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Rebecca Epstein, David New, TJ Hollingsworth, Isabelle Meunier, Nataliya Lenchik, Qingxian Lu, Ivan Gerling, Christian P Hamel, Marko Radic, Alessandro Iannaccone; Defective mer-tyrosine kinase (mer-TK) function is associated with anti-arrestin and anti-interphotoreceptor retinoid-binding protein (IRBP) autoantibodies (AAbs) in (TAM) mice and in autosomal recessive retinitis pigmentosa (arRP) patients with a null mutation. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):169. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
To test the hypothesis that both TAM mice, a model for MERTK-linked RP, and arRP patients with MERTK mutations develop the same AAbs that are found in RCS rats, a longtime established model for MERTK-linked RP in which RPE phagocytosis of outer segments is compromised and that exhibit anti-arrestin and anti-IRBP AAbs (Kyger et al. J Neuroimmunol 2013; 254:91-100).
Serum samples were collected from advanced disease, 4-mo old TAM mice (n=5) and from 3patients with arRP (9, 21 and 29 yo), all siblings homozygous for the stop codon mutation R775X with variable disease severity, previously reported by Ksantini et al. (Eur J Ophthalmol 2012). Serum immunoprecipitation (IP) was performed using 10 μl of serum plus 150 μg of RPE/choroid/retina protein lysate, followed by Western blots with anti-IRBP and anti-Arr antibodies. Retinal optical coherence tomography (OCT) and histology was also performed on select TAM mice before sacrifice. Eyes were fixed in 4% PFA for histology and immunohistochemistry (IHC).
TAM mice showed strong anti-Arr and IRBP autoreactivity at a stage when retinal thickness is markedly reduced and retinal lamination is partially altered. AAbs recognizing Arr (1.6 to 5.1-fold higher than control) and IRBP (3.2 to 6.8-fold higher) were found also in all arRP patients with the R775X mutation. The 9yo, the least affected patient, showed the lowest reactivity (Arr=1.6-fold, IRBP=3.2-fold). The 21yo patient, with overt inflammation on angiography, had the highest AAb titers (Arr=5.1-fold, IRBP=6.8-fold)
As in RCS rats, defective mer-TK function is associated with anti-arrestin and anti-IRBP AAbs also in TAM mice and in arRP patients with the<br /> null R775X MERTK mutation. This strongly suggests that a stereotypic AAb reaction triggered by the underlying genetic defect takes place in all MERTK-related phenotypes. Since these AAbs have been shown to be partially pathogenic in RCS rats and that AAb inhibition ameliorates the RCS phenotype (Adamus et al. Mol Vis 2012), human MERTK-related phenotypes too may benefit from immunosuppressive treatments when anti-arrestin and/or IRBP AAbs are present. These findings may also have implications for the ongoing MERTK gene therapy trial.
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