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.