Importance of Autoimmune Responses in Progression of Retinal Degeneration Initiated by Gene Mutations

Abstract

Inherited retinal diseases (IRDs) are clinically and genetically heterogeneous rare disorders associated with retinal dysfunction and death of retinal photoreceptor cells, leading to blindness. Among the most frequent and severe forms of those retinopathies is retinitis pigmentosa (RP) that affects 1:4,000 individuals worldwide. The genes that have been implicated in RP are associated with the proteins present in photoreceptor cells or retinal pigment epithelium (RPE). Asymmetric presentation or sudden progression in retinal disease suggests that a gene mutation alone might not be responsible for retinal degeneration. Immune responses could directly target the retina or be site effect of immunity as a bystander deterioration. Autoantibodies against retinal autoantigens have been found in RP, which led to a hypothesis that autoimmunity could be responsible for the progression of photoreceptor cell death initiated by a genetic mutation. The other contributory factor to retinal degeneration is inflammation that activates the innate immune mechanisms, such as complement. If autoimmune responses contribute to the progression of retinopathy, this could have an implication on treatment, such as gene replacement therapy. In this review, we provide a perspective on the current role of autoimmunity/immunity in RP pathophysiology.

The double-edged sword of inflammation in inherited retinal degenerations: Clinical and preclinical evidence for mechanistically and prognostically impactful but treatable complications

“…In summary, AAb-associated inflammation in IRDs is not a mere epiphenomenon and, at least in many cases, it is truly impactful yet treatable, in line with the mechanistic framework already proposed by Adamus ( Adamus, 2021 ). Thus, while this double-edged sword can prove to be a significant worsening factor for the prognosis of affected patients, recognizing the presence of inflammation in IRDs and treating it can be truly beneficial.…”

“…When the secondary autoimmune component affects also the retina beyond mere CME, such as retinal vasculitis or disseminated chorioretinitis-like features, like in the CORD case we presented, treatment can be fundamentally prognosis-altering. Based on these observations, autoimmunity in IRDs cannot be considered just an epiphenomenon, but appears to be an event of pathogenic and prognostic relevance, and of substantial therapeutic importance, a conclusion that is in line with the framework already proposed by Adamus ( Adamus, 2021 ).…”

“…IRD patients exhibiting inflammatory complications virtually invariably present also with AR- and/or AON-AAb patterns that correlate quite well with clinical and functional findings, especially at the retinal immunohistochemistry (rIHC) testing level, and respond favorably to the treatment of these complications. This is in line with a pathogenic view of these AAbs also in IRDs ( Adamus, 2021 ). Thus, we sought out to conduct a systematic retrospective review of our patients who presented with signs and symptoms of a possible IRD and also exhibited inflammatory signs and, thus, underwent AAb and rIHC testing between 2016 and 2022.…”

“…Over 3 years have gone by since the time when the role of the immune system in IRDs was being first investigated, and this hypothesis was set aside as the focus of IRD researchers rapidly shifted towards the discovery of new genes and the characterization of genotype-phenotype correlations. More recently, though, there has been a progressive reappraisal of the role of inflammation and activation of the immune system in IRDs ( Iannaccone et al, 1994b ; Iannaccone et al, 1995 ; Epstein et al, 2014 ; Epstein et al, 2015 ; Hollingsworth et al, 2015 ; Iannaccone et al, 2015 ; Hollingsworth et al, 2017 ; Iannaccone et al, 2017 ; Adamus, 2018 ; Hollingsworth et al, 2018 ; McMurtrey and Tso, 2018 ; Iannaccone and Radic, 2019 ; Birch et al, 2020 ; Duncan et al, 2020 ; Hollingsworth and Gross, 2020 ; Liu et al, 2020 ; Yang et al, 2020 ; Adamus, 2021 ; Alekseev et al, 2021 ; Iannaccone et al, 2021 ; Alekseev et al, 2022 ; Funatsu et al, 2022 ; Gupta et al, 2022 ). Several lines of evidence will be reviewed further in the discussion section to provide additional support to immune-mediated inflammation representing a potential treatment target for IRDs ( Adamus et al, 2004 ; Xiong et al, 2013 ; McMurtrey and Tso, 2018 ; Hollingsworth and Gross, 2020 ; Funatsu et al, 2022 ), including work from our group ( Epstein et al, 2014 ; Hollingsworth et al, 2015 ; Gattegna et al, 2019 ; Iannaccone and Radic, 2019 ).…”

The Clinical Spectrum and Disease Course of DRAM2 Retinopathy

“…Retinal dystrophies are believed to have an immunological component, most likely due to the reaction of the immune system to the decaying retinal tissue [45]. The acute onset in Patient 1 effectively mimicked an autoimmune retinopathy and interestingly, the patient reported some improvement on anti-inflammatory treatment.…”