The Lancet has spoken! Very interesting article if you are following the controversy over autoimmune or not autoimmune, and
if you can plough through some very long words. I guess this is the definitive word on the subject for the time being.
http://www.thelancet.com/journals/laneur/article/PIIS1474-4422(14)70168-1/fulltext?rss=yes
Nel, the link said Not Found, but is it because of the Lancet access technicalities? I’m in the US. Do we have access thru NORD?
I got "article not found" too, but if you search for 'autoreactivity' and 'narcolepsy', it will show you the article. Let's see if this link works:
http://www.thelancet.com/journals/laneur/article/PIIS1474-4422(14)70168-1/fulltext
Carol said:
Nel, the link said Not Found, but is it because of the Lancet access technicalities? I'm in the US. Do we have access thru NORD?
https://www.google.com/url?rct=j&sa=t&url=http://www.thelancet.com/journals/laneur/article/PIIS1474-4422(14)70168-1/fulltext%3Frss%3Dyes&ct=ga&cd=CAEYACoTNjAwMzY4MjgzMDQxMjA5MTA2MzIaNTc0NWE1N2JmY2JjNjczNDpjb206ZW46VVM&usg=AFQjCNEHVWzjNGq64g6i_EjVy9XNWAWc7A
I ca never understand how they manage to restrict it to one part of the world. Does this work for the US? Please let me know.
Sorry All,
The link does not work for me also in the USA?
"Cut and Paste might work"
One day at a time,
Ranger
It was 3 am here when I posted so I didn’t clock that it was an incomplete link. So frustrating but it is copyrighted and I am reluctant to just cut and paste. If you use my link and their searchbox to look for Narcolepsy does that work from the US? 4 hours later on just 3 hours sleep I can’t get my head round it but will keep trying. What are the rules about breaching copyright I wonder? It seems to me that once it is on the Internet copyright rules should go out the window.
Follow the link, and when you get the 'article not found' message search for 'narcolepsy' and 'autoreactivity'.
Thanks pwntek. Perhaps I am just being a wimp in not cutting and pasting.
I will watch out for what other organisations do with it. I doubt I would get permission to post it from the Lancet as it stresses that it is intended for health professionals.
After googling copyright law I believe that reproducing this article comes under the cover of ‘fair use’ so here it is
Does autoreactivity have a role in narcolepsy?
Markku Partinen a b, Birgitte Rahbek Kornum d e, Giuseppe Plazzi f g, Poul Jennum e, Ilkka Julkunen h i, Outi Vaarala c j
In our recent Review of the sleep disorder narcolepsy,1 we included the hypothesis that type 1 narcolepsy is an autoimmune disease. As part of this discussion, we identified 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,2 which has since been retracted. The retraction was based on an inability of the researchers to reproduce their finding of T-cell reactivity towards hypocretin and H1N1 antigenic epitopes.2 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-specific autoantibodies.3 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-melanocyte-stimulating hormone (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, Kleine-Levin 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.3 Intracerebroventricular injection of immunoglobulins from patients with anti-tribbles 2 antibodies also affected sleep patterns in mice.4 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,2 direct evidence of autoimmunity (table 2 in our Review) is weaker than the evidence seemed to be at the time of writing.1
The retraction of the article2 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 pathogenesis of H1N1 virus infection-induced narcolepsy. Other non-proteinaceous 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, final 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.
We declare no competing interests.
References
1 Partinen M, Kornum BR, Plazzi G, Jennum P, Julkunen I, Vaarala O. Narcolepsy as an autoimmune disease: the role of H1N1 infection and vaccination. Lancet Neurol 2014; 13: 600-613. Summary | Full Text | PDF(551KB) | CrossRef | PubMed
2 De la Herrán-Arita AK, Kornum BR, Mahlios J, et al. Retraction of the Research Article: “CD4+ T cell autoimmunity to hypocretin/orexin and cross-reactivity to a 2009 H1N1 influenza A epitope in narcolepsy”. Sci Transl Med 2014; 6: 247rt1. PubMed
3 Bergman P, Adori C, Vas S, et al. Narcolepsy patients have antibodies that stain distinct cell populations in rat brain and influence sleep patterns. Proc Natl Acad Sci USA 2014; 111: E3735-E3744. PubMed
4 Katzav A, Arango MT, Kivity S, et al. Passive transfer of narcolepsy: anti-TRIB2 autoantibody positive patient IgG causes hypothalamic orexin neuron loss and sleep attacks in mice. J Autoimmun 2013; 45: 24-30. CrossRef | PubMed
a Helsinki Sleep Clinic, Vitalmed Research Centre, Helsinki, Finland
b Department of Clinical Neurosciences, University of Helsinki, Helsinki, Finland
c Institute of Clinical Medicine, University of Helsinki, Helsinki, Finland
d Molecular Sleep Laboratory, Department of Diagnostics, Glostrup Hospital, Glostrup, Denmark
e Danish Center for Sleep Medicine, Department of Clinical Neurophysiology, University of Copenhagen, Glostrup Hospital, Glostrup, Denmark
f Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy
g IRCCS Istituto delle Scienze Neurologiche, Bologna, Italy
h Department of Virology, University of Turku, Turku, Finland
i Department of Infectious Disease Surveillance and Control, National Institute for Health and Welfare, Helsinki, Finland
j Respiratory, Inflammatory and Autoimmune Diseases, Innovative Medicine, AstraZeneca, Mölndal, Sweden
Thanks Nel! I’m going to read it again at least twice so I can get it.
Thank you Nell!
For posting, I also tried the link again and the article came up in the search box -(USA)
Ranger
Ranger said:
Sorry All,
The link does not work for me also in the USA?
"Cut and Paste might work"
One day at a time,
Ranger
Nel, thank you for posting this for us to read. It is quite interesting to see how they have now taken back the statements they made before for which they held so much confidence. Realistically, they have no clue. I have a positive genetic marker for both the HLA DQA1*01:02 and DQB1*06:02. I tend to believe that there is an immunological reaction that causes us to develop Narcolepsy. It will be interesting to see what they decided as their final decision on the matter.