Put to sleep by immune cells

Liblau, Roland

doi:10.1038/d41586-018-06666-w

Cited by 17 publications

(7 citation statements)

References 20 publications

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“…Indeed, while positivity for HLA-DPA1 or DQB1*0603 is thought to have a protective effect, DQB1*0602 ('DQ0602') is considered a genetic marker that strongly predisposes for NT1 (29,35). The latter is based on the observation that 95-98% of NT1 patients are positive for this HLA-II allele, and that DQ0602 homozygosity (versus heterozygosity) significantly increases susceptibility (30,(35)(36)(37), linking this allele tightly to the risk of NT1. However, the relative commonness of DQ0602positivity, found in 15-30% of the general population, also strongly suggests a role for environmental triggers in the overall NT1 etiology (36,38).…”

Section: Nt1 Immunopathogenesismentioning

confidence: 99%

“…The seminal data, identifying HCRT as a potential T-cell target in NT1, were published by Latorre and coworkers in 2018 ( 70 ). These data led several authors to propose a role of autoimmune T cells in NT1 ( 36 , 72 ). Investigations into a potential T-cell–mediated etiology for NT1 continued by evaluating potential T-cell cross-reactivity between HCRT and H1N1 influenza proteins.…”

Section: Clinical and Translational Mechanistic Researchmentioning

confidence: 99%

“…Hence, the critical event would likely be the loss of peripheral tolerance mechanisms, leading to the presence of unchecked activated autoreactive CD4 + T cells in the brain. It was hypothesized that, subsequently, local immune activation in the hypothalamus would (due to a phenomenon known as ‘epitope spreading’) lead to involvement of other T cells with different targets, including HLA-DR–restricted CD4 + and CD8 + T cells ( 36 ). Because these responses would be activated after disease initiation by cross-reactive T cells, it is expected that such secondary immune responses would then be more disease-specific and not necessarily cross-reactive.…”

Section: Clinical and Translational Mechanistic Researchmentioning

confidence: 99%

“…Any inflammation in the brain, caused by, for example, infection or other trauma, could entice these T cells to cross the blood-brain barrier, in order to survey the local inflammation. These activated cross-reactive CD4 + T cells could then recognize the mimicry HCRT peptide presented by microglia, and trigger autoimmunity ( 36 ).…”

Section: Clinical and Translational Mechanistic Researchmentioning

confidence: 99%

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Narcolepsy and H1N1 influenza immunology a decade later: What have we learned?

Buonocore

Most

2022

Front. Immunol.

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In the wake of the A/California/7/2009 H1N1 influenza pandemic vaccination campaigns in 2009-2010, an increased incidence of the chronic sleep-wake disorder narcolepsy was detected in children and adolescents in several European countries. Over the last decade, in-depth epidemiological and immunological studies have been conducted to investigate this association, which have advanced our understanding of the events underpinning the observed risk. Narcolepsy with cataplexy (defined as type-1 narcolepsy, NT1) is characterized by an irreversible and chronic deficiency of hypocretin peptides in the hypothalamus. The multifactorial etiology is thought to include genetic predisposition, head trauma, environmental triggers, and/or infections (including influenza virus infections), and an increased risk was observed following administration of the A/California/7/2009 H1N1 vaccine Pandemrix (GSK). An autoimmune origin of NT1 is broadly assumed. This is based on its strong association with a predisposing allele (the human leucocyte antigen DQB1*0602) carried by the large majority of NT1 patients, and on links with other immune-related genetic markers affecting the risk of NT1. Presently, hypotheses on the underlying potential immunological mechanisms center on molecular mimicry between hypocretin and peptides within the A/California/7/2009 H1N1 virus antigen. This molecular mimicry may instigate a cross-reactive autoimmune response targeting hypocretin-producing neurons. Local CD4+ T-cell responses recognizing peptides from hypocretin are thought to play a central role in the response. In this model, cross-reactive DQB1*0602-restricted T cells from the periphery would be activated to cross the blood-brain barrier by rare, and possibly pathogen-instigated, inflammatory processes in the brain. Current hypotheses suggest that activation and expansion of cross-reactive T-cells by H1N1/09 influenza infection could have been amplified following the administration of the adjuvanted vaccine, giving rise to a “two-hit” hypothesis. The collective in silico, in vitro, and preclinical in vivo data from recent and ongoing research have progressively refined the hypothetical model of sequential immunological events, and filled multiple knowledge gaps. Though no definitive conclusions can be drawn, the mechanistical model plausibly explains the increased risk of NT1 observed following the 2009-2010 H1N1 pandemic and subsequent vaccination campaign, as outlined in this review.

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Section: Nt1 Immunopathogenesismentioning

confidence: 99%

Section: Clinical and Translational Mechanistic Researchmentioning

confidence: 99%

Section: Clinical and Translational Mechanistic Researchmentioning

confidence: 99%

Section: Clinical and Translational Mechanistic Researchmentioning

confidence: 99%

See 2 more Smart Citations

Narcolepsy and H1N1 influenza immunology a decade later: What have we learned?

Buonocore

Most

2022

Front. Immunol.

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“… 34 Higher frequency of hypocretin responsive CD4+ and CD8+ T-cells was also observed in NT1 children. 42 However, it remains unclear if 43 and how CD4+ T-cells are involved in the destruction of the hypocretin neurons. Indeed, one critical observation is that neuronal cells do not express HLA class II molecules but only class I, which are recognized by CD8+ and not CD4+ T lymphocytes.…”

Section: Evidence Of Autoimmune Etiology In Narcolepsymentioning

confidence: 99%

Reviewing the Clinical Implications of Treating Narcolepsy as an Autoimmune Disorder

Giannoccaro¹,

Liguori²,

Plazzi³

et al. 2021

NSS

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Narcolepsy type 1 (NT1) is a lifelong sleep disorder, primarily characterized clinically by excessive daytime sleepiness and cataplexy and pathologically by the loss of hypocretinergic neurons in the lateral hypothalamus. Despite being a rare disorder, the NT1related burden for patients and society is relevant due to the early onset and chronic nature of this condition. Although the etiology of narcolepsy is still unknown, mounting evidence supports a central role of autoimmunity. To date, no cure is available for this disorder and current treatment is symptomatic. Based on the hypothesis of the autoimmune etiology of this disease, immunotherapy could possibly represent a valid therapeutic option. However, contrasting and limited results have been provided so far. This review discusses the evidence supporting the use of immunotherapy in narcolepsy, the outcomes obtained so far, current issues and future directions.

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Sleep and acute collapse disorders

2022

Large Animal Neurology

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Put to sleep by immune cells

Cited by 17 publications

References 20 publications

Narcolepsy and H1N1 influenza immunology a decade later: What have we learned?

Narcolepsy and H1N1 influenza immunology a decade later: What have we learned?

Reviewing the Clinical Implications of Treating Narcolepsy as an Autoimmune Disorder

Sleep and acute collapse disorders

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