title: Immune response after intermittent minimally invasive intraocular pressure elevations in an experimental animal model of glaucoma.
abstract: BACKGROUND
  Elevated intraocular pressure (IOP), as well as fluctuations in IOP, is a main risk factor for glaucoma, but its pathogenic effect has not yet been clarified. Beyond the multifactorial pathology of the disease, autoimmune mechanisms seem to be linked to retinal ganglion cell (RGC) death. This study aimed to identify if intermittent IOP elevations in vivo (i) elicit neurodegeneration, (ii) provokes an immune response and (iii) whether progression of RGC loss can be attenuated by the B lymphocyte inhibitor Belimumab.
  
  
  METHODS
  Using an intermittent ocular hypertension model (iOHT), Long Evans rats (n = 21) underwent 27 unilateral simulations of a fluctuating pressure profile. Nine of these animals received Belimumab, and additional seven rats served as normotensive controls. Axonal density was analyzed in PPD-stained optic nerve cross-sections. Retinal cross-sections were immunostained against Brn3a, Iba1, and IgG autoantibody depositions. Serum IgG concentration and IgG reactivities were determined using ELISA and protein microarrays. Data was analyzed using ANOVA and Tukey HSD test (unequal N) or student's independent t test by groups.
  
  
  RESULTS
  A wavelike IOP profile led to a significant neurodegeneration of optic nerve axons (-10.6 %, p < 0.001) and RGC (-19.5 %, p = 0.02) in iOHT eyes compared with fellow eyes. Belimumab-treated animals only showed slightly higher axonal survival and reduced serum IgG concentration (-29 %) after iOHT. Neuroinflammatory events, indicated by significantly upregulated microglia activation and IgG autoantibody depositions, were shown in all injured retinas. Significantly elevated serum autoantibody immunoreactivities against glutathione-S-transferase, spectrin, and transferrin were observed after iOHT and were negatively correlated to the axon density.
  
  
  CONCLUSIONS
  Intermittent IOP elevations are sufficient to provoke neurodegeneration in the optic nerve and the retina and elicit changes of IgG autoantibody reactivities. Although the inhibition of B lymphocyte activation failed to ameliorate axonal survival, the correlation between damage and changes in the autoantibody reactivity suggests that autoantibody profiling could be useful as a biomarker for glaucoma.
authors.affiliation: Experimental Ophthalmology, Department of Ophthalmology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany.|Glaucoma Cell Biology Laboratory, Department of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, IA, 62242, USA.
authors.forename: Oliver W
authors.initials: OW
authors.lastname: Gramlich
authors.affiliation: Experimental Ophthalmology, Department of Ophthalmology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Teister
authors.affiliation: Experimental Ophthalmology, Department of Ophthalmology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany.
authors.forename: Mareike
authors.initials: M
authors.lastname: Neumann
authors.affiliation: Experimental Ophthalmology, Department of Ophthalmology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany.
authors.forename: Xue
authors.initials: X
authors.lastname: Tao
authors.affiliation: Experimental Ophthalmology, Department of Ophthalmology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Beck
authors.affiliation: Department of Neuropathology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, Mainz, 55131, Germany.
authors.forename: Harald D
authors.initials: HD
authors.lastname: von Pein
authors.affiliation: Experimental Ophthalmology, Department of Ophthalmology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Pfeiffer
authors.affiliation: Experimental Ophthalmology, Department of Ophthalmology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany. grus@eye-research.org.
authors.forename: Franz H
authors.initials: FH
authors.lastname: Grus
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D004195:Disease Models, Animal; D005901:Glaucoma / Q000276:immunology* / Q000473:pathology; D007150:Immunohistochemistry; D007429:Intraocular Pressure; D008297:Male; D009410:Nerve Degeneration / Q000276:immunology* / Q000473:pathology; D009798:Ocular Hypertension / Q000150:complications / Q000276:immunology* / Q000473:pathology; D020318:Rats, Long-Evans; D012165:Retinal Ganglion Cells / Q000473:pathology; D012307:Risk Factors
chemical_list: D001323:Autoantibodies
keywords: Autoantibodies; B lymphocyte inhibitor; Belimumab; Glaucoma; Humoral immune system; Neuronal degeneration; Ocular hypertension; Pressure fluctuations; Retinal ganglion cells