Increased childhood incidence of narcolepsy in western Sweden after H1N1 influenza vaccination

Szakács, Attila; Darín, Niklas; Hallböök, Tove

doi:10.1212/wnl.0b013e31828ab26f

Cited by 144 publications

(131 citation statements)

References 21 publications

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“…Moreover, autoantibodies recognizing different antigenic targets expressed in the central nervous system (CNS) have been identified in the serum and cerebrospinal fluid (CSF) of narcoleptic patients (9-11). Finally, a dramatic increase in the incidence of T1N has been observed in Northern Europe during the 2009-2010 vaccination campaigns against pandemic H1N1 influenza virus using the Pandemrix vaccine (12)(13)(14). The immune mechanisms involved remain unknown, although molecular mimicry is strongly suspected (9,15).…”

Section: Cd8 T Cell-mediated Killing Of Orexinergic Neurons Induces Amentioning

confidence: 99%

CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice

Bernard‐Valnet

Yshii

Quériault

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

116

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Narcolepsy with cataplexy is a rare and severe sleep disorder caused by the destruction of orexinergic neurons in the lateral hypothalamus. The genetic and environmental factors associated with narcolepsy, together with serologic data, collectively point to an autoimmune origin. The current animal models of narcolepsy, based on either disruption of the orexinergic neurotransmission or neurons, do not allow study of the potential autoimmune etiology. Here, we sought to generate a mouse model that allows deciphering of the immune mechanisms leading to orexin + neuron loss and narcolepsy development. We generated mice expressing the hemagglutinin (HA) as a "neo-self-antigen" specifically in hypothalamic orexin + neurons (called Orex-HA), which were transferred with effector neo-self-antigen-specific T cells to assess whether an autoimmune process could be at play in narcolepsy. Given the tight association of narcolepsy with the human leukocyte antigen (HLA) HLA-DQB1*06:02 allele, we first tested the pathogenic contribution of CD4 Th1 cells. Although these T cells readily infiltrated the hypothalamus and triggered local inflammation, they did not elicit the loss of orexin + neurons or clinical manifestations of narcolepsy. In contrast, the transfer of cytotoxic CD8 T cells (CTLs) led to both T-cell infiltration and specific destruction of orexin + neurons. This phenotype was further aggravated upon repeated injections of CTLs. In situ, CTLs interacted directly with MHC class I-expressing orexin + neurons, resulting in cytolytic granule polarization toward neurons. Finally, drastic neuronal loss caused manifestations mimicking human narcolepsy, such as cataplexy and sleep attacks. This work demonstrates the potential role of CTLs as final effectors of the immunopathological process in narcolepsy.arcolepsy with cataplexy, referred to as type 1 narcolepsy (T1N), is a rare and chronic neurological disease characterized by excessive daytime sleepiness, sudden loss of muscle tone triggered by emotions (cataplexy), sleep paralysis, hypnagogic hallucinations, and fragmented nocturnal sleep (1). T1N is caused by a defective neurotransmission by the orexin/hypocretin neuropeptide and is associated with a selective and almost complete loss (85-100%) of orexinergic neurons in the hypothalamus (2, 3). The mechanisms leading to this neuronal loss are not yet elucidated, although current evidence points to an autoimmune process. Indeed, T1N is tightly associated with the human leukocyte antigen (HLA) HLA-DQB1*06:02 allele, carried by 98.4% of patients vs. 17.7% of the general European population (4). An independent association with HLA class I alleles was recently revealed in two independent studies (5, 6). Additionally, an association with polymorphisms in the T-cell receptor (TCR) α chain locus was found and replicated (7,8). Moreover, autoantibodies recognizing different antigenic targets expressed in the central nervous system (CNS) have been identified in the serum and cerebrospinal fluid (CSF) of narcoleptic patients (9-11)....

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Section: Cd8 T Cell-mediated Killing Of Orexinergic Neurons Induces Amentioning

confidence: 99%

CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice

Bernard‐Valnet

Yshii

Quériault

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

116

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“…About 67 % of the Swedish children were vaccinated against | 33 pH1N1 with Pandemrix [214]. A study in western Sweden found a 25-fold higher risk of developing narcolepsy after Pandemrix vaccination, and all narcolepsy patients in this study had HLA DQB1*0602 [223]. The report from the Swedish Medical Products Agency (MPA) reported a 6.6 higher risk in children <19 years of age for developing narcolepsy with cataplexy after vaccination [214].…”

Section: Narcolepsymentioning

confidence: 76%

Nasal vaccination using novel mucosal adjuvants : with main focus on influenza A virus

Falkeborn¹

2015

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“…Excipients: 1) A few months after Pandemrix ® (the influenza A vaccine containing the AS03 adjuvant) administration following the influenza A (H1N1) epidemic in Europe, more than 800 children across Europe (especially in Sweden and Finland) have been diagnosed with narcolepsy-cataplexy [21]. At present, assessments of the causal mechanisms about the adjuvant remains to be investigated and long term epidemiological studies about AS03-adjuvanted influenza A (H1N1) pandemic vaccine prepared with the European inactivation/ purification protocol are recommended [22].…”

Section: Adverse Events Following Immunization (Aefi)mentioning

confidence: 99%

Vaccination Age Changing from Infancy and Childhood to Adolescence and Adulthood: An In-Dispensable Approach in Immunization Programs

Tafreshi¹

2016

J Infect Dis Ther

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Objectives: Despite the positive effects of vaccines on control of many infectious diseases, they are not completely safe. The purpose of this article is to draw attention to the problems associated with newborns and infants immunization. Data Collection Method:For each subject, a review of electronic sources was carried out in the PubMed and Google Scholar using appropriate key words.Results: For different reasons including: the differences between the immune systems of newborns/children and adults, sever adverse events and inefficacy of vaccines, deceptive advertising and inadequate parental awareness about vaccines and vaccination; newborns and children are at risk and accordingly a decline in public confidence is observed. Conclusion:The revision of vaccination age changing (at least for some vaccines) in order to maintain newborns/children's health and to prevent the return of infectious diseases is required. To achieve this goal, new retrospective and prospective studies to reassess the safety, efficacy, quality and protection duration of vaccines, proper implementation of good clinical practice, establishment of a network vaccine safety database by collaboration of international organizations, vaccine manufacturers and academic centers for sharing of information and enhancement of awareness of healthcare professionals and people about immunization at global level are needed.

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Increased childhood incidence of narcolepsy in western Sweden after H1N1 influenza vaccination

Cited by 144 publications

References 21 publications

CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice

CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice

Nasal vaccination using novel mucosal adjuvants : with main focus on influenza A virus

Vaccination Age Changing from Infancy and Childhood to Adolescence and Adulthood: An In-Dispensable Approach in Immunization Programs

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