**1. Introduction**

Inherited retinal dystrophies (RDs) are the result of mutations in genes associated with cells of the outer retina, primarily rod and cone photoreceptors and retinal pigment epithelium (RPE) [1]. RDs are often highly heterogenous in every aspect of the disease, from the age of onset to the rate of progression, to the very mechanisms underlying the pathogenesis [2]. In order to study the molecular mechanisms of pathogenesis underlying retinal disease, numerous animal models, mostly in mouse, have been generated, carrying genetic defects in several genes causing the disease. A major cause of RDs, specifically, autosomal dominant retinitis pigmentosa (RP), is the presence of dominantly inherited mutations in the gene for the rod photoreceptor protein rhodopsin [2]. While most rhodopsin mutations cause protein misfolding and subsequent apoptosis, the more severe mutations result in improper rhodopsin trafficking and can lead to a subsequent loss of outer segmen<sup>t</sup> formation [2]. These mutations result in improper localization of both normal and mutant rhodopsin to the cellular membrane of the inner segment, nuclear, and axonal regions of the rod photoreceptor cells [1]. Two rhodopsin mutations resulting in the earliest onset of retinal degeneration, rhodopsin Ter349Glu and Gln344Ter, behave in this manner [2]. In recent years, many studies have shown the involvement of the immune system in the pathogenesis of many retinal diseases including glaucoma, age-related macular degeneration (AMD), RP, and others [3,4]. Also brought to light is the role of autoimmunity in RDs including AMD and RP [3,5–8]. While the eye is immune-privileged, the homeostatic disruptions caused by the progression of RDs can allow for a loss of this immune-privileged status, mainly due to the breakdown

of the blood retinal barrier and choroidal neovascularization. In this study, we show the involvement of pro-inflammatory pathways in the progression of rhodopsin-mediated RD using the Ter349Glu rhodopsin knock-in mouse model of the disease, including monocytic phagocytosis and activation of the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway. We also show the presence of known autoimmunity proteins and protein modifications in the rhodopsin Ter349Glu mutant mouse.
