Study on Molecular pathology of cancer associated retinopathy

在小细胞肺癌和其他恶性肿瘤患者中发现了一种称为癌症相关性视网膜病变(CAR)的视觉副肿瘤综合征。这些患者的临床特征是光视、进行性视力丧失并伴有环形暗点、视网膜小动脉变弱以及ERG的a波和b波异常。组织病理学和免疫学观察显示，在CAR中，光感受器细胞的丢失可能是由于对光受体特异性23 kDa钙结合蛋白的自身免疫反应引起的。在功能上，恢复素被发现通过钙依赖的方式调节视紫红质的磷酸化和去磷酸化，在明暗适应中起主要作用。最近，在CAR患者的癌细胞中发现了恢复素的表达，而CAR抗原(Recoverin)的表达是由小细胞癌腹膜腔内培养诱导的。这些观察结果让我们推测，癌细胞中恢复素的异常表达可能会引发自身免疫反应。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患者血清识别。在这些视网膜自身抗原中，以往报道中最常见的免疫反应条带是单一的或与65 kDa蛋白结合的恢复素。最近，我们的团队确定了65 kDa的蛋白是热休克相关蛋白70(HSC 70)。因此，我们认为抗恢复素抗体和抗HSC 70抗体都参与了CAR的发病机制。在本研究中，为了进一步研究抗恢复素抗体和抗HSC 70抗体在CAR中的病理作用，我们将这些抗体注射到Lewis大鼠的玻璃体腔内，并对视网膜进行了组织病理学和电生理特征的观察。

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.