# What Causes Human Narcolepsy?

> **NIH VA I01** · VA GREATER LOS ANGELES HEALTHCARE SYSTEM · 2020 · —

## Abstract

The title of this grant asks a question that most sleep researchers might think has been answered. Our paper
and Mignot’s group’s paper, both appearing in September 2000, showed that human narcolepsy is linked to a
loss of hypocretin/orexin (Hcrt) cells. We reported a 90% loss, with all narcoleptics having surviving cells, a
finding that has been repeatedly replicated. We know that, whereas the animal models of narcolepsy are
caused by genetic changes, the human disorder is not. HLA (human leukocyte antigen) linkage to narcolepsy
suggests that it is an autoimmune disease. The HLA, DQB1*0602 genotype is present in 85-95% of human
narcoleptics, but is also present in 20-30% of the general population. The incidence of narcolepsy is about 1 in
2,000. In most cases, identical twins living in the same household are discordant for narcolepsy. Various
correlations, much weaker than the HLA relation, have been reported between human narcolepsy and T cell
subtypes, antibodies to Tribbles, antibodies to the Hcrt receptor-2, strep infection and insect bites. But, despite
many attempts, no one has convincingly shown that narcolepsy can be induced in animals by immune system
manipulation. Recently, we and Scammell’s laboratory simultaneously reported a peculiar and massive
increase in the number of detectable histamine (histidine decarboxylase) cells in human narcoleptics. This
finding has important implications for the regulation of neurotransmitter expression and brain histamine
function in general, and may provide an insight into other disorders where inflammation has been linked to
pathology, such as Alzheimer’s and Parkinson’s. It also resonates with some earlier work we did showing
greatly increased glial fibrillary acidic protein (GFAP), indicative of inflammation, in the histamine cell region of
human narcoleptics. Although the peripheral role of histamine in inflammation is well understood, hence the
widespread use of antihistamines, it is also known that histamine is involved in CNS inflammation and toxicity.
Histamine opens the blood brain barrier. Furthermore Hcrt cells have been shown in in vitro studies to be much
more likely to die from insult than adjacent hypothalamic cells. This suggests that the apparent selectivity of
Hcrt cell loss that we and others have reported may be a reflection of the sensitivity of these cells to
inflammation, rather than evidence for specific immunological targeting. We propose that the greatly increased
number of histamine cells in human narcoleptics may mediate the destruction of Hcrt cells that causes
narcolepsy. The mouse genetic work focusing on Hcrt may have discouraged a more comprehensive
investigation of whether other regions of the brain are damaged or altered in human narcolepsy. We propose
to investigate this hypothesis by looking for other evidence of damage explainable by histamine attack in
narcoleptics. We will compare the damage present in human narcolepsy to that present in 4 animal genetic
models...

## Key facts

- **NIH application ID:** 9815406
- **Project number:** 5I01BX001753-08
- **Recipient organization:** VA GREATER LOS ANGELES HEALTHCARE SYSTEM
- **Principal Investigator:** JEROME M SIEGEL
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2012-10-01 → 2020-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9815406

## Citation

> US National Institutes of Health, RePORTER application 9815406, What Causes Human Narcolepsy? (5I01BX001753-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9815406. Licensed CC0.

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