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GCAP1, Rab6, and HSP27: Novel Autoantibody Targets in Cancer-Associated Retinopathy and Autoimmune Retinopathy
Sufang Yang1, Alexander Dizhoor2, David J Wilson1
1Casey Eye Institute, School of Medicine, Oregon Health and Science University, Portland, OR, USA.
Purpose:
Autoantibodies (AAbs) with different retinal specificities were reported in cancer-associated retinopathy (CAR) and autoimmune retinopathy (AR). The goal was to identify the small retinal proteins of apparent molecular mass of 23-kDa often recognized by patients' AAbs.
Methods:
Sera specific for a 23-kDa retinal protein of 173 patients were investigated retrospectively by Western blotting and double immunofluorescence confocal microscopy. A proteomic analysis revealed new 23-kDa protein candidates, including guanylyl cyclase-activating proteins (GCAPs), heat shock protein 27 (HSP27), and Rab6A GTPase (Rab6A).
Results:
Among the cohort of 173 patients, only 68 had anti-recoverin AAbs and the remaining 105 reacted with 4 unique proteins, which were identified as a Rab6A, HSP27, GCAP1, and GCAP2. Confocal images from a double labeling study confirmed the reactivity of AAbs with different types of cells in human retina, consistent with the target protein's respective cellular functions. Patients (62/173) had been diagnosed with various kinds of cancer, including 20% of patients who had anti-recoverin, 11% anti-Rab6A, and 5% anti-HSP27 AAbs. Only 50% of recoverin-seropositive patients had cancer and the individuals with anti-recoverin AAbs had a significantly higher likelihood to be diagnosed with cancer than patients with other anti-23-kDa AAbs.
Conclusions:
The newly discovered retinal autoantigens may be involved in pathogenicity of CAR and AR. The recognition of AAbs against various retinal proteins associated with autoimmune retinal degeneration broadens the group of proteins related with these entities.
Translational Relevance:
Patients with anti-recoverin, anti-GCAP1, anti-Rab6A, and anti-HSP27 AAbs represented diverse clinical phenotypes, so the presence of disease-associated AAbs provides important information for molecular diagnosis.
Insights
Researchers identified novel retinal autoantigens, including Rab6A, HSP27, GCAP1, and GCAP2, in patients with autoimmune retinopathy (AR) and cancer-associated retinopathy (CAR). Anti-recoverin autoantibodies were more frequently linked to cancer than other identified autoantibodies.
Area of Science:
- Ophthalmology
- Immunology
- Oncology
Background:
- Autoantibodies (AAbs) with varying retinal specificities are implicated in cancer-associated retinopathy (CAR) and autoimmune retinopathy (AR).
- Identifying specific retinal targets of these AAbs is crucial for understanding disease mechanisms.
Purpose of the Study:
- To identify small retinal proteins, approximately 23-kDa, that are frequently targeted by patient autoantibodies in CAR and AR.
- To expand the understanding of autoantigens involved in autoimmune retinal diseases.
Main Methods:
- Western blotting and double immunofluorescence confocal microscopy were used to analyze sera from 173 patients.
- Proteomic analysis was employed to identify potential 23-kDa retinal protein candidates.
Main Results:
- Four novel retinal autoantigens were identified: Rab6A GTPase (Rab6A), heat shock protein 27 (HSP27), guanylyl cyclase-activating protein 1 (GCAP1), and GCAP2.
- While 68 patients had anti-recoverin AAbs, 105 reacted with the newly identified proteins.
- Patients with anti-recoverin AAbs showed a significantly higher incidence of cancer diagnosis compared to those with other anti-23-kDa AAbs.
Conclusions:
- The newly identified retinal autoantigens (Rab6A, HSP27, GCAP1, GCAP2) are potentially pathogenic in CAR and AR.
- The diverse clinical phenotypes associated with these AAbs underscore their importance for molecular diagnosis in autoimmune retinal degeneration.
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