Blood-borne soluble protein antigen intensifies T cell activation in autoimmune CNS lesions and exacerbates clinical disease
Blood-borne soluble protein antigen intensifies T cell activation in autoimmune CNS lesions and exacerbates clinical disease
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血源性可溶性蛋白抗原增强自身免疫性中枢神经系统病变中的 T 细胞活化并加剧临床疾病
DOI：
10.1073/pnas.0705033104
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发表时间：
2007
期刊：
影响因子：
--
通讯作者：
Alexander Flügel
中科院分区：
文献类型：
--
作者：
F. Odoardi;N. Kawakami;W. Klinkert;H. Wekerle;Alexander Flügel
我们探讨了在急性实验性自身免疫性脑脊髓炎（EAE）期间静脉注射可溶性抗原对靶器官内自身侵袭性髓鞘碱性蛋白特异性效应T细胞的影响。活体双光子成像显示，自体抗原在注射后30分钟内到达中枢神经系统，被抗原提呈细胞吸收处理。外源性自身抗原显著改变了EAE病变内自身反应效应T细胞的运动和功能：在组织中巡游的T细胞在1小时内减慢并与局部抗原呈递细胞拴在一起。1小时后，效应T细胞大量产生促炎细胞因子和上调膜活化标志物。这种T细胞的强烈激活促进了中枢神经系统炎症和加重了临床疾病。对非中枢神经系统抗原（卵清蛋白）特异性的后激活效应T细胞和静息记忆T细胞被招募到EAE病变，并在不接触抗原提呈细胞的情况下移动到那里。静脉输注卵清蛋白后，这些细胞同样被阻滞和激活，并且它们也加重了临床疾病。我们的数据与基于自身抗原的自身免疫性疾病治疗相关。此外，该研究表明，大脑无关的抗原（微生物成分）如何通过血液渗入慢性炎症的中枢神经系统，可能引发多发性硬化症的复发。
We explored the effect of i.v. soluble antigen on autoaggressive, myelin basic protein-specific effector T cells within their target organ during acute experimental autoimmune encephalomyelitis (EAE). Intravital two-photon imaging revealed that i.v. autoantigen reached the CNS and was taken up and processed by antigen-presenting cells within 30 min after injection. The exogenous autoantigen dramatically changed the motility and function of autoreactive effector T cells within the EAE lesions: T cells that had been cruising through the tissue slowed down and became tethered to local antigen-presenting cells within 1 h. One hour later, the effector T cells massively produced proinflammatory cytokines and up-regulated membranous activation markers. This strong activation of the T cells boosted CNS inflammation and aggravated clinical disease. Postactivated effector and resting memory T cells specific for a non-CNS antigen (ovalbumin) were recruited to EAE lesions and moved there without contacting antigen-presenting cells. These cells were similarly arrested and activated after i.v. infusion of ovalbumin, and they also exacerbated clinical disease. Our data are relevant for autoantigen-based therapies of autoimmune disorders. Further, the study indicates how brain unrelated antigens (microbial components) leaking into the chronically inflamed CNS through the bloodstream might trigger relapses in multiple sclerosis.