti et al, 2015), which can accumulate in the trabecular meshwork, the main outflow pathway of the eye, and may reduce the outflow of aqueous humor and increased intraocular pressure (IOP) (Johnson and Brubaker, 1982)
We analyzed the sera of patients with PEXS and PEX glaucoma (PEXG) and controls for the presence of agonistic and inhibitory AAbs directed against the β2-adrenergic receptor (AR)
Summary
Pseudoexfoliation syndrome (PEXS) is an age-related disorder affecting the extracellular matrix of the whole body (Elhawy et al, 2012; Scharfenberg and Schlotzer-Schrehardt, 2012). Clinical data of patients with POAG, showing a reduced IOP after removal of all circulating IgG antibodies by immunoadsorption, support this hypothesis (Junemann et al, 2018) These findings indicated a potential role for autoimmune processes in the dysregulation of IOP. Various types of agAAbs, directed against the β2-AR, were described in literature (Wallukat and Wollenberger, 1991; Wallukat, 2002; Junemann et al, 2018): agonistic and inhibitory AAbs activate and block the β2-AR, respectively It was the aim of this study to analyze serum samples from patients with PEXS and PEXG for agAAbs against β2-AR
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