PurposeAutoimmune retinopathies and optic neuropathies are complex disorders of the retina and the optic nerve, in which patients develop autoantibodies (AAbs) against retinal and optic nerve proteins. Autoimmunity might significantly influence the outcome of retinal and optic nerve degenerative process but the pathogenic process is not fully elucidated. To better understand the role of AAbs in pathogenicity of these suspected autoimmune visual disorders, we focused on unique AAbs specificities associated with the syndrome to identify their antigenic targets in the optic nerve and retina.MethodsSerum samples were obtained from patients, whose visual disorders were potentially autoimmune in nature, including patients with cancer with possible paraneoplastic syndrome. Autoantibodies were tested against human optic nerve and retinal antigens for specificity by Western blotting and immunofluorescence.ResultsOut of 209 tested for anti-optic nerve autoantibodies, 55% showed specific neuronal autoantibodies. The repertoire of anti-optic nerve autoantibodies often differed from anti-retinal antibodies. The major antigenic targets for these antibodies could be divided into four groups. Autoantibodies specific to classical glycolytic enzymes involved in energy production (α and γ enolases, glyceraldehyde 3-phosphate dehydrogenase) also reacted with retinal antigens. Autoantibodies targeted neuronal-specific myelin proteins (MBP, MOG), aquaporin 4, and collapsing response mediator protein 5 reacted with optic nerve antigens. They showed immunostaining of axons and myelin in the optic nerve as determined by double immunofluorescence.ConclusionWe identified novel neuronal autoantigens not previously known to be associated with acquired autoimmune retinopathy and optic neuropathy. Knowledge of the full autoantibody repertoire perpetuating this syndrome is an important first requirement in increasing our understanding of the autoimmune process to facilitate better diagnosis, prognosis, and treatment.
Autoimmune retinopathies (AR) are uncommon retinal degenerations with vision loss associated with unique clinical symptoms and findings and with serum anti-retinal autoantibodies. The experimental and clinical studies corroborate that autoantibodies in high titers can penetrate into the retina affecting function of the target antigens, which leads to retinal dysfunction and degeneration. Anti-recoverin and anti-enolase α-enolase autoantibodies were more frequently recognized in AR but autoantibodies with other specificities have also been documented, indicating immunological heterogeneity. Our goal was to examine the associations of anti-retinal autoantibodies with retinopathy in order to identify molecular biomarkers for better diagnosis and prognosis of retinopathies. In these studies we examined 39 patients (10 with cancers) of average age of ∼57 years old with sudden onset of unexplained progressive vision loss and the presence of circulating serum autoantibodies against 40-kDa retinal protein. The patients presented the retinal phenotype characterized by defects in visual fields and reduced scotopic ERG responses. Anti-40-kDa autoantibodies had specificity to the amino terminus of transducin-α. None of the normal subjects' sera had anti-40-kDa autoantibodies. In conclusion, clinical phenotype of patients with anti-transducin-α autoantibodies differed from other phenotypes of AR. These patients, often women at a ratio ∼2:1, had defects in rod (scotopic) photoreceptor function and typically did not have cancers, whereas anti-recoverin phenotype is associated with cancer and severe loss of rod and cones function, and anti-enolase retinopathy typically presents with cone dysfunction and is equal in cancer and non-cancer patients. Our studies suggest that anti-transducin autoantibodies can serve as molecular biomarkers for retinal phenotypes and could be used for progression of retinal dysfunction and degeneration.
BackgroundAutoimmune retinopathy (AR) and Cancer-Associated Retinopathy (CAR) are associated with a diverse repertoire of anti-retinal autoantibodies (AAbs) but not all antigenic targets have been characterized. Identification of new AAbs may help with clinical diagnosis and prognosis of retinal dysfunction in AR. The goal was to identify frequently targeted retinal autoantigens within the 60-70-kDa molecular weight range.MethodsHuman retinal proteins were separated by SDS-PAGE and 2D gel electrophoresis (2-DE) and sera from AR patients with and without cancer were used to identify immunoreactive proteins by Western blotting. Proteins were identified following separation by electrophoresis, Coomassie staining using in-gel trypsin digestion and mass spectrometric analysis. Circulating serum hsp60 and anti-hsp60 antibody levels were determined by quantitative ELISA.ResultsRetrospective evaluation of 819 patients with anti-retinal AAbs showed that 29% patients had AAbs targeted proteins between 60-70-kDa. Shotgun mass spectrometry of human retinal proteins present in 1D-gel found 66 species within this range. To identify the immunoreactive proteins, we performed Western blots of 2-DE gels and showed a group of heat shock proteins (hsps), including hsp60 and CRMP proteins that were frequently recognized by AR patient AAbs, irrespective of cancer status. These results were validated by immunostaining of purified hsp60 and CRMP2 proteins. ELISA results revealed that patients with AR and CAR had significantly increased levels of serum anti-hsp60 antibodies compared to control healthy subjects (p < 0.0001). However, circulating hsp60 protein was not significantly elevated in sera of either patient group.ConclusionsDifferent anti-retinal antibodies frequently co-exist in a single patient, creating antibody-arrays related to the syndrome. Hsps and CRMP-2 are newly identified autoantigens in AR. A frequent co-association of anti-hsp antibodies with other anti-retinal AAbs may augment pathogenic processes, leading to retinal degeneration.
RTL342M suppressed clinical and histologic signs of EAE/ON by preventing the recruitment of inflammatory cells into the optic nerve and showed neuroprotective effects against ON. However, to achieve full therapeutic benefit, more doses may be needed. These findings suggest a possible clinical application of this novel class of T-cell-tolerizing drugs for patients with optic neuritis.
Anti‐Ro60 is one of the most important and common autoantibodies found in systemic autoimmune diseases. Using a range of traditional diagnostic laboratory assays and innovative mass spectrometry, authors dissect low from high expression of anti‐Ro60 and the clinical implications of this. Low expression of anti‐Ro60 was found to be a serologically and molecularly distinct entity that has important clinical relevance.
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