Antibodies to glycoconjugates in autoimmune neuropathies.
Antibodies to glycoconjugates in autoimmune neuropathies.
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自身免疫性神经病中糖缀合物的抗体。
DOI：
10.1111/cen3.12256
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发表时间：
2015
影响因子：
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通讯作者：
Kenichi Kaida
中科院分区：
文献类型：
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作者：
Makoto Ishihara;Natsumi Araya;Tomoo Sato;Risa Fujii;Ayako Tatsuguchi;Naomi Saichi;Hidewaki Nakagawa;Yoshihisa Yamano;Koji Ueda;儘田直美，田之頭大輔，保坂 愛，玉岡 晃，亀谷富由樹，荒木 亘;Kenichi Kaida
人类嗜T淋巴病毒1型（HTLV‐1）可引起HTLV‐1相关的脊髓病/热带痉挛性截瘫和成人T细胞白血病/淋巴瘤。HTLV‐1相关脊髓病/热带痉挛性截瘫发病机制的主要特征是病毒诱导的免疫反应过度活跃，引起中枢神经系统（CNS）的慢性炎症，但问题仍然存在：HTLV‐1解除免疫反应并诱导慢性炎症的机制是什么？虽然中枢神经系统的T细胞浸润包括HTLV‐1感染的细胞，但HTLV‐1似乎不会感染神经元细胞本身。已经确定HTLV‐1是一种主要感染CD4+辅助性T细胞的独特病毒。我们最近发现HTLV‐1严重感染CCR4+细胞，其中已知包括调节性T细胞。我们发现HTLV‐1通过T‐bet表达在这些CCR4+细胞中诱导Th1‐样状态。我们还发现CXCL10在维持中枢神经系统炎症的正反馈循环中起着重要作用。星形胶质细胞是CNS中CXCL10的主要产生者，也是这个循环中的另一个关键角色。为了完善这幅图，我们发现受感染的CCR4+ Th1样T细胞产生干扰素γ，这是刺激星形胶质细胞产生CXCL10的原因。现在我们对HTLV - 1相关脊髓病/热带痉挛性麻痹发病机制的分子机制有了更好的了解，并且很明显CCR4+细胞是炎症途径的重要贡献者。因此，我们目前正在进行I/IIa期临床试验，以测试一种使用抗体依赖性细胞介导的细胞毒性靶向CCR4+细胞的治疗方法的效果和安全性。
Human T‐lymphotropic virus type 1 (HTLV‐1) can cause HTLV‐1‐associated myelopathy/tropical spastic paraparesis and adult T cell leukemia/lymphoma. The main feature of HTLV‐1‐associated myelopathy/tropical spastic paraparesis pathogenesis is a virus‐induced hyperactive immune response that causes chronic inflammation in the central nervous system (CNS), but the question remains: what is the mechanism by which HTLV‐1 deregulates the immune response and induce chronic inflammation? While T cell infiltrates in the CNS include HTLV‐1‐infected cells, HTLV‐1 does not appear to infect the neuronal cells themselves. It has been established that HTLV‐1 is a unique virus that mainly infects CD4+ helper T cells. We recently showed that HTLV‐1 heavily infects CCR4+ cells, which are known to include regulatory T cells. We showed that HTLV‐1 induces a Th1‐like state in these CCR4+ cells through T‐bet expression. We have also found that CXCL10 plays an important role in a positive feedback loop that maintains inflammation in the CNS. Astrocytes, which were shown to be the main producers of CXCL10 in the CNS, are another key player in the loop. To complete the picture, we showed that the infected CCR4+ Th1‐like T cells produce interferon‐γ, which is what stimulates astrocytes to produce CXCL10. Now we have a much better understanding of the molecular mechanisms at play in HTLV‐1‐associated myelopathy/tropical spastic paraparesis pathogenesis, and clearly CCR4+ cells are a significant contributor to the inflammatory pathways. Thus, we are currently carrying out a phase I/IIa clinical trial to test the effects and safety of a therapy that uses antibody‐dependent cell‐mediated cytotoxicity to target CCR4+ cells.