MINIREVIEW: The link between narcolepsy and respiratory diseases: could COVID-19 help to undestand it?

Author of summary: Giulia Colombo Reviewer: Marianna Coppola

It is now consolidated that environmental factors, like infections, play an important role in the development and progression of many autoimmune diseases, such as narcolepsy is thought to be. Increased susceptibility to narcolepsy is associated to common upper airway infections, like those caused by Streptococcus pyogenes and by influenza A virus, as well as to some vaccine preparations against H1N1, even if with much lower confidence. This link highlights an important translational medicine opportunity: the current COVID-19 pandemic may be a setting where interdisciplinary research can uncover further mechanistic insight into the early biological events that shape the development of narcolepsy in susceptible individuals.

Narcolepsy is a neurological disorder characterized by excessive daytime sleepiness, cataplexy, hypnagonic hallucinations, sleep paralysis and disturbed nocturnal sleep patterns. It is caused by the selective loss of hypocretin (orexin) function and narcoleptic patients typically have low hypocretin cerebrospinal fluid (CSF) levels, which can be explained by the loss of over 90% of their hypocretinergic neurons in the lateral hypothalamus, a process that has been associated with disease onset.

With more than 98% of narcoleptic patients with low CSF hypocretin-1 carrying the HLA DQB1*06:02 allele in the major histocompatibility complex locus, frequently in combination with HLA DRB1*15:01, narcolepsy has one of the strongest known associations with HLA, regardless of ethnicity. This potently suggests an autoimmune reaction targeting hypocretinergic neurons as the pathogenetic trigger. Genome-wide association studies have strengthened the association between narcolepsy and immune system gene polymorphisms, including the identification of polymorphisms in the T cell receptor alpha locus, TNFSF4 (also called OX40L), Cathepsin H (CTSH), the purinergic receptor P2RY11 and the DNA methyltransferase DNMT1.

Susceptibility to narcolepsy has been associated with common upper airway infections, including those caused by Streptococcus pyogenes and by influenza A virus. In fact, individuals infected by Streptococcus are more than five times as likely to develop narcolepsy, with Streptococcus-specific antibodies found in 65% of narcoleptic patients as compared to 26% of age-matched controls. In China, the onset of narcolepsy in children appears to follow seasonal patterns, with significant increases in cases reported in the months following winter-related infections. Moreover, attention has been raised regarding a spike in cases of childhood narcolepsy in 2010 following the 2009 H1N1 pandemic (pH1N1) in China and vaccination with Pandemrix, an adjuvanted H1N1 vaccine that was used in Europe and linked to a 12.7-fold increased risk of narcoleptic diagnosis in children and young adults approximately eight months following the vaccination in Scandinavia, whereas no increases were reported in Italy or the Netherlands.

How the immune system may be involved in disease initiation and/or progression remains a challenge to researchers. Potential immunological pathways that could lead to the specific elimination of hypocretin producing neurons include molecular mimicry or bystander activation and are likely a combination of genetic and environmental factors, such as upper airway infections. Molecular mimicry would involve processing and presenting bacterial and viral peptides in the context of DQB1*06:02, which would activate a population of cross-reactive T cells present in predisposed individuals. Bystander activation from the generalized proinflammatory environment associated with infections could facilitate the destruction of hypocretinergic neurons in many ways. Pandemrix vaccine has been associated to cross-reactive antibodies against both influenza nucleoprotein and hypocretin receptor 2, but in a narcoleptic mouse model with conditional knockout of HctrR2 this receptor has been shown not to be expressed by hypocretinergic neurons, suggesting other pathogenetic mechanisms.

Considering the link between the onset of narcolepsy and upper airway infections, it could be useful to conduct interdisciplinary research during the current COVID-19 pandemic to discover new pathogenetic mechanisms that lead to the development of this neurological disorder in susceptible subjects. To this aim, active medical surveillance of newly diagnosed narcolepsy patients is essential and desirable.

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