Today is a disappointing day in the narcolepsy community.The scientific
manuscript reported to have “confirmed” narcolepsy as an autoimmune disease has been formally retracted.
The retraction notice states, “The researchers report that they have been unable to reproduce the paper’s key findings.” (source www.retractionwatch.com)
The paper, entitled “CD4+ T cell autoimmunity to hypocretin/orexin and cross-reactivity to a 2009 H1N1 influenza A epitope in narcolepsy,” and published by Science Translational Medicine in December 2013, caused more than media ripple. Submitted by co-senior authors Mellins and Mignot and collaborators, the original article was highlighted in more than 100 news and press releases, and received featured articles and posts on major news sites including Nature News, Scientific American, The Huffington Post, Medical News Today, National Geographic, Psychology Today — it even made waves in The New Reddit Journal of Science.
The article has been cited 4 times since it’s publication in Dec. 2013, according to PubMedCentral.
At the time of publication, the paper was reported to demonstrate immune cross-reactivity between a flu antigen and the orexin protein — so-called molecular mimicry. In layman’s terms, if an immune response was generated recognizing flu antigen (such as during natural infection or in a vaccine), that immune response could also target neurons in the brain expressing orexin. Specifically reported was (1) characterization of narcolepsy-specific auto-immune CD4+ T cells, (2) their corresponding epitopes, and (3) evidence of a mimicry-based mechanism potentially explaining the association between narcolepsy and influenza infection.
Orexin is a hormone critical for maintaining wakefulness. Loss of orexin-producing neurons is believed to be the primary cause of symptoms in many individuals with narcolepsy. You can learn more about narcolepsy here.
These results were poised to explain the increases in narcolepsy following Pandemrix vaccinations in Europe during the 2009 H1N1 influenza pandemic. Earlier studies suggested that the adjuvant used in the Pandemrix vaccine, AS03 (which was not approved for use in the United States) may have been to blame.
The findings of the paper in question caused a stir because for many years studies have failed to demonstrate orexin immunoreactivity or a cell-specific immune response to orexin producing neurons, despite the fact that narcolepsy contains other “autoimmune signatures” including a high (90%) association with a specific HLA genotype (HLA-DQB1*0602), and a strong association with the T-cell receptor alpha locus, among others.
A quote from the Nature News article summarizes the general sentiment well:
“Thomas Scammell, a neurologist at Harvard Medical School in Boston, Massachusetts, says that the results are welcome after “years of modest disappointment”, marked by many failures to find antibodies made by a person’s body against their own hypocretin. “It’s one of the biggest things to happen in the narcolepsy field for some time.”
Co-senior author of the study Mellins is quoted:
“Up till now, the idea that narcolepsy was an autoimmune disorder was a very compelling hypothesis, but this is the first direct evidence of autoimmunity. I think these cells are a smoking gun,”
With many basic science manuscripts which make significant discoveries, the excitement is often confined to the scientific community. What is different about this paper is that the enthusiasm bubbled over into patient circles and prominent outreach organizations. Narcolepsy has been long suspected to be of immune origin, and the fact that this theory hasn’t been yet confirmed has meant the often stimatized patient population continues to struggle with being incorrectly diagnosed with mental and behavioral disorders, often up to 15 years before receiving a correct diagnosis. One of the important advancements that might have been made from the discoveries of this paper was the development of a new diagnostic test for narcolepsy, which could improve diagnosis and time-to-diagnosis for patients.
Interestingly, a letter written by inventors of Pandemrix was submitted in February 2014 stating that “CD4+ T cell cross reactivity” was part of a “research plan.” (update 9-9/30/14: the letter has since been retracted). The research plan, authored by GlaxoSmithKline researchers is entitled “Narcolepsy and A(H1N1)pdm09 vaccination: Shaping the research on the obeserved signal” was published in December 2013. In it, they listed key areas of research needed to fill the information gap about how the Pandemrix AS03-adjuvanted influenza vaccine could have caused increases in narcolepsy:
Therefore, the following key areas of research can be identified, (1) characterization of hypothetical narcolepsy-specific auto-immune CD4+ T cells, (2) mapping epitopes of such T cells, and (3) evaluating potential mechanisms that would enable such cells to gain access to the hypothalamus. Addressing these questions could further our understanding of the potential links between narcolepsy and A(H1N1)pdm09 vaccination and/or infection. Of particular interest is that any evidence of a mimicry-based mechanism could also explain the association between narcolepsy and A(H1N1)pdm09 influenza infection.
As a reminder, the reported findings of the now retracted “CD4+ T cell cross reactivity…” paper were: (1) characterization of narcolepsy-specific auto-immune CD4+ T cells, (2) their corresponding epitopes, and (3) evidence of a mimicry-based mechanism potentially explaining the association between narcolepsy and influenza infection.
A timeline of events is shown below:
It should be noted that the publications of GlaxoSmithKline researchers did not reportedly contribute to the rectraction of “CD4+ T cell Autoimmunity…”
According to RetractionWatch.com, Mignot has said regarding the retraction:
Mignot tells us:
We were just continuing our work based on the finding, trying to establish it as a diagnostic test, but could not replicate it. No other work is affected, and in fact the DQ binding studies of that article are perfectly fine. Only the [Enzyme-Linked ImmunoSpot (ELISPOT)] results are in question.
The retraction notice first appeared on the mobile site of Science Translational Medicine on July 23, 2014, but linked to a “Content Not Found” page. The “Retraction” section was missing from the non-mobile version of the website, and no reply was received when the Editors of STM were contacted to clarify whether the article had been retracted or not.
In spite of this disappointing turn of events, the community is hopeful that we will continue to move forward in our pursuit of understanding the molecular mechanisms of narcolepsy and that these developments will lead to improved diagnostic tools and treatments.
CD4+ T Cell Autoimmunity to Hypocretin/Orexin and Cross-Reactivity to a 2009 H1N1 Influenza A Epitope in Narcolepsy. Sci. Transl. Med. 5, 216ra176 (2013).
M. Brandt. “Narcolepsy is an Autoimmune Disorder, Researcher Says.” Stanford Medicine News Center. (2009.)
K. Conger. “H1N1-triggered narcolepsy may stem from ‘molecular mimicry,’ study finds.” Standford Medicine News Center. (2013)
E. Yong. “Narcolepsy confirmed as autoimmune disease.” Nature News. (2013).
S. Harris. Notes on Narcolepsy. Psychology Today. (2012).
J. Hallmayer et al. Narcolepsy is strongly associated with the T-cell receptor alpha locus. Nature Genetics. 41, 708 – 711 (2009)