Autoantibodies against various retinal proteins, including anti-carbonic anhydrase II (CAII) autoantibodies, have been found in patients with cancer-associated retinopathy and autoimmune retinopathy without diagnosed cancer. We studied sera from retinopathy patients that showed reactivity with a 30-kDa retinal protein, which was identified as carbonic anhydrase II (CAII), and immunolabeled cells in human retina. The goal of the study was to examine whether patients’ autoantibodies induce pathogenic effects on the catalytic function of CAII, which may have metabolic consequences on cell survival. Our findings revealed that anti-CAII autoantibodies have the capacity to induce cellular damage by impairing CAII cellular function through inhibiting the catalytic activity of CAII in a dose dependent manner, decreasing intracellular pH, increasing intracellular calcium, which in effect decreases retinal cell viability. The destabilized catalytic function of CAII and alterations in cytosolic pH were found very early, suggesting that autoantibodies are the inducers of apoptosis. In summary, our study showed that anti-CAII autoantibodies provoke pathogenic effects on retinal cells by decreasing cell survival by blocking the CAII cellular functions. The current experiments may facilitate better understanding the role of the immune system in retinal degeneration and help to develop better strategies for therapy of autoimmune retinopathy.

Introduction: Chronic autoimmune uveitis is a major cause of vision loss from intraocular inflammation in humans. In this study we report that a recombinant TCR ligand (RTL220) composed of the α1 and β1 domains of MHC class II molecules linked to the uveitogenic interphotoreceptor retinoid-binding protein (IRBP) 1177–1191 peptide is effective in the suppression of acute and recurrent experimental autoimmune uveitis (EAU). Material and Methods: EAU was induced with IRBP1177–1191 peptide or by adoptive transfer of specific T cells in Lewis rats. The rats received 5 doses of RTL220 subcutaneously every other day starting at the onset of clinic signs of EAU. Results: The administration of RTL220 resulted in a delayed onset and a significant amelioration of the disease severity at clinical levels and showed protection of the retina from inflammatory damage at histological levels. In treatment of recurrent EAU, RTL220 administrated at the first or second onset of clinical disease significantly inhibited EAU, modulated immune responses and provided protection from relapses of uveitis. The systemic and local proinflammatory cytokines were significantly reduced, including IL-17. There was local and systemic increase in IL-10 and reduction in the expression of the proinflammatory chemokines CCL2, CCL3 and CCL5. Conclusions: Our studies demonstrate a successful treatment of acute and recurrent EAU with RTL220, which effectively suppressed the recurrence of inflammation and reversed clinical and histological EAU by altering cytokine and chemokine expression. These findings strongly support a possible clinical application of this novel class of peptide/MHC class II drugs for patients with autoimmune uveitis.