Does autoreactivity have a role in narcolepsy?

Abstract

In our recent Review of the sleep disorder narcolepsy, we included the hypothesis that type 1 narcolepsy is an autoimmune disease. As part of this discussion, we identifi ed hypocretin as a possible target of an autoimmune attack leading to narcolepsy. At the time of writing, this idea was supported by data from a report by De la Herrán-Arita and colleagues, which has since been retracted. The retraction was based on an inability of the researchers to reproduce their fi nding of T-cell reactivity towards hypocretin and H1N1 antigenic epitopes. In view of this retraction, no direct evidence exists of autoreactive T cells playing a part in the pathophysiology of narcolepsy. The autoimmune hypothesis of narcolepsy, however, is based on many other observations described in our Review. Briefly, these observations include the following: a strong association with HLA class II DQB1*06:02 and genetic associations with other genes involved in the regulation of host immune responses (such as TCRα, OX40L, CTSH, and P2RY11); and environmental associations with upper airway infections, Streptococcus pyogenes, and, importantly, influenza A virus H1N1 vaccination and infection. Furthermore, several articles have reported the presence of autoimmune antibodies in serum samples from patients with narcolepsy. A common theme in these studies is that only a minority of patients is seropositive for the autoantibody under investigation, which is the case for hypocretin antibodies and tribbles 2 antibodies, and some patients were recently shown to have other brain-specifi c autoantibodies. Three immunohistochemical patterns were shown in rat brain. For one of these antibody staining patterns, the target epitope was the common C-terminal epitope of neuropeptide glutamic acid-isoleucine/α-melan o c y t e s t i m u l a t i n g h o r m o n e (NEI/αMSH); for the others, the target epitope is unknown. None of the autoantibodies mentioned targeted hypocretin neurons and, curiously, these autoantibodies were detected in the serum of patients with other sleep disorders such as idiopathic hypersomnia, KleineLevin syndrome, obstructive sleep apnea, delayed sleep phase, restless legs syndrome and periodic limb movements and parasomnias, and even in some healthy controls. The results argue against these autoantibodies being related directly to the pathogenesis of narcolepsy, but NEI/αMSH IgG antibodies from a patient with narcolepsy affected sleep patterns when injected intracerebroventricularly in mice, which suggests some functional relevance. Intracerebroventricular injection of immunoglobulins from patients with anti-tribbles 2 antibodies also aff ected sleep patterns in mice. These results support the idea that autoantibodies might be involved in the symptomatology of narcolepsy. Autoantibodies might be produced as part of a secondary immune response to the initial neuronal damage in narcolepsy, or they might contribute to the development of narcolepsy by an as yet unknown mechanism. Reports that the H1N1 Pandemrix vaccinations and H1N1 infection have been associated with an increased incidence of narcolepsy strongly point to an immune-mediated pathogenesis but since the retraction of the report by De la Herrán-Arita and colleagues, direct evidence of autoimmunity (table 2 in our Review) is weaker than the evidence seemed to be at the time of writing. The retraction of the article means that we do not have any clear evidence for molecular mimicry between hypocretin and H1N1 virus. A paucity of evidence, however, does not exclude the possibility that molecular mimicry might be at play in the patho genesis of H1N1 virus infection-induced narcolepsy. Other non-protein aceous components of the vaccine might also have an important role. The notion that autoimmune antibodies have a role in the pathogenesis of narcolepsy is supported by many studies. However, fi nal proof of autoimmunity directed towards hypocretin neurons is still missing, because autoreactive T cells against hypothalamic neurons or neuronal molecules have not been shown. Additionally, autoantibodies against neuronal or other host factors have been shown only in a subgroup of patients. No convincing animal model of narcolepsy-type disease exists to show that the disorder can develop from the transfer of autoreactive T cells or antibodies to host factors. Future research should aim to address these gaps in our knowledge.

DOI: 10.1016/S1474-4422(14)70168-1

Cite this paper

@article{Partinen2014DoesAH, title={Does autoreactivity have a role in narcolepsy?}, author={Markku Partinen and Birgitte Rahbek Kornum and Giuseppe Plazzi and Poul Jennum and Ilkka Julkunen and Outi Vaarala}, journal={The Lancet. Neurology}, year={2014}, volume={13 11}, pages={1072-1073} }