HLA high-resolution typing by next-generation sequencing in Pandemrix-induced narcolepsy

Lind, A. R.; Akel, Omar; Wallenius, Madeleine; Ramelius, Anita; Maziarz, Marlena; Zhao, Lue Ping; Geraghty, Daniel E.; Palm, Lars; Lernmark, Åke; Larsson, Helena Elding

doi:10.1371/journal.pone.0222882

Cited by 12 publications

(17 citation statements)

References 35 publications

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“…These findings are in line with those of two recent reports describing these associations in small numbers of post-H1N1 NT1 patients that report positive associations of post-H1N1 with HLA-DQ7 and negative associations with HLA-DQ2 (Lind et al, 2019;Juvodden et al, 2019). Both these and other studies in NT1 patients before and after the H1N1 pandemic also describe the same associations that we found (Mignot et al, 2001;van der Heide et al, 2015;Hong et al, 2007;Tafti et al, 2014;Bomfim et al, 2017;Tafti et al, 2016;Han et al, 2013).…”

Section: Discussionsupporting

confidence: 93%

“…Following these epidemiological and laboratory reports, a discussion on the existence of a post-H1N1 NT1 variant has arisen, with specifically Scandinavian countries making the distinction between sporadic and post-H1N1 NT1. Several recent Scandinavian studies report HLA-DQ-haplotypes associated specifically with post-H1N1 NT1 (HLA-DQ2, HLA-DQ7) (Juvodden et al, 2019;Lind et al, 2019). These reports started a discussion about whether different immunological mechanisms may be involved in post-H1N1 NT1.…”

Section: Introductionmentioning

confidence: 99%

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HLA associations in narcolepsy type 1 persist after the 2009 H1N1 pandemic

Schinkelshoek

Fronczek

Verduijn

et al. 2020

Journal of Neuroimmunology

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We aimed to compare HLA-DQB1-associations in narcolepsy type 1 (NT1) patients with disease onset before and after the 2009 H1N1 pandemic in a large Dutch cohort. 525 NT1 patients and 1272 HLA-DQB1*06:02-positive healthy controls were included. Because of the discussion that has arisen on the existence of sporadic and post-H1N1 NT1, HLA-DQB1-associations in pre-and post-H1N1 NT1 patients were compared. The associations between HLA-DQB1 alleles and NT1 were not significantly different between pre-and post-H1N1 NT1 patients. Both HLA-DQB1-associations with pre-and -post H1N1 NT1 reported in recent smaller studies were replicated. Our findings combine the results of studies in pre-and post-H1N1 NT1 and argue against considering post-H1N1 NT1 as a different entity. Schinkelshoek et al., 2019), with detected T cell cross-reactivity https://doi.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

HLA associations in narcolepsy type 1 persist after the 2009 H1N1 pandemic

Schinkelshoek

Fronczek

Verduijn

et al. 2020

Journal of Neuroimmunology

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“…In a previous report, people carrying HLA-DQB1*06:02, DRB1*15:01, DQAl*01:02 and DRB5*01:01:01 developed narcolepsy with OR 6.75 after Pandemrix influenza vaccination. 12 Almost all narcoleptic patients are known to carry HLA-DQB1*06:02, DRB1*15:01, and DQAl*01:02, regardless of race. 8 19 In particular, 100% of Japanese narcoleptic patients are reported to carry DQB1*06:02 and DRB1*15:01.…”

Section: Resultsmentioning

confidence: 99%

“… 11 After Pandemrix H1N1 influenza vaccination, 96.8% of patients who developed narcolepsy were found to carry a haplotype in the HLA-DRB5*01:01:01, DRB1*15:01, DQA1*01:02, DQB1*06:02 compared with 28.0% of general population controls (p=6.17×10 –16 ). 12 For development of narcolepsy, in addition to genetic predisposition, environmental factors such as vaccination is likely required. In most patients, narcolepsy results from a loss of hypocretin neurons in the lateral hypothalamus.…”

Section: Introductionmentioning

confidence: 99%

Risk of immunotherapy-related narcolepsy in genetically predisposed patients: a case report of narcolepsy after administration of pembrolizumab

Natori

Sasaki

Soeda

et al. 2020

J Immunother Cancer

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BackgroundImmune-related adverse events associated with immune checkpoint therapy cause autoimmune disease-like symptoms. People who carry specific genotypes or haplotypes of human leucocyte antigen (HLA) are known to be predisposed to develop autoimmune diseases including narcolepsy. Immunotherapy could be a trigger to develop narcolepsy in predisposing HLA positive patients.Case presentationA 66-year-old woman with stage IVB endometrial carcinosarcoma experienced daytime sleepiness and temporary muscle weakness 14 days after the administration of an immune checkpoint inhibitor, pembrolizumab. These were consistent with the main symptoms of narcolepsy with cataplexy. This patient carried a highly predisposing HLA haplotype for narcolepsy; HLA-DQB1*06:02, DRB1*15:01, DQA1*01:02 and DRB5*01:01:01. A hypocretin-1/orexin-A concentration in the patient’s cerebrospinal fluid was low at 9.6 pg/mL in ELISA, and 155.5 pg/mL in radioimmunoassay that was below the normal level of 200 pg/mL. Therefore, she was diagnosed with narcolepsy tentatively according to the International Classification of Sleep Disorders, third edition diagnostic criteria for narcolepsy. The onset of narcolepsy in the 60s is very rare, and narcoleptic symptoms in our patient were likely to be caused by pembrolizumab.ConclusionsThis case suggests that treatment with immune checkpoint inhibitors potentially causes narcolepsy in genetically predisposed patients.

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“…The causes and triggering mechanism behind this specific hypocretin cell-death are not well defined 15 , 16 . With a typical young age at onset and an almost complete association with the HLA-DQB1*06:02:01 allele, implying a connection to antigen-presentation 17 , 18 , NT1 is assumed to be the likely consequence of an autoimmune process.…”

Section: Introductionmentioning

confidence: 99%

A/H1N1 hemagglutinin antibodies show comparable affinity in vaccine-related Narcolepsy type 1 and control and are unlikely to contribute to pathogenesis

Lind

Marzinotto

Brigatti

et al. 2021

Sci Rep

Self Cite

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An increased incidence of narcolepsy type 1 (NT1) was observed in Scandinavia following the 2009–2010 influenza Pandemrix vaccination. The association between NT1 and HLA-DQB1*06:02:01 supported the view of the vaccine as an etiological agent. A/H1N1 hemagglutinin (HA) is the main antigenic determinant of the host neutralization antibody response. Using two different immunoassays, the Luciferase Immunoprecipitation System (LIPS) and Radiobinding Assay (RBA), we investigated HA antibody levels and affinity in an exploratory and in a confirmatory cohort of Swedish NT1 patients and healthy controls vaccinated with Pandemrix. HA antibodies were increased in NT1 patients compared to controls in the exploratory (LIPS p = 0.0295, RBA p = 0.0369) but not in the confirmatory cohort (LIPS p = 0.55, RBA p = 0.625). HA antibody affinity, assessed by competition with Pandemrix vaccine, was comparable between patients and controls (LIPS: 48 vs. 39 ng/ml, p = 0.81; RBA: 472 vs. 491 ng/ml, p = 0.65). The LIPS assay also detected higher HA antibody titres as associated with HLA-DQB1*06:02:01 (p = 0.02). Our study shows that following Pandemrix vaccination, HA antibodies levels and affinity were comparable NT1 patients and controls and suggests that HA antibodies are unlikely to play a role in NT1 pathogenesis.

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HLA high-resolution typing by next-generation sequencing in Pandemrix-induced narcolepsy

Cited by 12 publications

References 35 publications

HLA associations in narcolepsy type 1 persist after the 2009 H1N1 pandemic

HLA associations in narcolepsy type 1 persist after the 2009 H1N1 pandemic

Risk of immunotherapy-related narcolepsy in genetically predisposed patients: a case report of narcolepsy after administration of pembrolizumab

A/H1N1 hemagglutinin antibodies show comparable affinity in vaccine-related Narcolepsy type 1 and control and are unlikely to contribute to pathogenesis

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