Are Anti-Retinal Autoantibodies a Cause or a Consequence of Retinal Degeneration in Autoimmune Retinopathies?

Abstract

Autoantibodies (AAbs) against various retinal proteins have been associated with vision loss in paraneoplastic and non-paraneoplastic autoimmune retinopathies (AR). There are two major paraneoplastic syndromes associated anti-retinal AAbs, cancer-associated retinopathy (CAR), and melanoma-associated retinopathy. Some people without a cancer diagnosis may present symptoms of CAR and have anti-retinal AAbs. The etiology and pathogenesis of those entities are not fully understood. In this review, we provide evidence for the role of AAbs in retinal death and degeneration. Studies of epitope mapping for anti-recoverin, anti-enolase, and anti-carbonic anhydrase II revealed that although patients' AAbs may recognize the same retinal protein as normal individuals they bind to different molecular domains, which allows distinguishing between normal and diseased AAbs. Given the great diversity of anti-retinal AAbs, it is likely some antibodies have greater pathogenic potential than others. Pathogenic, but not normal antibodies penetrate the target cell, reach their specific antigen, induce apoptosis, and impact retinal pathophysiology. Photoreceptors, dying by apoptosis, induced by other than immunologic mechanisms produce substantial amounts of metabolic debris, which consequently leads to autoimmunization and enhanced permeability of the blood-retinal barrier. AAbs that were made as a part of anti-cancer response are likely to be the cause of retinal degeneration, whereas others, generated against released antigens from damaged retina, contribute to the progression of retinopathy. Altogether, AAbs may trigger retinal degeneration and may also exacerbate the degenerative process in response to the release of sequestered antigens and influence disease progression.

Keywords: autoantibody; cancer-associated retinopathy; enolase; epitope mapping; melanoma-associated retinopathy; recoverin; retinal degeneration; transient receptor potential channel protein 1.

Figure 1

Pathology of retinal degeneration. A picture that illustrates a rod photoreceptor cell next to normal human retina (on the left) that is composed of several cell layers as follows: inner and outer segments of rod and cones of photoreceptors cells, outer nuclear layer, outer plexiform layer, inner nuclear layer, inner plexiform layer, ganglion cells layer, nerve fiber layer (axons of ganglion cells), and outer limiting membrane that neighbors with vitreous. A photograph of degenerated retina from a patient who lost completely photoreceptor cell layer (on the right), only inner part of the retina remained unaffected.

Figure 2

Possible causes for generation of autoantibodies reacted with retinal antigens: anti-microbial responses (infection) against similar antigens released after infection, antitumor responses (tumor) against upregulated similar proteins, or anti-retinal responses to released sequestered proteins (retinal injury) from dying retinal cells.

Figure 3

Immunofluorescent labeling of the human retina with cancer-associated retinopathy patients’ anti-retinal autoantibodies (AAbs) specific for different cellular structures. From left to right: AAbs label photoreceptor cells and bipolar cells, cone photoreceptors, ganglion cells, and amacrine cells; arrows point at immunofluorescent cells.

Figure 4

Overview of pathogenic autoimmune processes on the retina. Anti-retinal autoantibodies (AAbs) can provoke and can be a consequence of retinal degeneration. AAbs attract activated microglia/microphages that produce pro-inflammatory cytokines and chemokines, and induce apoptosis of cone and rod photoreceptor cells (showing on the right), resulting in retinal degeneration. Inflammatory cytokines and chemokines, activation of microglia and photoreceptor apoptosis can trigger secondary autoimmunity, and production of new anti-retinal AAbs. Cytotoxic T cells specific for retinal antigens are likely also involved in the pathogenic process.