Authors retract paper “confirming” that narcolepsy is an autoimmune disease

A group of researchers at Stanford and elsewhere is retracting a 2013 paper that another scientist told Nature was “one of the biggest things to happen in the narcolepsy field for some time.”

The Science Translational Medicine paper caused a buzz because it claimed to show that narcolepsy was an autoimmune disease. Here’s the notice:

A.K. De la Herrán-Arita and colleagues retract their Research Article “CD4+ T Cell Autoimmunity to Hypocretin/Orexin and Cross-Reactivity to a 2009 H1N1 Influenza A Epitope in Narcolepsy,” which appeared in the 18 December 2013 issue of Science Translational Medicine. The researchers report that they have been unable to reproduce the paper’s key findings. Specifically, they could not demonstrate a differential Enzyme-Linked ImmunoSpot response of CD4+ T cells from patients with narcolepsy compared to those from normal controls after exposure to the hypocretin peptides HCRT56–68 or HCRT87–99. Because the validity of the conclusions reported in the study cannot be confirmed, they are retracting the article.

Here’s the original abstract:

Narcolepsy, a disorder strongly associated with human leukocyte antigen (HLA)–DQA1*01:02/DQB1*06:02 (DQ0602), is characterized by excessive daytime sleepiness, cataplexy, and rapid eye movement sleep abnormalities. It is caused by the loss of ~70,000 posterior hypothalamic neurons that produce the wake-promoting neuropeptide hypocretin (HCRT) (orexin). We identified two DQ0602-binding HCRT epitopes, HCRT_56–68 and HCRT_87–99, that activated a subpopulation of CD4⁺ T cells in narcolepsy patients but not in DQ0602-positive healthy control subjects. Because of the established association of narcolepsy with the 2009 H1N1 influenza A strain (pH1N1), we administered a seasonal influenza vaccine (containing pH1N1) to patients with narcolepsy and found an increased frequency of circulating HCRT_56–68– and HCRT_87–99–reactive T cells. We also identified a hemagglutinin (HA) pHA1 epitope specific to the 2009 H1N1 strain, pHA1_275–287, with homology to HCRT_56–68 and HCRT_87–99. In vitro stimulation of narcolepsy CD4⁺ T cells with pH1N1 proteins or pHA1_275–287 increased the frequency of HCRT_56–68– and HCRT_87–99–reactive T cells. Our data indicate the presence of CD4⁺ T cells that are reactive to HCRT in narcolepsy patients and possible molecular mimicry between HCRT and a similar epitope in influenza pH1N1, pHA1_275–287.

The paper has been cited nine times, according to Thomson Scientific’s Web of Knowledge.

We asked the paper’s corresponding authors, Stanford’s Emmanuel Mignot and Elizabeth Mellins, how the issues with the findings came to light. 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.

DQ refers to a type of protein on immune system cells, while the ELISPOT assay measures certain kinds of immune system activity.

Mellins tells Retraction Watch:

All the work in question was done in the Mignot lab and then could not be repeated in the Mignot lab. As you can imagine, it is important to me that this be known because I am an immunologist and the work at issue could be mistakenly attributed to my lab.

An aside: A heads-up about this retraction actually appeared online last week, in some versions of the Science Translational Medicine online table of contents. That headline wasn’t linked to anything, however, and the journal tells us it was a snafu.