Elevated Tribbles homolog 2-specific antibody levels in narcolepsy patients
Elevated Tribbles homolog 2-specific antibody levels in narcolepsy patients
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DOI：
10.1172/jci41366
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发表时间：
2010-03-01
影响因子：
15.9
通讯作者：
Tafti, Mehdi
中科院分区：
文献类型：
--
作者：
Cvetkovic-Lopes, Vesna;Bayer, Laurence;Tafti, Mehdi
发作性睡病是一种睡眠障碍，其特征是白天过度嗜睡和由强烈情绪引发的肌肉无力发作（cataepsy）。发作性睡病是由下丘脑分泌下视丘素的神经元大量减少引起的下视丘素（食欲素）缺乏。据信，嗜睡症是一种自身免疫性疾病，虽然这一点的确切证据，如自身抗体的存在，仍然缺乏。我们设计了一个转基因小鼠模型，以确定富含下丘脑分泌素的神经元内的肽，这些肽可以作为潜在的自身免疫靶点。初步分析表明，转录编码Tribbles同源物2（Trib 2），以前确定为自身免疫性葡萄膜炎的自身抗原，在这些小鼠的下丘脑泌素神经元富集。ELISA分析显示，与正常对照组或特发性睡眠过度、多发性硬化或其他炎性神经系统疾病患者相比，发作性睡病患者的血清具有更高的Trib 2特异性抗体滴度。Trib 2特异性抗体滴度在发作性睡病发作后早期最高，在2-3年内急剧下降，然后稳定在显著高于对照组的水平长达30年。高Trib 2特异性抗体滴度与中毒的严重程度相关。患者血清中有86%以上的下丘脑分泌素神经元呈特异性免疫反应。因此，我们已经确定了反应性自身抗体在人类嗜睡症，提供证据表明，嗜睡症是一种自身免疫性疾病。
Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness and attacks of muscle atonia triggered by strong emotions (cataplexy). Narcolepsy is caused by hypocretin (orexin) deficiency, paralleled by a dramatic loss in hypothalamic hypocretin-producing neurons. It is believed that narcolepsy is an autoimmune disorder, although definitive proof of this, such as the presence of autoantibodies, is still lacking. We engineered a transgenic mouse model to identify peptides enriched within hypocretin-producing neurons that could serve as potential autoimmune targets. Initial analysis indicated that the transcript encoding Tribbles homolog 2 (Trib2), previously identified as an autoantigen in autoimmune uveitis, was enriched in hypocretin neurons in these mice. ELISA analysis showed that sera from narcolepsy patients with cataplexy had higher Trib2-specific antibody titers compared with either normal controls or patients with idiopathic hypersomnia, multiple sclerosis, or other inflammatory neurological disorders. Trib2-specific antibody titers were highest early after narcolepsy onset, sharply decreased within 2-3 years, and then stabilized at levels substantially higher than that of controls for up to 30 years. High Trib2-specific antibody titers correlated with the severity of cataptexy. Serum of a patient showed specific immunoreactivity with over 86% of hypocretin neurons in the mouse hypothalamus. Thus, we have identified reactive autoantibodies in human narcolepsy, providing evidence that narcolepsy is an autoimmune disorder.