Recent Research In Narcolepsy

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Figure 1. Structure of DQB1*0602 allele. Image Source: HLA-DQB1

In recent years, significant scientific breakthrough has been made in understanding the cause of narcolepsy. One aspect of narcolepsy being currently researched is what makes narcolepsy an autoimmune disease. It is currently known that there is an autoimmune basis for the disease based on T cell activation by H1N1 epitopes (which mimic hypocretin peptide sequences) that result in damage to the hypocretin neurons, a main cause of narcolepsy. One specific gene hypothesized to be involved in an immune response is DQB1∗06:02 (Figure 1) [1]. This gene is part of the Human Leukocyte Antigen (HLA) system, which is involved in immune system function, as well as protection against diseases, in humans. Tafti et al. investigated the HLA, DQB1∗06:02, in narcoleptic patients. The authors found that DQB1*06:02 positive patients had a 251-fold higher risk of having narcolepsy. In addition, 99.32% of patients with narcolepsy in the study had this specific HLA gene variant [1]. Along with the gene DQB1*06:02, four additional DQB1 genes are involved in immune system protection against narcolepsy. These are DQB1*06:03, DQB1*05:01, DQB1*06:09 and DQB1*02 [2]. In turn, the DQB1 locus is thought to be involved greatly in causing a genetic predisposition to narcolepsy. Activation of DQB1*0602 is thought to activate the immune system’s destruction of hypocretin cells [1].

As an autoimmune disease, one current area of research involving narcolepsy is the investigation of environmental factors, such as bacterial infections, which may be causing narcolepsy [3]. In addition, the autoimmune hypothesis is supported by studies that account for an increase in the occurrence of narcolepsy in children and adolescents in several European countries (ie. Finland, Sweden) after the use of the H1N1 vaccine [4, 5]

1.1 Auto-immunity and narcolepsy

Similar to other autoimmune disorders, narcolepsy also develops as a result of both genetic factors (ie. having the DQB1*06:02 allele), as well as environmental factors. For instance, a study found that from sixteen monozygotic twin pairs, only 25 to 31% developed narcolepsy [6]. This finding is suggestive of environmental factors playing a role in the development of narcolepsy in certain individuals, who have a genetic disposition to the disease. As an autoimmune disease, one current area of research involving narcolepsy is the investigation of environmental factors, such as bacterial infections, which may be causing narcolepsy. In many autoimmune diseases, streptococcal infections are known to cause an autoimmune response. For instance, rheumatic fever is an example of an autoimmune disease, which is caused by post-streptococcal infection antigens triggering cardiac inflammation [7].

1.1a Auto-immunity and environmental factors

In a study in 2009, Aran et al. investigated the effect of Streptococcus pyogenes and Helicobacter pylori infections on patients with narcolepsy. The study consisted of 200 participants with narcolepsy, all having the DQB1*06:02 gene variant, and all having low hypocretin levels. The authors concluded that streptococcal infections are involved in causing a considerable environmental trigger for narcolepsy. However, for H. pylori bacteria, the study found that from the 200 narcoleptic participants, only 9.5% had antibodies against H. pylori. Where as, from the 200 narcoleptic participants, 34.5% had antibodies against β hemolytic streptococcus. This finding showed that H. pylori bacteria do not play a role in the development of narcolepsy, but Streptococcus bacteria do [3]. This study was an important one because it was the first of its kind to investigate environmental factors, such as bacterial infections, and their role in the development of narcolepsy. The findings of this study have important implications for the diagnosis, treatment, and prevention of narcolepsy.

1.1b T-cell activation through molecular mimicry

An explanation for why the body initiates an autoimmune response and destroys hypocretin cells was also propped by Aran et al. The authors explained that in rheumatic fever, the degree of similarity between Streptococcus bacteria and cardiac antigens confuses the immune system, which as a result, causes cardiac inflammation. The structural similarity between the host antigens and bacterial antigens is referred to as molecular mimicry. Similarly, the authors propose that this concept of molecular mimicry is what causes streptococcal infections to be able to destroy hypocretin cells, and in turn, cause narcolepsy [3].

Example of molecular mimicry in post-streptococcal infection
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Figure 2. Homology between streptococcal bacteria antibodies, SLO, and host antibodies, PDI.
Adapted from Aran et al. [2010] [9].

Molecular mimicry allows for T cell activation by these bacterial antigens that are structurally related to the host antigens, leading to progression and/or development of a disease [8]. Aran et al. conducted a study in 2010 that investigated the effect of Streptococcus bacteria antigens on autoimmunity and disturbances caused in the host. The researchers found that Streptococcus bacteria antigens share conserved residues with host antigens. This homology contributes to molecular mimicry, allowing Streptococcus bacteria antigens to bind to T cells and initiating an immune response. In Figure 1, the results of molecular mimicry between Streptococcus bacteria and host (ie. human) from the study are shown. As shown on the figure, there is significant homology between human and rat antibodies (ie. host) that bind to protein disulfide isomerase (PDI) and anti-PDI antibodies, SLO, which are from Streptococcus bacteria. There are 8 conserved amino acid residues between SLO and human PDI, and 9 conserved residues between SLO and rat PDI. It is also important to note that in human PDI, the last amino acid lysine (K) in the rat PDI and SLO is changed to an arginine (R). The authors suggest this residue change causes a decreased likelihood of the PDI-antibody in a human host to bind, resulting in a greater binding of bacterial antigens, in this case SLO, anti-PDI antibodies (Figure 2) [9]. Hence, through the use of molecular mimicry, anti-PDI antibodies from Streptococcus bacterial infections cause reduced activation of PDI, contributing to harmful effects on the biological functioning of the host. In the context of this experiment, reduced activation of PDI led to increased levels of insulin in the blood, as well as insulin resistance.

1.2 H1N1 vaccine and narcolepsy

1.2a Pandemrix and its effect on narcolepsy prevalence

In response to the 2009 H1N1 influenza pandemic,Pandemrix, an influenza vaccine, was used in many countries to control the spread of the virus. In August 2012, cases of narcolepsy surfaced in children and adolescents who were vaccinated with Pandemrix [10]. Finland was the first country in which the risk of developing narcolepsy following the Pandemrix vaccination was found. A study showed that approximately eight months following the Pandemrix vaccination, children and adolescents had a 12.7% increased chance of developing narcolepsy [6]. The authors proposed a biological mechanism underlying for why Pandemrix enhanced the likelihood of developing narcolepsy. They stated that since narcolepsy is strongly associated with the HLA gene variant DQB1*0602, it is likely the vaccine works through immunological mechanisms that, in turn, cause destruction of hypocretin cells in people who have a genetic predisposition (ie. have the DQB1*0602 allele) [4].

1.2b Underlying biological mechanisms

Currently, it is thought that, in narcolepsy, T cell activation is increased by two specific hypocretin epitopes, HCRT56–68 and HCRT87–99. Using a peptide binding competition assay, it was found that these epitopes have very good binding to the HLA DQB1*0602 allele, when compared to other epitopes (Figure 3). These two epitopes bind to HLA DQB1*0602 allele and, in turn, activate CD4+ T cells in people with narcolepsy.

Epitopes of the HLA DQB1*0602 allele
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Figure 3. Peptide binding competition assay results showing which hypocretin (HCRT) epitopes bind best to the
DQB1*0602 allele. Adapted from De la Herrán-Arita et al. [2013][11].

However, it is interesting to note that the epitopes do not activate CD4+ T cells in healthy individuals with the DQB1*0602 allele. This emphasizes the likelihood that the Pandemrix vaccine consists of an epitope that is structurally homologous to HCRT56–68 and HCRT87–99, which may possibly be activating CD4+ T cells through molecular mimicry. De la Herrán-Arita et al. found a hemagglutinin pHA1 epitope that is exclusive to the H1N1 influenza virus, pHA1275–287. The authors conducted an in vitro antigen stimulation, and found that pHA1275–287 allows for the activation of CD4+ T cells by mimicking HCRT56–68 and HCRT87–99 epitopes. It is through this molecular mimicry that the Pandemrix vaccination is able to allow for CD4+ T cell activation, and in turn allows for the development of narcolepsy[11].

The authors also investigated whether this pHA1275–287 epitope is specific to the 2009 H1N1 influenza. The authors aligned HCRT56–68, HCRT87–99 and pHA1275–287 with peptide sequences from various seasonal and pandemic flu strains, such as H1N2. The results showed that a very low amount of sequence homology between pHA1275–287 and these flu strains. The peptide sequences in most of these flu strains also had weak or no binding affinity to the DQB1*0602 allele [11]. One flu strain that shared sequence homology with pHA1275–287 was then 1998 influenza strain from the swine flu [12]. Overall, the results showed that the pHA1275–287 epitope is exclusive to the 2009 H1N1 influenza and binds specifically to the DQB1*0602 allele, having a direct effect on the development of narcolepsy [11].

CD4+ T cell activation by Pandemrix
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Figure 4. HCRT56–68 and HCRT87–99 epitopes activate CD4+ T cells in patients with narcolepsy.
In children who, after being vaccinated with Pandemrix, developed narcolepsy, CD4+ T cell activation levels increased.
Seven of their healthy siblings, who had the DQB1*0602 allele and were vaccinated with Pandemrix, did not show increased CD4+ T cell activation.
Adapted from De la Herrán-Arita et al. [2013][11].

De la Herrán-Arita et al. also investigated CD4+ T cell activation and its association with HCRT epitopes in children from Ireland who, after being vaccinated with Pandemrix, developed narcolepsy. The researchers used ten vaccinated children with narcolepsy and compared them to seven of their siblings, who both had the DQB1*0602 allele and were vaccinated with Pandemrix; however, they did not develop narcolepsy. The researchers found that in the ten vaccinated children with narcolepsy, CD4+ T cell activation levels by HCRT56–68 and HCRT87–99 epitopes rose, but in their siblings, no increase in CD4+ T cell levels was observed (Figure 4). These findings show that CD4+ T cell activation by HCRT56–68 and HCRT87–99 epitopes is, in fact, specifically related to narcolepsy, and this can be used as a novel method of diagnosis [11].

2.1 Automatic behaviour in narcoleptics

Automatic behavior is a poorly understood symptom of narcolepsy, which involves carrying out a task during a brief, involuntary sleep episode. Narcolepsy patients often behave automatically without conscious awareness during tasks that are of second nature, such as driving or writing notes. Automatic behavior cannot be recalled by narcoleptics, and performance during such tasks is typically impaired. This symptom of automatic behaviour occurs in as many as 80% of people with narcolepsy. These automatic actions without conscious awareness can occur every day, and can last anywhere from seconds to hours [13].

2.1a Automatic behaviour phenomenon

Currently, research is being conducted to further our understanding about automatic behavior in people with narcolepsy. One important finding relating to automatic behaviour has been recognizing that various conditions can trigger automatic behaviour in individuals with narcolepsy. Morandin & Bruck (2013) reported three conditions are thought to give rise to automatic behaviour, these are: sleepiness with little cognitive stimulation (Type 1), sleepiness with elevated cognitive stimulation (Type 2), and elevated cognitive stimulation in the absence of sleepiness (Type 3). Sleepiness is often triggered by repetitive tasks. In the first type, low stress levels induce sleep often during tedious, repetitive tasks. In the second type, narcoleptic individuals exhibit high stress levels in order to complete the tasks, and this high cognitive load triggers sleepiness. In the last type, though patients report not being sleepy, similar to type 2, unmanageable tasks lead to overburdening their system, causing automatic behaviour. In these three conditions, 2 factors trigger automatic behaviour and these are decreased alertness and decreased conscious awareness of actions in narcoleptics. Decreased alertness results from conducting tasks that are long, tedious, and repetitive. Secondly, decreased conscious awareness of actions is caused by a poor feedback system (ie. being unaware of errors during a task). These two elements together trigger sleepiness in narcoleptic individuals in each of the three conditions[14].

2.1b Implications of study

Understanding the symptom of automatic behaviour in narcoleptic individuals has several implications. For one, having a better understanding of the aspects of automatic behaviour can help individuals with narcolepsy in controlling automatic behaviour. Morandin & Bruck (2013) reported that several participants in their study felt understanding the automatic behaviour phenomena allowed them to fell better psychologically, and allowed them to better regulate their episodes[14]. However, more research needs to be conducted in order to better understand the internal states and conditions that trigger automatic behaviour in individuals with narcolepsy.

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11. De la Herran-Arita, AK, B.R. Kornum, J. Mahlios, W. Jiang, L. Lin, T. Hou et al. CD4+ T cell autoimmunity to hypocretin/orexin and cross-reactivity to a 2009 H1N1 influenza a epitope in narcolepsy. Sci Transl Med 5, 216-ra176 (2013).
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14. Morandin, Michelle, and Dorothy Bruck. "Understanding Automatic Behavior in Narcolepsy: New Insights Using a Phenomenological Approach." The Open Sleep Journal 6.1, 1-7 (2013).

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