Immunological consequences of compromised ocular immune privilege accelerate retinal degeneration in retinitis pigmentosa

Abstract

Background Retinitis pigmentosa (RP) is a hereditary retinal disease which leads to visual impairment. The onset and progression of RP has physiological consequences that affects the ocular environment. Some of the key non-genetic factors which hasten the retinal degeneration in RP include oxidative stress, hypoxia and ocular inflammation. In this study, we investigated the status of the ocular immune privilege during retinal degeneration and the effect of ocular immune changes on the peripheral immune system in RP. We assessed the peripheral blood mononuclear cell stimulation by retinal antigens and their immune response status in RP patients. Subsequently, we examined alterations in ocular immune privilege machineries which may contribute to ocular inflammation and disease progression in rd1 mouse model. Results In RP patients, we observed a suppressed anti-inflammatory response to self-retinal antigens, thereby indicating a deviated response to self-antigens. The ocular milieu in rd1 mouse model indicated a significant decrease in immune suppressive ligands and cytokine TGF-B1, and higher pro-inflammatory ocular protein levels. Further, blood–retinal-barrier breakdown due to decrease in the expression of tight junction proteins was observed. The retinal breach potentiated pro-inflammatory peripheral immune activation against retinal antigens and caused infiltration of the peripheral immune cells into the ocular tissue. Conclusions Our studies with RP patients and rd1 mouse model suggest that immunological consequences in RP is a contributing factor in the progression of retinal degeneration. The ocular inflammation in the RP alters the ocular immune privilege mechanisms and peripheral immune response. These aberrations in turn create an auto-reactive immune environment and accelerate retinal degeneration.

Pigmentation level of human iPSC-derived RPE does not indicate a specific gene expression profile

“…In this study, we showed the degree of pigmentation of in vitro cultured iPSC-RPE cells did not project specific gene ontological clusters, although it correlated to some extent with the expressions of functional genes of the RPE, such as complement- and lysosome-related genes. Eye, as well as brain and testis, is an immune privilege organ, where inflammation by the immune system is minimized ( Zhou and Caspi, 2010 ; Chen et al, 2019 ; Mohan et al, 2022 ). To protect the photoreceptors from pathogens in this immune suppressive environment, RPE has an immune cell-like aspect with the capability of complement activation ( Kunchithapautham et al, 2014 ; Chen et al, 2019 ; Jensen et al, 2020 ; Tan et al, 2020 ; Schäfer et al, 2020 ) and phagocytosis ( Boulton, 2014 ; Lehmann et al, 2014 ).…”

Cellular Immune Responses Induced by Subretinal AAV Gene Transfer can be Restrained by the Subretinal Associated Immune Inhibition Mechanism

“…Be that as it may, this peripheral expression is correlated with the induction of the anti-transgene immune response that we describe. Several questions must be further investigated, especially the impact in a pathophysiological context in which the retina and the blood-retinal barrier is degenerated 46 . A leakage at lower doses might occur and could trigger a pro-inflammatory immune response at doses lower than ones we have tested in wild type mice.…”

Pigmentation level of human iPSC-derived retinal pigment epithelium cell does not indicate a specific gene expression profile

“…In this study, we showed the degree of pigmentation of in vitro cultured iPSC-RPE cells did not project specific gene ontological clusters, although it correlated to some extent with the expressions of complement-and lysosome-related genes. Eye, as well as brain and testis, is an immune privilege organ, where inflammation by the immune system is minimized (Zhou et al 2010;Chen et al 2019;Mohan et al 2022).…”

“…In this study, we showed the degree of pigmentation of in vitro cultured iPSC-RPE cells did not project specific gene ontological clusters, although it correlated to some extent with the expressions of functional genes of the RPE, such as complement- and lysosome-related genes. Eye, as well as brain and testis, is an immune privilege organ, where inflammation by the immune system is minimized (Zhou et al 2010; Chen et al 2019; Mohan et al 2022). To protect the photoreceptors from pathogens at this immune suppressive environment, RPE has an immune cell-like aspect with the capability of complement activation (Kunchithapautham et al, 2014; Chen et al 2019; Jensen et al, 2020; Li et al, 2020; Schäfer et al, 2020) and phagocytosis (Boulton, 2014; Lehmann et al, 2014).…”