猝睡症__勇士部落

 Emmanuel J. M. Mignot

Narcolepsy affects 1 in 2,000 people. It is characterized by excessive daytime sleepiness, cataplexy and abnormal transitions from wakefulness to REM sleep. Recent findings have shown that the disorder is caused by the loss of ∼70,000 hypothalamic neurons (Peyron et al., 2000). These neurons produce an excitatory neuropeptide called hypocretin/orexin. The lack of this peptide results in narcolepsy, in both humans and animals. The hypocretin system is now the object of pharmaceutical efforts in the area of sleep and sleep disorders.

The cause of the hypocretin cell loss is the subject of intense research. Narcolepsy is tightly associated with human leukocyte antigen (HLA) DQB1*0602 (Mignot et al., 2001), suggesting an autoimmune mediation. Despite decades of investigations, however, no definitive evidence has ever been found. Recently, a genome wide association study (GWAS) was completed which found a genetic association with Rs1154155 within theT-cell receptor alpha (TCRα) locus across multiple ethnic groups (Asians, Caucasians, African American) (Hallmayer et al., 2009). Since the TCR is the receptor for HLA-peptide presentation, this result suggests autoimmunity. Interestingly, another study recently found an increased prevalence of streptococcal infection markers in onset cases of narcolepsy (Aran et al., 2009). As streptococcal infections are known to trigger other autoimmune manifestations, e.g., Sydenham's chorea and rheumatic heart disease, narcolepsy may also be a post-streptococcal autoimmune condition.

Interestingly, narcolepsy onset is not associated with detectable inflammation. We suggest that in narcolepsy, the immune-mediated destruction of hypocretin cells is selective and self-limited, without significant epitope-spreading. Limited epitope spreading may be a feature of neurons as an immune-protected target, and could explain difficulties in detecting autoimmune abnormalities. The fact that HLA class II expression in neurons remains constantly repressed (unlike in glial cells), even in the face of local inflammation, may be important. The specificity of this process may also explain the genetic association with TCRs, an association not found in other autoimmune diseases. In this model, Rs1154155 or a tightly linked marker within the TCR Jα region, fa-vors the occurrence of a very specific V-J TCRα pathogenic T-cell clone recombinants or marks a coding change within a J segment that alters TCRα-peptide binding.

If narcolepsy is a selective autoimmune brain disease, it raises the possibility that other diseases remain to be discovered. The fact that hypocretin lesions can produce a clinically very easily identifiable phenotype (narcolepsy-cataplexy) may have made these discoveries possible. It is likely that other brain area selective autoimmune diseases (with selective neuronal cell loss) do occur but have less specific clinical effects, such as psychiatric manifestations. The recent finding that HLA is a susceptibility locus for schizophrenia and bipolar disorder in large scale GWAS studies provide some support for this concept (Stefansson et al., 2009). We hope that in time, narcolepsy will not only inform us about sleep, but about other autoimmune diseases of the brain.

Emmanuel J. M. Mignot is the Craig Reynolds Professor of Sleep Medicine, Professor of Psychiatry and Director of the Center for Narcolepsy at Stanford University. He is a world-renowned expert in sleep medicine, having discovered the cause of narcolepsy, a lack of hypocretin in the brain. Dr. Mignot applies basic science techniques, such as genetics, pharmacology and molecular biology, to the study of sleep disorders, most notably sleep apnea and narcolepsy. He also directs a specialized consultation devoted to the evaluation of patients with narcolepsy and hypersomnia.
mignot@stanford.edu

origin: http://www.frontiersin.org/narcolepsyasamodel/