Researchers have gained new insights into the autoimmune roots of narcolepsy – findings that will allow both easier diagnosis of the disorder, and “a model to understand other autoimmune disorders,” Stanford University’s Emmanuel Mignot told BioWorld Today.

Mignot is the senior author of a study reporting that individuals with narcolepsy had helper T cells that were reactive both to two separate peptide fragments. One was a piece of hypocretin, a wakefulness-promoting hormone that is present only in the neurons that are lost in narcolepsy. The other was a similar peptide that is part of the H1N1 influenza virus, and was used in vaccines during the 2009 pandemic. They published their results in the Dec. 19, 2013, issue of Science Translational Medicine.

There had been suggestions previously that those neurons die under autoimmune attack, but no direct experimental support for this idea.

Mignot and his team looked at the responses of helper T cells to the H1N1 virus because epidemiological studies have shown that vaccination with the anti-H1N1 Pandemrix vaccine (Glaxosmithkline plc) increased the risk of developing narcolepsy in Europe. (For reasons that are not entirely clear – possibly because no adjuvant was used – vaccination in the U.S. did not lead to such an increased risk.)

Screening T cells from narcolepsy patients, the team found that such patients – but not healthy controls – had T cells that reacted to two epitopes that were part of the hypocretin protein. Moreover, exposure to H1N1 antigens could stimulate those same T cells.

Scientifically, the findings are the first direct confirmation of the “mimicry hypothesis” – the idea that autoimmune disorders get their start through cross-reactivity of T cells that start by responding to a pathogen. That idea, Mignot said, has been around for a while. But “no one has ever found a clear example” of such mimicry.

Mignot and his team are currently working out the chain of events that leads from cross-reactive helper T cells to dead hypocretin neurons. They have not been able to detect autoantibodies to those neurons; Mignot suspects that the helper T cells are affecting killer T cells that ultimately go after the neurons, but so far, this is speculation.

Another open question is what sort of cross-reactivity might have triggered narcolepsy before 2009. H1N1 was able to become a pandemic precisely because the global population had no pre-existing immunity to the strain, and so older triggers must exist.

Epidemiological data from Asia shows seasonal variations in the risk of coming down with narcolepsy that would be consistent with other flu strains leading to cross-reactivity. There is also evidence that infection with a specific streptococcus strains increased narcolepsy risk. But the specific epitopes behind all these associations have yet to be identified.

Mignot said that in a practical sense, the biggest short-term implication of the work is that there is now a blood test for narcolepsy, albeit for the time being, only a research test. Still, the existence of such a test is a vast improvement over current diagnostic methods – lumbar puncture or complicated and expensive sleep tests – and is likely to change clinical practice.

In the long run, such a test could possibly allow the prevention of outright narcolepsy, if individuals with hypocretin-reactive T cells can be identified early, before those T cells have killed hypocretin-containing neurons.

Scientifically, the work also is another piece of evidence that the immune system is less specific than currently thought to be. Growing evidence suggests that cross-reactivity is actually fairly common for both T and B cells, long held to be magic bullets that hone in on one target and one target only, to be cross-reactive to similar epitopes.

Mignot said that this lack of complete specificity is likely an advantage overall, because it can provide a level of pre-existing immunity to pathogens a person has never encountered, potentially giving the host a critical advantage at first contact. But “the price you pay is that sometimes it bleeds through to an autoimmune disease.”