Deletional tolerance prevents AQP4-directed autoimmunity in mice.
Deletional tolerance prevents AQP4-directed autoimmunity in mice.
复制标题
缺失耐受可防止小鼠 AQP4 导向的自身免疫。
DOI：
10.1002/eji.201646855
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发表时间：
2017
影响因子：
5.4
通讯作者：
Korn,Thomas
中科院分区：
文献类型：
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作者：
Vogel,Anna-Lena;Knier,Benjamin;Lammens,Katja;Kalluri,SudhakarReddy;Kuhlmann,Tanja;Bennett,JeffreyL;Korn,Thomas
视神经脊髓炎(NMO)是一种由星形胶质细胞表达的水通道蛋白AQP4抗体介导的中枢神经系统自身免疫性疾病。AQP4特异性T细胞在致病AQP4特异性抗体的类开关重组和血脑屏障炎症中的作用尚不完全清楚，因为AQP4的免疫原性自然处理的T细胞表位尚不清楚。通过用全长小鼠AQP4蛋白免疫−/−小鼠，然后用重叠多肽召回，我们确定AQP4(201-220)是AQP4的主要免疫原性IAb限制性表位。我们证明，由于缺失耐受，WT小鼠在其自然谱系中没有AQP4(201-220)特异性T细胞克隆。然而，用Aqp4−/−小鼠的成熟T细胞库重组的Rag1−/−小鼠接种AQP4(201-220)可引起脑脊髓炎综合征。与T细胞库相似，WT小鼠的B细胞库被“清除”了AQP4特异性的B细胞，而对AQP4的强劲血清反应仅在Aqp4−/−小鼠中安装。虽然AQP4(201-220)特异性T细胞单独引起脑脊髓炎，但中枢神经系统和视网膜中的NMO特异性皮损模式只有在额外存在抗AQP4抗体的情况下才会发生。因此，缺失的T细胞和B细胞对AQP4的耐受性失败是临床表现NMO的先决条件。
Neuromyelitis optica (NMO) is an autoimmune disorder of the central nervous system (CNS) mediated by antibodies to the water channel protein AQP4 expressed in astrocytes. The contribution of AQP4‐specific T cells to the class switch recombination of pathogenic AQP4‐specific antibodies and the inflammation of the blood–brain barrier is incompletely understood, as immunogenic naturally processed T‐cell epitopes of AQP4 are unknown. By immunizingAqp4−/−mice with full‐length murine AQP4 protein followed by recall with overlapping peptides, we here identify AQP4(201‐220) as the major immunogenic IAb‐restricted epitope of AQP4. We show that WT mice do not harbor AQP4(201–220)‐specific T‐cell clones in their natural repertoire due to deletional tolerance. However, immunization with AQP4(201–220) ofRag1−/−mice reconstituted with the mature T‐cell repertoire ofAqp4−/−mice elicits an encephalomyelitic syndrome. Similarly to the T‐cell repertoire, the B‐cell repertoire of WT mice is “purged” of AQP4‐specific B cells, and robust serum responses to AQP4 are only mounted inAqp4−/−mice. While AQP4(201–220)‐specific T cells alone induce encephalomyelitis, NMO‐specific lesional patterns in the CNS and the retina only occur in the additional presence of anti‐AQP4 antibodies. Thus, failure of deletional T‐cell and B‐cell tolerance against AQP4 is a prerequisite for clinically manifest NMO.