PDF(Pubmed)
Abstract：
Choroideremia (CHM) is a recessive, X-linked disease that affects 1 in 50,000 people worldwide. CHM causes night blindness in teenage years with vision loss progressing over the next two to three decades. While CHM is known to cause progressive loss of retinal pigment epithelial (RPE) cells, photoreceptors and choroidal vessels, little attention has been given to retinal glial changes in eyes with CHM. In addition, while choroidal loss has been observed clinically, no histopathologic assessment of choroidal loss has been done. We investigated glial remodeling and activation as well as choriocapillaris changes and their association with RPE loss in postmortem eyes from two donors with CHM. Eyes were fixed and cryopreserved or the retina and choroid/RPE were processed as flatmounts with a small piece cut for transmission electron microscopy. A dense glial membrane, made up of vimentin and GFAP double-positive cells, occupied the subretinal space in the area of RPE and photoreceptor loss of both eyes. The membranes did not extend into the far periphery, where RPE and photoreceptors were viable. A glial membrane was also found on the vitreoretinal surface. Transmission electron microscopy analysis demonstrated prominence and disorganization of glial cells, which contained exosome-like vesicles. UEA lectin demonstrated complete absence of choriocapillaris in areas with RPE loss while some large choroidal vessels remained viable. In the far periphery, where the RPE monolayer was intact, choriocapillaris appeared normal. The extensive glial remodeling present in eyes with CHM should be taken into account when therapies such as stem cell replacement are considered as it could impede cells entering the retina. This gliosis would also need to be reversed to some extent for Müller cells to perform their normal homeostatic functions in the retina. Future studies investigating donor eyes as well as clinical imaging from carriers or those with earlier stages of CHM will prove valuable in understanding the glial changes, which could affect disease progression if they occur early. This would also provide insights into the progression of disease in the photoreceptor/RPE/choriocapillaris complex, which is crucial for identifying new treatments and finding the windows for treatment.
摘要：
脉络膜血症(CHM)是一种隐性,X连锁疾病影响全球50,000人中的1人。CHM会在青少年时期导致夜盲症，并且在接下来的两到三十年中视力下降。虽然已知CHM会导致视网膜色素上皮（RPE）细胞的进行性丧失，光感受器和脉络膜血管，很少关注CHM患者眼中的视网膜胶质细胞变化。此外,虽然临床上观察到脉络膜损失，尚未对脉络膜丢失进行组织病理学评估.我们调查了两名CHM供体死后眼中的神经胶质重塑和激活以及脉络膜毛细血管变化及其与RPE损失的关系。将眼睛固定并冷冻保存，或将视网膜和脉络膜/RPE加工为扁平的小片，用于透射电子显微镜。致密的神经胶质膜，由波形蛋白和GFAP双阳性细胞组成，RPE区的视网膜下隙和双眼的光感受器丧失。膜没有延伸到远处的外围，其中RPE和光感受器是可行的。在玻璃体视网膜表面也发现了神经胶质膜。透射电子显微镜分析显示神经胶质细胞的突出和解体，其中含有外泌体样的囊泡。UEA凝集素在RPE丧失的区域显示完全没有脉络膜毛细血管，而一些大的脉络膜血管仍然存活。在遥远的外围，其中RPE单层是完整的，脉络膜毛细血管似乎正常。当考虑诸如干细胞替代之类的疗法时，应考虑CHM眼中存在的广泛的神经胶质重塑，因为它可能会阻碍细胞进入视网膜。这种神经胶质增生也需要在一定程度上逆转，以使Müller细胞在视网膜中执行其正常的稳态功能。未来的研究调查供体眼睛以及来自携带者或患有早期CHM的患者的临床成像将证明对了解神经胶质变化有价值。如果早期发生，可能会影响疾病进展。这也将提供对光感受器/RPE/脉络膜毛细血管复合体的疾病进展的见解，这对于确定新的治疗方法和寻找治疗窗口至关重要。
