Abstract
The pathogenesis of glaucoma is strongly associated with the occurrence of autoimmune-mediated loss of retinal ganglion cells (RGCs) and additionally, recent evidence shows that specific antibody-derived signature peptides are significantly differentially expressed in sera of primary-open angle glaucoma patients (POAG) compared to healthy controls. Synthetically antibody-derived peptides can modulate various effector functions of the immune system and act as antimicrobial or antiviral molecules. In an ex vivo adolescent glaucoma model, this study, for the first time, demonstrates that polyclonal-derived complementarity-determining regions (CDRs) can significantly increase the survival rate of RGCs (p = 0.013). We subsequently performed affinity capture experiments that verified the mitochondrial serine protease HTRA2 (gene name: HTRA2) as a high-affinity retinal epitope target of CDR1 sequence motif ASGYTFTNYGLSWVR. Quantitative proteomic analysis of the CDR-treated retinal explants revealed increased expression of various anti-apoptotic and anti-oxidative proteins (e.g., VDAC2 and TXN) compared to untreated controls (p < 0.05) as well as decreased expression levels of cellular stress response markers (e.g., HSPE1 and HSP90AA1). Mitochondrial dysfunction, the protein ubiquitination pathway and oxidative phosphorylation were annotated as the most significantly affected signaling pathways and possibly can be traced back to the CDR-induced inhibition or modulation of the master regulator HTRA2. These findings emphasize the great potential of synthetic polyclonal-derived CDR peptides as therapeutic agents in future glaucoma therapy and provide an excellent basis for affinity-based biomarker discovery purposes.
Highlights
Glaucoma is a neurodegenerative ocular disease characterized by the progressive loss of retinal ganglion cells (RGCs) and their axons, resulting in optic nerve damage and visual field defects [1]
Besides the great potential of these immune-related biomarker candidates for diagnostic applications [14], we have provided important evidence for the neuroprotective effects of various AAB molecules on RGCs in in vivo and ex vivo glaucoma models [15,16,17,18,19]
Liquid-chromatography mass spectrometry (LC-MS) represents a powerful instrument for reproducible identification and quantification of peptides from the variable domain of highly diverse antibodies without any prior knowledge about the targeted antigens [21,22,23,24]. By implementation of this MS-based analytical approach we identified several polyclonal IgG V domain peptides, complementarity-determining regions (CDR), which were significantly differentially expressed in the protein backbone of sera-derived IgG from primary open-angle glaucoma (POAG) patients in comparison to healthy controls [25]
Summary
Glaucoma is a neurodegenerative ocular disease characterized by the progressive loss of retinal ganglion cells (RGCs) and their axons, resulting in optic nerve damage and visual field defects [1]. Besides the great potential of these immune-related biomarker candidates for diagnostic applications [14], we have provided important evidence for the neuroprotective effects of various AAB molecules (e.g., against GFAP, 14-3-3, α-and γ-synuclein) on RGCs in in vivo and ex vivo glaucoma models [15,16,17,18,19] These findings underline the important therapeutic potential of AABs found in low abundant titers in glaucoma patients and could serve as an additional treatment option in glaucoma therapy in combination with IOP-lowering medications. Often, therapeutic macromolecules, including antibodies, have several disadvantages, such as immunogenic properties, poor tissue penetration and high manufacturing costs, limiting their application spectrum in daily clinical routine [20]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
