Study on Molecular pathology of cancer associated retinopathy

一种称为癌症相关视网膜病变（CAR）的视觉副肿瘤综合征已经在肺小细胞癌和其他恶性肿瘤患者中被发现。这些患者的临床特征为视力减退，进行性视力丧失伴环状暗斑，视网膜小动脉减弱，ERG a波和b波异常。组织病理学和免疫学观察显示，在CAR中，光感受器细胞的损失可能是由一种针对光感受器特异性23 kDa钙结合蛋白（称为恢复蛋白）的自身免疫反应引起的。功能上，恢复蛋白通过钙依赖的方式调节视紫红质磷酸化和去磷酸化，在光暗适应中发挥重要作用。最近，在CAR患者的癌细胞中发现了recoverin的表达，并且通过腹腔培养的小细胞癌诱导了CAR抗原（recoverin）的表达。这些观察结果使我们推测，癌细胞中异常表达的recoverin可能引发自身免疫反应。此外，其他视网膜抗原包括65 kDa蛋白、48 kDa蛋白、烯醇化酶（46 kDa蛋白）和神经丝（58-62 kDa、145 kDa和205 kDa蛋白）可被部分CAR患者的血清识别。在这些视网膜自身抗原中，在western blot分析中，recoverin单独或与65kda蛋白的组合最常被显示为免疫反应带。最近，我们的研究小组鉴定了65 kDa蛋白为热休克同源蛋白70（hsc70）。因此，我们认为抗recoverin和抗hsc 70抗体都参与了CAR的发病机制。在本研究中，为了进一步研究抗recoverin和抗hsc 70抗体在CAR中的病理作用，我们将这些抗体注射到Lewis大鼠的玻璃体腔中，并对视网膜进行组织病理学和电生理表征。

A visual paraneoplastic syndrome called cancer-associated retinopathy(CAR) has been identified in patients with small cell carcinoma of lung and other malignant tumors. These patients are clinically characterized with photopsia, progressive visual loss with a ring scotoma, attenuated retinal arterioles, and abnormalities of the a- and b-waves of the ERG.Histopathological and immunological observations revealed that, in CAR, loss of photoreceptor cells may be caused by an autoimmune reaction against a photoreceptor specific 23 kDa calcium binding protein called recoverin. Functionally, recoverin was found to play a major role in light and dark adaptation by regulating rhodopsin phosphorylation and dephosphorylation in a calcium-dependent manner. Recently, expression of recoverin has been identified in the cancer cells of CAR patients, and expression of the CAR antigen(recoverin)is induced by an intraperitoneal cultivation of small-cell carcinoma. These observations allowed us to speculate that aberrant expression of recoverin in cancer cells may trigger an autoimmune reaction. In addition, other retinal antigens including 65 kDa protein, 48 kDa protein, enolase(46 kDa protein), and neurofilament(58-62 kDa, 145 kDa and 205 kDa proteins)are recognized by some CAR patients' sera. Among these retinal autoantigens, recoverin alone or a combination of recoverin and 65 kDa protein have most frequently been shown as the immunoreactive bands in western blot analysis in the previous reports. Most recently our group identified the 65 kDa protein as heat shock cognate protein 70(hsc 70). Therefore, we suggested that both anti-recoverin and anti-hsc 70 antibodies are involved in the pathogenesis of CAR.In the present study, to further investigate the pathological roles of anti-recoverin and anti-hsc 70 antibodies in CAR, we injected these antibodies into the vitreous cavity of Lewis rats, and performed histopathological and electrophysiological characterization of the retinas.