Autoantibody targets and their cancer relationship in the pathogenicity of paraneoplastic retinopathy

Abstract

Paraneoplastic retinopathies (PR), including cancer-associated retinopathy (CAR) or the closely related melanoma-associated retinopathy (MAR) occur in a small subset of patients with retinal degeneration and systemic cancer. This autoimmune syndrome is characterized by sudden, progressive loss of vision in association with circulating anti-retinal autoantibodies. The PR syndromes are heterogeneous, may produce a number of ocular symptoms, and may be associated with several different neoplasms, including lung, breast, prostate, gynecological, and colon cancer, melanoma, and hematologic malignancies. We examined the onset of retinopathy in correlation to the diagnosis of cancer and the presence of specific anti-retinal autoantibodies in PR patients. In some patients without diagnosed malignant tumors, the onset of ocular symptoms and the presence of autoantibodies preceded the diagnosis of cancer by months to years, including anti-recoverin, antitransducin-α, and anti-carbonic anhydrase II antibodies. Although anti-retinal autoantibodies may not be a good predictor of a specific neoplasm, they can be used as biomarkers for different subtypes of retinopathy. Identification of autoantibodies involved in autoimmune-mediated PR will help elucidate the mechanisms underlying the PR syndromes and develop targeted therapies for these sight-threatening disorders. KeywordsCancer-associated retinopathy; anti-retinal autoantibodies; recoverin; enolase; autoimmune retinopathy Take home message• Retinal autoantigens can be used as biomarkers for different subtypes of CAR.• Autoantibodies to retinal antigens that also recognize tumor autoantigens may be useful biomarkers for the cause and origin of paraneoplastic disease.• In some patients, the onset of ocular symptoms and the detection of anti-retinal autoantibodies may precede the diagnosis of systemic cancer.• The recognition of retinopathy as part of a paraneoplastic syndrome should prompt an immediate search for an occult neoplasm.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. • Early detection of anti-retinal autoantibodies may serve to identify those who are at risk of retinal deterioration and blindness. NIH Public Access

Autoimmune Retinopathy

“…A related clinical phenotype was reported in patients with cutaneous malignant melanoma in 1988 [4], who were found to have autoantibodies to an unknown antigen on bipolar cells [5]. These paraneoplastic diseases were termed ‘cancer-associated retinopathy’ (CAR) and ‘melanoma-associated retinopathy’ (MAR), and since their discovery, hundreds of cases have been reported in the literature [6,7]. Subsequently, a non-paraneoplastic autoimmune retinopathy, of uncertain aetiology, similar in phenotype and electrophysiology to CAR, has also been reported [8].…”

“…Predominant cone dysfunction is suggested by worsening acuity and colour vision, symptoms of photosensitivity, glare, flickering or shimmering lights and central scotoma, whilst impaired dark adaptation, night blindness, ring scotoma and peripheral field defects indicate predominant rod dysfunction [14,15]. Simultaneous rod and cone involvement is common, especially in association with antirecoverin antibodies, but the phenotype is heterogeneous [7,14]. Symptoms are typically worse than the clinical signs, and the fundus frequently appears normal [14].…”

Onconeural Antibodies in Acute Psychiatric Inpatient Care

“…Antirecoverin is an antibody associated with tumorassociated retinopathy. 13 Using the same immunohistochemical analytical methods performed by the same laboratory used in our study (Euroimmun, Lübeck, Germany), Dahm et al 6 also found a low prevalence of onconeural IgG autoantibodies in healthy individuals and in patients with schizophrenia, affective disorders, and personality disorders.…”

The Enigma of Autoimmune Retinopathy

“…14,15 The mean age of onset has been described in the range of 55 to 65 years, with npAIR having a younger age of onset than CAR and MAR. [15][16][17] Cystoid macular edema has also been described in AIR. 14 Ancillary studies that can be useful in the diagnosis of AIR include visual field (VF) testing, electroretinography (ERG), fundus autofluorescence (FAF) imaging, and optical coherence tomography (OCT).…”

“…[40][41][42] Autoantibodies targeting various other retinal proteins have also been implicated as putative causative agents based on the identification of these antibodies in the serum of patients with presumed AIR. These include antibodies against carbonic anhydrase II (which is abundant in ocular tissues) 17,43,44 and the retina-specific tubby-like protein 1 (TULP1). 45 The mere presence of autoantibodies in patient sera does not imply pathogenicity, as the antibodies could represent either "the secondary consequence of tissue damage, or the harmless footprint of an etiologic agent."…”