HSP27 immunization reinforces AII amacrine cell and synapse damage induced by S100 in an autoimmune glaucoma model

Reinehr, Sabrina; Kuehn, Sandra; Casola, Christina; Koch, David; Stute, Gesa; Grotegut, Pia; Dick, H. Burkhard; Joachim, Stephanie C.

doi:10.1007/s00441-017-2710-0

Cited by 36 publications

(35 citation statements)

References 54 publications

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“…Similar observations were recently made by our group, when S100B was injected intravitreally [34]. Also, after systemic immunization of HSP27 in combination with S100B, a degeneration of amacrine cells was noted [46]. Moreover, in glaucoma animal models, like the DBA/2J mouse model or high pressure models, a reduction of amacrine cells was also described [47,48].…”

Section: Further Degeneration and Slightly Changed Retinal Electrophysupporting

confidence: 73%

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Destructive Effect of Intravitreal Heat Shock Protein 27 Application on Retinal Ganglion Cells and Neurofilament

Grotegut¹,

Kuehn²,

Dick³

et al. 2020

IJMS

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Heat shock protein 27 (HSP27) is commonly involved in cellular stress. Increased levels of HSP27 as well as autoantibodies against this protein were previously detected in glaucoma patients. Moreover, systemic immunization with HSP27 induced glaucoma-like damage in rodents. Now, for the first time, the direct effects of an intravitreal HSP27 application were investigated. For this reason, HSP27 or phosphate buffered saline (PBS, controls) was applied intravitreally in rats (n = 12/group). The intraocular pressure (IOP) as well as the electroretinogram recordings were comparable in HSP27 and control eyes 21 days after the injection. However, significantly fewer retinal ganglion cells (RGCs) and amacrine cells were observed in the HSP27 group via immunohistochemistry and western blot analysis. The number of bipolar cells, on the other hand, was similar in both groups. Interestingly, a stronger neurofilament degeneration was observed in HSP27 optic nerves, while no differences were noted regarding the myelination state. In summary, intravitreal HSP27 injection led to an IOP-independent glaucoma-like damage. A degeneration of RGCs as well as their axons and amacrine cells was noted. This suggests that high levels of extracellular HSP27 could have a direct damaging effect on RGCs.

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Section: Further Degeneration and Slightly Changed Retinal Electrophysupporting

confidence: 73%

“…Furthermore, the immunization of HSP27 together with S100B did not impair PKCα + bipolar cells. Only recoverin + cone bipolar cells were affected [46]. In a glaucoma model with elevated IOP, significantly fewer rod bipolar cells were noted [51].…”

Section: Further Degeneration and Slightly Changed Retinal Electrophymentioning

confidence: 95%

Destructive Effect of Intravitreal Heat Shock Protein 27 Application on Retinal Ganglion Cells and Neurofilament

Grotegut¹,

Kuehn²,

Dick³

et al. 2020

IJMS

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“…The images were transferred to Corel Paint Shop Pro (V13, Corel Corporation) and equal excerpts were cut out. 19 Afterwards, Brn-3a + , PKCα + and opsin + cells were counted using ImageJ software. Regarding GFAP, glutamine synthetase, vimentin, rhodopsin and recoverin, area analyses were performed using an ImageJ macro.…”

Section: Histological Examinationmentioning

confidence: 99%

“…Regarding GFAP, glutamine synthetase, vimentin, rhodopsin and recoverin, area analyses were performed using an ImageJ macro. 19,20 Briefly, images were transformed into grayscale. To minimize interference with background labeling, a defined rolling ball radius was subtracted ( Table 2).…”

Section: Histological Examinationmentioning

confidence: 99%

Loss of retinal ganglion cells in a new genetic mouse model for primary open‐angle glaucoma

Reinehr

Koch

Weiß

et al. 2019

J Cellular Molecular Medi

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Primary open‐angle glaucoma (POAG) is one of the most common causes for blindness worldwide. Although an elevated intraocular pressure (IOP) is the main risk factor, the exact pathology remained indistinguishable. Therefore, it is necessary to have appropriate models to investigate these mechanisms. Here, we analysed a transgenic glaucoma mouse model (βB1‐CTGF) to elucidate new possible mechanisms of the disease. Therefore, IOP was measured in βB1‐CTGF and wildtype mice at 5, 10 and 15 weeks of age. At 5 and 10 weeks, the IOP in both groups were comparable ( P > 0.05). After 15 weeks, a significant elevated IOP was measured in βB1‐CTGF mice ( P < 0.001). At 15 weeks, electroretinogram measurements were performed and both the a‐ and b‐wave amplitudes were significantly decreased in βB1‐CTGF retinae (both P < 0.01). Significantly fewer Brn‐3a + retinal ganglion cells (RGCs) were observed in the βB1‐CTGF group on flatmounts ( P = 0.02), cross‐sections ( P < 0.001) and also via quantitative real‐time PCR ( P = 0.02). Additionally, significantly more cleaved caspase 3 + RGCs were seen in the βB1‐CTGF group ( P = 0.002). Furthermore, a decrease in recoverin + cells was observable in the βB1‐CTGF animals ( P = 0.004). Accordingly, a significant down‐regulation of Recoverin mRNA levels were noted ( P < 0.001). Gfap expression, on the other hand, was higher in βB1‐CTGF retinae ( P = 0.023). Additionally, more glutamine synthetase signal was noted ( P = 0.04). Although no alterations were observed regarding photoreceptors via immunohistology, a significant decrease of Rhodopsin ( P = 0.003) and Opsin mRNA ( P = 0.03) was noted. We therefore assume that the βB1‐CTGF mouse could serve as an excellent model for better understanding the pathomechanisms in POAG.

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“…For example, the prevalence of single-nucleotide polymorphisms in the genes coding for complement factor H, complement factor I, as well as many other components of the innate immune system bolster the chances of developing AMD in otherwise normal patients [27,28]. In addition, models of glaucoma have shown the presence of macrophages and T-lymphocytes in the eye along with autoantibodies to proteins of the retina [3,4,29,30]. Models of RP have also shown similar features, including monocytic phagocytosis of both diseased and healthy retinal cells as well as numerous cytokines such as interleukin-1, interleuken-6, vascular endothelial growth factor, and others [4,31,32].…”

Section: Discussionmentioning

confidence: 99%

Innate and Autoimmunity in the Pathogenesis of Inherited Retinal Dystrophy

Hollingsworth

Gross

2020

Cells

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Inherited retinal dystrophies (RDs) are heterogenous in many aspects including genes involved, age of onset, rate of progression, and treatments. While RDs are caused by a plethora of different mutations, all result in the same outcome of blindness. While treatments, both gene therapy-based and drug-based, have been developed to slow or halt disease progression and prevent further blindness, only a small handful of the forms of RDs have treatments available, which are primarily for recessively inherited forms. Using immunohistochemical methods coupled with electroretinography, optical coherence tomography, and fluorescein angiography, we show that in rhodopsin mutant mice, the involvement of both the innate and the autoimmune systems could be a strong contributing factor in disease progression and pathogenesis. Herein, we show that monocytic phagocytosis and inflammatory cytokine release along with protein citrullination, a major player in forms of autoimmunity, work to enhance the progression of RD associated with a rhodopsin mutation.

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HSP27 immunization reinforces AII amacrine cell and synapse damage induced by S100 in an autoimmune glaucoma model

Cited by 36 publications

References 54 publications

Destructive Effect of Intravitreal Heat Shock Protein 27 Application on Retinal Ganglion Cells and Neurofilament

Destructive Effect of Intravitreal Heat Shock Protein 27 Application on Retinal Ganglion Cells and Neurofilament

Loss of retinal ganglion cells in a new genetic mouse model for primary open‐angle glaucoma

Innate and Autoimmunity in the Pathogenesis of Inherited Retinal Dystrophy

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