Abstract
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.
Highlights
Autoimmune 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
Autoimmunity is increasingly recognized as possible underlying cause of retinal degeneration in autoimmune retinopathies (AR), including paraneoplastic syndromes, such as cancerassociated retinopathy (CAR) and melanoma-associated retinopathy (MAR)
The profiling of AAbs led to valuable data aiding clinical diagnosis and prognosis of retinal dysfunction in AR; for instance, anti-recoverin AAbs are associated with severe retinal dysfunction of rods and cones whereas anti-enolase AAbs are associated with slow progressive dysfunction mostly in cones [7,8]
Summary
Autoimmune 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. As in other autoimmune disorders, AR including CAR is characterized by the presence of a diverse serum autoantibody repertoire, but not all target antigens have been identified [1,6]. It is important to point out that in CAR, retinal dysfunction and AAbs may manifest months or years prior to the onset and diagnosis of cancer, could be useful biomarkers for this disease [1]. Anti-Hsp autoantibodies that often co-existed with other anti-retinal AAbs, including antirecoverin and anti-α-enolase, may contribute to the autoimmune pathology in AR
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