Currently, the theory that narcolepsy is of a neurodegenerative autoimmune cause is the most widely supported among narcolepsy researchers, but the data to support this theory has been somewhat lacking (admittedly in part because there are simply fewer studies on narcolepsy than other autoimmune diseases).
In the first case, narcolepsy has a high HLA association, which is seen with other autoimmune diseases. In fact, narcoleptics with cataplexy have a 90% chance of being a carrier of the gene HLA DQB1*0602, an association among the highest of all autoimmune diseases.
Secondly, there is a reduction of hypocretin (a.k.a. orexin) producing neurons in the hypothalamus of narcoleptic patients, which leads to a reduction of hypocretin in the cerebrospinal fluid (CSF). While it is still possible that the neurons are there and just not producing hypocretin, current data suggests there is a total loss of the neurons according to some imaging data via Mignot et al, which is covered in a separate post. In spite of this lack of hypocretin, no antibody to neurons or hypocretin have been found in narcoleptic patients.
So, if narcolepsy is indeed autoimmune and neurodegenerative, where is the proof?
Back in 2010, a paper came out in the Journal of Clinical Investigation suggesting that there was an association with narcolepsy and antibodies to a protein called Trib2 (tribbles homolog 2). This work was redone by Mignot et al. and also replicated by a Japanese group, demonstrating that the antibodies seen in the study were found in multiple populations, including those of different ethnic origin. While tribbles is made by many cells in the brain, hypocretin-producting neurons make larger amounts of it, and it is theorized that these neurons could be preferentially attacked by the immune system.
In short, they found that 25% of individuals with the so-called narcolepsy gene (HLA DQB1*0602) with cataplexy had antibodies to Trib2, while antibodies to Trib2 were rare in individuals without cataplexy or controls. In addition, anti-trib2 antibody positivity correlated with disease progression, with antibody being higher in those individuals who were more recently diagnosed.
While the findings themselves are not disputable, it does beg the question of where the antibodies are coming from in the first place. Antibodies do not arise de novo to do the body harm, but rather are products of a sustained encounter by the body with antigen under the context of inflammation. Antibodies are products of adaptive immunity; that is, B cells which have been activated through their B cell receptor in an antigen-specific manner, and have had the antigen presented to them by an antigen presenting cell. So the fact that antibodies against Trib2 are found does not necessarily mean that Trib2 is the primary target of the immune response, although it could be. In reality, antibodies to Trib2 in narcoleptic patients could arise by several mechanisms, and may be secondary to neuronal cell death. To me, this seems the most plausible explanation, as Trib2 is normally found intracellularly, and it is widely expressed in the brain.
In the first place, it is clear that an individual (probably) must be genetically susceptible to developing narcolepsy at some point in their lives. These individuals generally harbor the HLA DQB1*0602 gene, or a TCRalpha chain polymorphism. On this background of genetic predisposition, environmental factors begin to play a role, as they do in other autoimmune diseases. Whatever the inciting factor may be, the role of Trib2 antibodies is not clear, despite their association in narcoleptic patients. It is entirely possible that already damaged neurons are engulfed by the innate immune systems phagocytic cells, and their contents presented to adaptive immune systems B cells and T cells, which then coordinate to produce antibody to multiple components of the damaged neurons, one target of which may be Trib2.
While the finding of a self-protein or “autoantigen” response in narcolepsy is compelling, and serves an important piece in bolstering the autoimmune theory of disease progression in narcolepsy, it is by no means necessarily the causative agent or end of the story, particularly for individuals who do not have cataplexy or the classical HLA DQB1*0602 gene. In this way, although an autoantibody has been found in some patients, a Trib2 antibody response is clearly not necessary or sufficient to cause narcolepsy in all cases.
In future studies, it will be interesting to determine if other autoantibodies will be found, or if there are multiple self-targets that may give rise to narcolepsy symptoms.