Doheny Eye Institute, University of Southern California, Los Angeles, California, United States of America.
PLoS One. 2012;7(3):e33582. doi: 10.1371/journal.pone.0033582. Epub 2012 Mar 30.
The small heat shock protein, αA-crystallin null (αA-/-) mice are known to be more prone to retinal degeneration than the wild type mice in Experimental Autoimmune Uveoretinitis (EAU). In this report we demonstrate that intravenous administration of αA preserves retinal architecture and prevents photoreceptor damage in EAU. Interestingly, only αA and not αB-crystallin (αB), a closely related small heat shock protein works, pointing to molecular specificity in the observed retinal protection. The possible involvement of αA in retinal protection through immune modulation is corroborated by adaptive transfer experiments, (employing αA-/- and wild type mice with EAU as donors and Rag2-/- as the recipient mice), which indicate that αA protects against the autoimmune challenge by modulating the systemic B and T cell immunity. We show that αA administration causes marked reduction in Th1 cytokines (TNF-α, IL-12 and IFN-γ), both in the retina and in the spleen; notably, IL-17 was only reduced in the retina suggesting local intervention. Importantly, expression of Toll-like receptors and their associated adaptors is also inhibited suggesting that αA protection, against photoreceptor loss in EAU, is associated with systemic suppression of both the adaptive and innate immune responses.
在实验性自身免疫性葡萄膜炎（EAU）中，已知小型热休克蛋白αA-晶状体蛋白缺失（αA-/-）小鼠比野生型小鼠更容易发生视网膜变性。在本报告中，我们证明了静脉内给予αA 可保持视网膜结构并防止 EAU 中的光感受器损伤。有趣的是，只有αA 而不是与αA 密切相关的小型热休克蛋白αB（αB）起作用，这表明在观察到的视网膜保护中存在分子特异性。通过免疫调节的αA 参与视网膜保护的可能性通过适应性转移实验得到证实（采用 EAU 的αA-/-和野生型小鼠作为供体和 Rag2-/-作为受体小鼠），表明αA 通过调节系统 B 和 T 细胞免疫来抵抗自身免疫挑战。我们表明，αA 给药导致 Th1 细胞因子（TNF-α、IL-12 和 IFN-γ）在视网膜和脾脏中均显著减少;值得注意的是，仅在视网膜中减少了 IL-17，这表明存在局部干预。重要的是，Toll 样受体及其相关衔接子的表达也被抑制，这表明αA 对 EAU 中光感受器丧失的保护作用与适应性和固有免疫反应的全身性抑制有关。
