Interleukin-1 receptor mediates the interplay between CD4+ T cells and ocular resident cells to promote keratinizing squamous metaplasia in Sjögren's syndrome.
Interleukin-1 receptor mediates the interplay between CD4+ T cells and ocular resident cells to promote keratinizing squamous metaplasia in Sjögren's syndrome.
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DOI：
10.1038/labinvest.2011.189
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发表时间：
2012-04
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影响因子：
--
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中科院分区：
文献类型：
--
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眼粘膜上皮的角化性鳞状皮化生（SQM）是一种致盲性角膜疾病，其特征是结膜杯状细胞（GCs）的丧失、病理性眼表面角化和免疫细胞的组织募集。利用自身免疫调节因子（Aire）缺陷小鼠作为Sjögren 's综合征（SS）相关SQM的模型，我们发现CD4+ T淋巴细胞是驱动SQM的主要免疫效应因子，并揭示了白细胞介素-1 （IL-1）的致病作用。IL-1是一个多效细胞因子家族，富集于眼上皮，控制组织稳态和粘膜免疫。在这里，我们使用自身反应性CD4+ T细胞的过继性转移来剖析IL-1促进SQM的机制。从Aire敲除（KO）和Aire/IL-1受体1型（IL-1R1）双KO供者过继转移的CD4+ T细胞使具有功能性IL-1R1的严重联合免疫缺陷（scid）受者获得SQM，但没有缺乏IL-1R1的scid受者。在泪腺中，IL-1R1主要免疫定位于被CD4+ T细胞包围的导管上皮。在眼睛中，IL-1R1在局部粘膜上皮细胞和基质细胞上表达，但在常驻抗原呈递细胞和浸润性免疫细胞上不表达。在这两种组织中，仅在存在il - 1r1阳性驻留细胞时才观察到自身反应性CD4+ t细胞浸润。此外，IL-1R1信号的持续激活通过将CD4+ T细胞保留在局部微环境中导致慢性免疫介导的炎症。在il - 1r1依赖的CD4+ T细胞浸润后，我们在局部组织中观察到SQM特征-角膜角化，结膜GC粘蛋白酸化和整个眼表粘膜上皮细胞增生。眼上皮细胞促炎IL-1表达与泪液分泌减少显著相关，泪腺CD4+ t细胞浸润可预测眼SQM的发生。总的来说，本研究的数据表明，在SQM的发病机制中，IL-1在协调免疫细胞和ss靶向组织的驻留细胞之间的功能相互作用中发挥了核心作用。
Keratinizing squamous metaplasia (SQM) of the ocular mucosal epithelium is a blinding corneal disease characterized by the loss of conjunctival goblet cells (GCs), pathological ocular surface keratinization and tissue recruitment of immune cells. Using the autoimmune regulator (Aire)-deficient mouse as a model for Sjögren’s syndrome (SS)-associated SQM, we identified CD4+ T lymphocytes as the main immune effectors driving SQM and uncovered a pathogenic role for interleukin-1 (IL-1). IL-1, a pleiotropic cytokine family enriched in ocular epithelia, governs tissue homeostasis and mucosal immunity. Here, we used adoptive transfer of autoreactive CD4+ T cells to dissect the mechanism whereby IL-1 promotes SQM. CD4+ T cells adoptively transferred from both Aire knockout (KO) and Aire/IL-1 receptor type 1 (IL-1R1) double KO donors conferred SQM to severe-combined immunodeficiency (scid) recipients with functional IL-1R1, but not scid recipients lacking IL-1R1. In the lacrimal gland, IL-1R1 was primarily immunolocalized to ductal epithelium surrounded by CD4+ T cells. In the eye, IL-1R1 was expressed on local mucosal epithelial and stromal cells, but not on resident antigen-presenting cells or infiltrating immune cells. In both tissues, autoreactive CD4+ T-cell infiltration was only observed in the presence of IL-1R1-postive resident cells. Moreover, persistent activation of IL-1R1 signaling led to chronic immune-mediated inflammation by retaining CD4+ T cells in the local microenvironment. Following IL-1R1-dependent infiltration of CD4+ T cells, we observed SQM hallmarks in local tissues—corneal keratinization, conjunctival GC mucin acidification and epithelial cell hyperplasia throughout the ocular surface mucosa. Proinflammatory IL-1 expression in ocular epithelial cells significantly correlated with reduced tear secretion, while CD4+ T-cell infiltration of the lacrimal gland predicted the development of ocular SQM. Collectively, data in this study indicated a central role for IL-1 in orchestrating a functional interplay between immune cells and resident cells of SS-targeted tissues in the pathogenesis of SQM.
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影响因子：
7
作者：
Curtsinger JM;Mescher MF
通讯作者：
Mescher MF
影响因子：
3.4
作者：
Gao, JP;Morgan, G;Stern, ME
通讯作者：
Stern, ME
DOI：
10.1073/pnas.0902745106
发表时间：
2009-04-28
影响因子：
11.1
作者：
Ben-Sasson, Shlomo Z.;Hu-Li, Jane;Paul, William E.
通讯作者：
Paul, William E.
影响因子：
4.4
作者：
Matsuki, T;Nakae, S;Iwakura, Y
通讯作者：
Iwakura, Y
自身免疫性多边形综合征1型的鼠模型中自身免疫综合征的效应器机制。
影响因子：
4.4
作者：
DeVoss, Jason J.;Shum, Anthony K.;Johannes, Kellsey P. A.;Lu, Wen;Krawisz, Anna K.;Wang, Peter;Yang, Ting;LeClair, Norbert P.;Austin, Cecilia;Strauss, Erich C.;Anderson, Mark S.
通讯作者：
Anderson, Mark S.