Innate and Autoimmunity in the Pathogenesis of Inherited Retinal Dystrophy.

T J Hollingsworth,Alecia K Gross

doi:10.3390/cells9030630

T J Hollingsworth, Alecia K Gross

Open Access

https://doi.org/10.3390/cells9030630

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Abstract

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.

Highlights

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]
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
Compared to +/+ mice (n = 5), the Ter349Glu/Ter349Glu mice (n = 5) showed an increase in the threshold of the dark-adapted b-wave by three orders of magnitude, with a maximum amplitude about 25% that of +/+ mice, while the maximum a-wave amplitude was only about 6% that of +/+ mice. This indicated a drastic loss of rod photoreceptor function

Summary

Introduction

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]. 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 segment 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]. Brought to light is the role of autoimmunity in RDs including

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