These findings indicate for the first time the presence of identified and autoreactive antibodies in human narcolepsy. High Trib2-specific antibody titers (>2.5–3 SD) were found in narcolepsy with cataplexy patients exclusively, but we did not find an overall difference between narcolepsy with and without cataplexy. Furthermore, antibody titers correlate both with the severity of cataplexy and sleepiness, suggesting that the 2 conditions might share a similar pathophysiology. Note that hypocretin deficiency is also found in up to 20% of narcolepsy without cataplexy patients and a recent study found 30% hypocretin neuron loss in a narcolepsy without cataplexy patient (20
), corroborating our finding that Trib2-specific antibodies might target hypocretin neurons in both groups but at lesser extend in narcolepsy without cataplexy.
Although neither Trib2 nor any other peptide was found specific to hypocretin neurons, given the low level of Trib2 expression, but its specific enrichment in hypocretin neurons, it may be that in addition to other sporadic neurons, hypocretin neurons are the major target of the autoimmune attack, resulting primarily in narcolepsy symptoms. Nevertheless, other colocalized and/or enriched transcripts, such as Igf2bp2
, might play some functional role in hypocretinergic neurotransmission, as is also suggested for Igfbp3
). Trib2-specific antibodies seem to predominate in narcolepsy patients, with recent disease onset further suggesting that these antibodies are pathogenic. Although only 14% of all our narcolepsy patients had Trib2-specific antibody titers over 2 SD above controls, 30% of patients with an interval from disease onset of less than 1 year had titers greater than 2 SD. Trib2-specific antibody titers sharply decreased within the first 2–3 years of disease onset but remained significantly higher than controls up to 30 years, suggesting that narcolepsy might be triggered by an acute autoimmune process and not a recurrent process as in many other autoimmune disorders. Together with HLA and T cell receptor α associations, our findings strongly suggest that narcolepsy can be an autoimmune disorder.
Obviously not all narcolepsy patients have high Trib2-specific antibody titers even close to the disease onset, suggesting more complex mechanisms leading to the development of the condition. The time course of a potential autoimmune process targeting hypocretin neurons may vary from patient to patient. Some patients may have a rapid course with major deficit in hypocretin production, resulting in sudden appearance of excessive daytime sleepiness and cataplexy, while others may have a slower course, resulting in excessive daytime sleepiness followed, up to several years later, by cataplexy when the number of hypocretin neurons reaches a critical value. It may also be that Trib2 is not the only autoantigen and/or not the most specific one. As in other autoimmune disorders (e.g., type 1 diabetes), several autoantibodies may be involved but not all are detectable in the majority of patients. Finally, although we have showed here for the first time that an autoimmune reaction can be detected, this does not imply that autoimmunity is involved in all forms of narcolepsy.
We have reported several cases of narcolepsy treated with intravenous immunoglobulins (IVIg) soon after the first symptoms with unexpected positive results, suggesting that the autoimmune process may be counteracted if treated early (21
). Most recently, we have reported a narcolepsy patient with hypocretin deficiency, in whom the CSF hypocretin level normalized after IVIg treatment (23
). Our present findings strengthen the autoimmune hypothesis and suggest that patients with an early diagnosis and high Trib2-specific antibody titers might benefit from immunotherapy.