Kielczewski Jennifer L, Horai Reiko, Jittayasothorn Yingyos, Chan Chi-Chao, Caspi Rachel R
Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892.
Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892
J Immunol. 2016 Feb 1;196(3):1013-25. doi: 10.4049/jimmunol.1501570. Epub 2015 Dec 28.
During chronic inflammation, tertiary lymphoid tissue (TLT) can form within an inflamed organ, including the CNS. However, little is known about TLT formation in the neuroretina. In a novel spontaneous autoimmune mouse model of uveitis (R161H), we identified well-organized lymphoid aggregates in the retina and examined them for TLT characteristics. Presence of immune cells, tissue-specific markers, and gene expression patterns typically associated with germinal centers and T follicular helper cells were examined using immunohistochemistry and gene analysis of laser capture microdissected retina. Our data revealed the retinal lymphoid structures contained CD4(+) T cells and B cells in well-defined zonal areas that expressed classic germinal center markers, peanut lectin (agglutinin) and GL-7. Gene expression analysis showed upregulation of T follicular helper cell markers, most notably CXCR5 and its ligand CXCL13, and immunohistochemical analysis confirmed CXCR5 expression, typically associated with CD4(+) T follicular helper cells. Highly organized stromal cell networks, a hallmark of organized lymphoid tissue, were also present. Positive staining for phospho-Zap70 in retina-specific T cells indicated CD4(+) T cells were being activated within these lymphoid structures. CD138(+)/B220(+) plasma cells were detected, suggesting the retinal lymphoid aggregates give rise to functional germinal centers, which produce Abs. Interestingly, eyes with lymphoid aggregates exhibited lower inflammatory scores by fundus examination and a slower initial rate of loss of visual function by electroretinography, compared with eyes without these structures. Our findings suggest that the lymphoid aggregates in the retina of R161H mice represent organized TLT, which impact the course of chronic uveitis.
在慢性炎症期间，三级淋巴组织（TLT）可在包括中枢神经系统在内的发炎器官内形成。然而，对于神经视网膜中TLT的形成了解甚少。在一种新型的葡萄膜炎自发自身免疫小鼠模型（R161H）中，我们在视网膜中鉴定出组织良好的淋巴聚集物，并检查它们是否具有TLT特征。使用免疫组织化学和激光捕获显微切割视网膜的基因分析，检测了通常与生发中心和T滤泡辅助细胞相关的免疫细胞、组织特异性标志物和基因表达模式。我们的数据显示，视网膜淋巴结构在明确的区域含有CD4(+) T细胞和B细胞，这些区域表达经典的生发中心标志物、花生凝集素和GL-7。基因表达分析显示T滤泡辅助细胞标志物上调，最显著的是CXCR5及其配体CXCL13，免疫组织化学分析证实了CXCR5的表达，这通常与CD4(+) T滤泡辅助细胞相关。高度组织化的基质细胞网络也是有组织的淋巴组织的一个标志。视网膜特异性T细胞中磷酸化Zap70的阳性染色表明CD4(+) T细胞在这些淋巴结构内被激活。检测到CD138(+)/B220(+)浆细胞，表明视网膜淋巴聚集物产生了功能性生发中心，这些生发中心产生抗体。有趣的是，与没有这些结构的眼睛相比，有淋巴聚集物的眼睛通过眼底检查显示出较低的炎症评分，并且通过视网膜电图检查显示出较慢的初始视觉功能丧失率。我们的研究结果表明，R161H小鼠视网膜中的淋巴聚集物代表有组织的TLT，其影响慢性葡萄膜炎的病程。
