An immunologically privileged retinal antigen elicits tolerance: major role for central selection mechanisms.
An immunologically privileged retinal antigen elicits tolerance: major role for central selection mechanisms.
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DOI：
10.1084/jem.20030413
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发表时间：
2003-12-01
期刊：
影响因子：
--
通讯作者：
Caspi RR
中科院分区：
文献类型：
--
作者：
Avichezer D;Grajewski RS;Chan CC;Mattapallil MJ;Silver PB;Raber JA;Liou GI;Wiggert B;Lewis GM;Donoso LA;Caspi RR
免疫豁免视网膜抗原可以作为实验性自身免疫性葡萄膜炎（EAU）的靶点，EAU是人类葡萄膜炎的模型。敏感品系的耐受性状态尚不清楚，其靶抗原在胸腺中的表达水平不可检测。在这里，我们直接解决这个问题，通过分析遗传缺陷与充足的葡萄膜视网膜抗原，感光细胞间类维生素A结合蛋白（IRBP）的后果。在高度EAU易感背景下，用IRBP攻击IRBP敲除（KO）和野生型（WT）小鼠。KO小鼠对IRBP的反应大大提高，IRBP表位的识别发生改变，并且它们的致敏T细胞诱导WT受体的疾病加重。超灵敏免疫组化染色可视化稀疏IRBP阳性细胞，常规检测无法检测到，在胸腺的WT（但不是KO）小鼠。显微切割后，从这些细胞中PCR扩增IRBP信息。KO和WT宿主之间的胸腺移植表明，这种表达水平是功能相关的，并设定了免疫（和自身免疫）反应性的阈值。即，WT胸腺的KO受体产生减少的IRBP特异性应答，而KO胸腺的WT受体产生增强的应答和高度恶化的疾病。库剔除和胸腺依赖性CD25+ T细胞参与了这种效应。因此，葡萄膜炎易感个体对其靶抗原表现出可检测的和功能上显著的耐受性，其中中枢机制起着突出的作用。
Immunologically privileged retinal antigens can serve as targets of experimental autoimmune uveitis (EAU), a model for human uveitis. The tolerance status of susceptible strains, whose target antigen is not expressed in the thymus at detectable levels, is unclear. Here, we address this issue directly by analyzing the consequences of genetic deficiency versus sufficiency of a uveitogenic retinal antigen, interphotoreceptor retinoid-binding protein (IRBP). IRBP-knockout (KO) and wild-type (WT) mice on a highly EAU-susceptible background were challenged with IRBP. The KO mice had greatly elevated responses to IRBP, an altered recognition of IRBP epitopes, and their primed T cells induced exacerbated disease in WT recipients. Ultrasensitive immunohistochemical staining visualized sparse IRBP-positive cells, undetectable by conventional assays, in thymi of WT (but not of KO) mice. IRBP message was PCR amplified from these cells after microdissection. Thymus transplantation between KO and WT hosts demonstrated that this level of expression is functionally relevant and sets the threshold of immune (and autoimmune) reactivity. Namely, KO recipients of WT thymi generated reduced IRBP-specific responses, and WT recipients of KO thymi developed enhanced responses and a highly exacerbated disease. Repertoire culling and thymus-dependent CD25+ T cells were implicated in this effect. Thus, uveitis-susceptible individuals display a detectable and functionally significant tolerance to their target antigen, in which central mechanisms play a prominent role.
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影响因子：
12.8
作者：
CHAN, CC;CASPI, RR;NUSSENBLATT, RB
通讯作者：
NUSSENBLATT, RB
影响因子：
56.9
作者：
Anderson, MS;Venanzi, ES;Mathis, D
通讯作者：
Mathis, D
影响因子：
30.5
作者：
Derbinski, J;Schulte, A;Klein, L
通讯作者：
Klein, L
影响因子：
32.4
作者：
Harrington, CJ;Paez, A;Goverman, J
通讯作者：
Goverman, J
影响因子：
2
作者：
CASPI, RR;CHAN, CC;CHADER, GJ
通讯作者：
CHADER, GJ