Autoantibodies against the Ca2+-binding protein recoverin in blood sera of patients with various oncological diseases

Abstract

Abstract. In cancer, the retinal Ca 2+ -binding protein recoverin is a paraneoplastic antigen, the aberrant expression of which is capable of triggering the appearance of specific autoantibodies in the serum of patients with malignant tumors and the subsequent development of a paraneoplastic syndrome, cancer-associated retinopathy (CAR). The frequency of serum autoantibodies against recoverin (AAR), earlier determined at a rate of 15-20% in lung cancer, is much higher than the frequency of CAR syndrome, which is approximately 1%. In the present study, we estimated for the first time the frequencies of serum AAR in patients with various types of malignancies other than lung cancer. Patient biospecimens were collected to analyze for the presence of AAR. Additionally, various cell lines were cultivated and analyses were performed using Western blotting and RT-PCR. Results showed that in all cases tested, the AAR frequencies did not exceed 10%. Five AAR-positive patients with various types of cancer were available for ophthalmological investigation and only one of these patients had CAR syndrome. This result is consistent with the conclusion made in our previous studies of lung cancer that serum AAR do not necessarily trigger the development of CAR syndrome. IntroductionNeuronal proteins, which are usually present only within the nervous system but may also be expressed in malignant tumors localized outside the nervous system, are assigned to paraneoplastic (onconeural) antigens (PNA). The immune system of certain patients responds to PNA by producing specific autoantibodies and/or cytotoxic T-cells that trigger the development of a paraneoplastic neurological syndrome (PNS) (1). One such PNA is the photoreceptor Ca 2+ -binding protein recoverin (2,3), which is normally specific to the retina and the pineal gland but may also be aberrantly expressed in malignant tumors of the lung and other tissues (4,5). In certain patients with lung cancer, high-titer serum autoantibodies against recoverin (AAR) trigger the development of a PNS, cancer-associated retinopathy (CAR) (6,7). However, low-titer serum AAR of patients with lung cancer do not necessarily cause CAR syndrome (8-10). Instead, this syndrome only occurs in approximately 1% of cancer patients, whereas the frequencies of serum AAR in patients with small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC) equal 15 and 20%, respectively (10).By analogy with cancer-testis antigens, recoverin has been classified as a cancer-retina antigen (5) for the following reasons: i) its normal expression is restricted to an immunoprivileged tissue (retina), ii) it is aberrantly expressed in tumor cells, iii) it subsequently demonstrates high antigenicity (autoantibodies and/or T-cells), and iv) aberrant demethylation of the gene promoter is involved in the aberrant expression of recoverin (11).In this study, we analyzed serial specimens of blood sera of patients with a number of different malignancies to estimate the frequency of serum AAR in oncological disea...

Paraneoplastic and non-paraneoplastic retinopathy and optic neuropathy: Evaluation and management

“…None of the cumulative 143 patients developed visual compromise concerning for CAR, however. In a follow-up study by the same group, 250 five patients with non-lung cancers (breast, ovary, stomach, and bladder) and anti-recoverin antibodies present in their sera were subject to ophthalmologic examination. Only one individual had narrowing of the visual field and corresponding s u r v e y o f o p h t h a l m o l o g y 5 8 ( 2 0 1 3 ) 4 3 0 e4 5 8 retinal degeneration consistent with a diagnosis of CAR.…”

Latest Updates on Antiretinal Autoantibodies Associated With Vision Loss and Breast Cancer

“…Thus, the absence of anti-recoverin AAbs does not exclude the diagnosis of paraneoplastic retinopathy. 53,63 Moreover, it is important to point out that antiretinal AAbs, such as anti-enolase and antirecoverin, have also been detected in patients with cancer but without clinical signs of CAR, 44,64 and it is not known whether individuals with antiretinal AAbs advance to paraneoplastic disease, and what regulates such a progression. The rare development of paraneoplastic disease caused by the autoimmune response could also be influenced by restricting mechanisms related to the blood-retina barrier (BRB) and the immune privileged status of the retina.…”

Significance of Anti-retinal Autoantibodies in Cancer-associated Retinopathy with Gynecological Cancers

“…In the cancer group, only one woman with neuroendocrine fallopian tube cancer out of 21 subjects had anti-recoverin AAbs (4.7%). This retinal calcium-binding protein has been recognized as a CAR antigen, which its aberrant expression is capable of triggering the generation of specific AAbs in patients with malignant tumors and the subsequent development of the paraneoplastic syndrome, cancer-associated retinopathy [ 10 , 17 , 18 ]. In the case of fallopian tube cancer without retinopathy, 12 out of 21 patients were seropositive with 19% of anti-enolase and 38% of anti-CAII AAbs.…”