History of narcolepsy at Stanford University.
History of narcolepsy at Stanford University.
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DOI：
10.1007/s12026-014-8513-4
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发表时间：
2014-05
影响因子：
4.4
通讯作者：
Mignot, Emmanuel J. M.
中科院分区：
文献类型：
--
作者：
Mignot, Emmanuel J. M.
虽然嗜睡症最早是在世纪末在德国和法国被描述的，但对这种疾病的大部分研究都是在斯坦福大学进行的，首先是由威廉·C. Dement和Christian Guilleminault在20世纪70年代。发作性睡病的患病率被确定，并发现了犬模型。在日本发现几乎所有的发作性睡病患者都携带一种特定的HLA亚型HLA-DR 2。Carl Grumet和Larry Steinman发起了免疫学研究，但结果通常是阴性的。西野博士和我通过对发作性睡病犬的研究证实，兴奋剂通过刺激多巴胺能传递来增加清醒，而抗抑郁药通过抑制肾上腺素能再摄取来抑制紧张症。1988年，Grumet博士开始了一项连锁研究，经过10年的工作，1999年，犬嗜睡症基因被克隆出来，并被鉴定为下丘脑泌素（食欲素）受体2。1992年，在研究非裔美国人时，我们还发现DQ 0602而不是DR 2是所有种族群体中嗜睡症的更好标志物。2000年，西野博士和我与荷兰的拉默斯博士合作，发现在大多数情况下，脑脊液（CSF）中的下丘脑泌素1水平无法检测到，确定下丘脑泌素缺乏是发作性睡病的原因。在进行这项研究时，我们和Siegel博士的小组检查了死后的大脑，发现CSF下丘脑分泌素1的减少是继发于下丘脑中7万个产生下丘脑分泌素的神经元的损失。这一发现复兴了自身免疫假说，但直到2013年，证明下视丘分泌素细胞免疫靶向的尝试都失败了。此时，伊丽莎白·梅林斯博士和我发现发作性睡病的特征是存在对下丘脑分泌素片段（当被DQ 0602呈现时）具有自身反应性的CD 4 + T细胞。在报道嗜睡症病例是由接种疫苗和感染甲型流感2009 pH 1 N1（2009年爆发的一种新的大流行毒株）引发的之后，我们的研究小组还确定了pH 1 N1的一个小表位类似于下丘脑泌素，并且可能参与分子模拟。虽然还有很多工作要做，这些成就，建立下丘脑泌素缺乏症的原因嗜睡症，证明其自身免疫的基础，并显示下丘脑泌素和流感大流行株的序列之间的分子模拟，可能仍然是人类免疫学的经典。
Although narcolepsy was first described in the late nineteenth century in Germany and France, much of the research on this disorder has been conducted at Stanford University, starting with Drs. William C. Dement and Christian Guilleminault in the 1970s. The prevalence of narcolepsy was established, and a canine model discovered. Following the finding in Japan that almost all patients with narcolepsy carry a specific HLA subtype, HLA-DR2, Hugh Mac Devitt, F. Carl Grumet, and Larry Steinman initiated immunological studies, but results were generally negative. Using the narcoleptic canines, Dr. Nishino and I established that stimulants increased wakefulness by stimulating dopaminergic transmission while antidepressants suppress cataplexy via adrenergic reuptake inhibition. A linkage study was initiated with Dr. Grumet in 1988, and after 10 years of work, the canine narcolepsy gene was cloned by in 1999 and identified as the hypocretin (orexin) receptor 2. In 1992, studying African Americans, we also found that DQ0602 rather than DR2 was a better marker for narcolepsy across all ethnic groups. In 2000, Dr. Nishino and I, in collaboration with Dr. Lammers in the Netherlands, found that hypocretin 1 levels in the cerebrospinal fluid (CSF) were undetectable in most cases, establishing hypocretin deficiency as the cause of narcolepsy. Pursuing this research, our and Dr. Siegel’s group, examining postmortem brains, found that the decreased CSF hypocretin 1 was secondary to the loss the 70,000 neurons producing hypocretin in the hypothalamus. This finding revived the autoimmune hypothesis but attempts at demonstrating immune targeting of hypocretin cells failed until 2013. At this date, Dr. Elisabeth Mellins and I discovered that narcolepsy is characterized by the presence of autoreactive CD4+ T cells to hypocretin fragments when presented by DQ0602. Following reports that narcolepsy cases were triggered by vaccinations and infections against influenza A 2009 pH1N1, a new pandemic strain that erupted in 2009, our groups also established that a small epitope of pH1N1 resembles hypocretin and is likely involved in molecular mimicry. Although much remains to be done, these achievements, establishing hypocretin deficiency as the cause of narcolepsy, demonstrating its autoimmune basis, and showing molecular mimicry between hypocretin and sequences derived from a pandemic strain of influenza, are likely to remain classics in human immunology.
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影响因子：
29
作者：
Andlauer, Olivier;Moore, Hyatt;Jouhier, Laura;Drake, Christopher;Peppard, Paul E.;Han, Fang;Hong, Seung-Chul;Poli, Francesca;Plazzi, Giuseppe;O'Hara, Ruth;Haffen, Emmanuel;Roth, Thomas;Young, Terry;Mignot, Emmanuel
通讯作者：
Mignot, Emmanuel
影响因子：
5.6
作者：
Black, JL;Silber, MH;Slocumb, NL
通讯作者：
Slocumb, NL
影响因子：
10.6
作者：
Black, JL;Silber, MH;Slocumb, NL
通讯作者：
Slocumb, NL
流感病毒疫苗：2009年H1N1大流行的教训。
影响因子：
5.9
作者：
Broadbent, Andrew J.;Subbarao, Kanta
通讯作者：
Subbarao, Kanta
DOI：
10.1136/bmj.d5956
发表时间：
2011-10-12
期刊：
BMJ (Clinical research ed.)
影响因子：
--
作者：
Bardage C;Persson I;Ortqvist A;Bergman U;Ludvigsson JF;Granath F
通讯作者：
Granath F