Amelioration of Experimental Autoimmune Uveoretinitis by Inhibiton of Toxic AGEs Formation

Abstract

Purpose: : Advanced glycation end products (AGEs) are permanently modified protein derivatives, forming through non-enzymatic glycation of amino groups. Since glyceraldehyde-derived AGEs have strong toxicity, it is considered as toxic AGEs (TAGE). TAGE has been demonstrated to play an important role in the pathogenesis of chronic inflammatory diseases through interaction with its receptor for AGEs (RAGE). Pyridoxamine, one of the vitamin B6 derivatives, has been demonstrated to inhibit the Amadori rearrangement in the process of AGEs production. In this study, we quantified the serum TAGE levels in patients with endogenous uveitis. In addition, therapeutic effects of pyridoxamine were examined on experimental autoimmune uveoretinitis (EAU), a murine model of human endogenous uveitis.

Methods: : One hundred three consecutive patients of uveitis (31 VKH disease patients in convalescent stage, 21 with HLA-B27 associated uveitis, 14 with Behcet disease, and 37 with sarcoidosis) and 33 healthy volunteers were enrolled. Serum TAGE levels of participants were quantified with ELISA. In EAU experiments, female B10.BR (H-2^k) mice were immunized with interphotoreceptor retinoid-binding protein (IRBP)-derived peptide emulsified with complete Freund’s adjuvant containing M.tuberculosis, and continuously administered 200mg/kg or 400mg/kg of pyridoxamine every 24 hours orally. Severity of EAU was evaluated both clinically and histopathologically. Translocation of NF-ΚB p65 into nucleus, and retinal levels of TAGE were also examined immunohistochemically.

Results: : Serum TAGE levels of uveitis patients with each etiology were significantly higher than those of healthy controls (P<0.001 for all). EAU was significantly milder both clinically and histopathologically when treated with 400mg/kg of pyridoxamine (P<0.05). TAGE levels were decreased in both sera and retina (P<0.05 for both), and translocation of NF-ΚB p65 into nucleus was down-regulated in retinas in pyridoxamine-treated EAU mice.

Conclusions: : TAGE levels were upregulated in sera of uveitis patients, and systemic administration of pyridoxamine ameliorated EAU. Our results suggest that TAGE-RAGE system contributes to the phathogenesis of uvetitis and is a novel therapeutic target for endogenous uveitis.

Keywords: uvea • chorioretinitis