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Enhanced influenza A H1N1 T cell epitope recognition and cross-reactivity to protein-O-mannosyltransferase 1 in Pandemrix-associated narcolepsy type 1.

ABSTRACT: Narcolepsy type 1 (NT1) is a chronic neurological disorder having a strong association with HLA-DQB1*0602, thereby suggesting an immunological origin. Increased risk of NT1 has been reported among children or adolescents vaccinated with AS03 adjuvant-supplemented pandemic H1N1 influenza A vaccine, Pandemrix. Here we show that pediatric Pandemrix-associated NT1 patients have enhanced T-cell immunity against the viral epitopes, neuraminidase 175-189 (NA_175-189) and nucleoprotein 214-228 (NP_214-228), but also respond to a NA_175-189-mimic, brain self-epitope, protein-O-mannosyltransferase 1 (POMT1_675-689). A pathogenic role of influenza virus-specific T-cells and T-cell cross-reactivity in NT1 are supported by the up-regulation of IFN-γ, perforin 1 and granzyme B, and by the converging selection of T-cell receptor TRAV10/TRAJ17 and TRAV10/TRAJ24 clonotypes, in response to stimulation either with peptide NA_175-189 or POMT1_675-689. Moreover, anti-POMT1 serum autoantibodies are increased in Pandemrix-vaccinated children or adolescents. These results thus identify POMT1 as a potential autoantigen recognized by T- and B-cells in NT1.

SUBMITTER: Vuorela A

PROVIDER: S-EPMC8052463 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The incidence of narcolepsy type 1 (NT1) increased in Sweden following the 2009-2010 mass-vaccination with the influenza Pandemrix-vaccine. NT1 has been associated with Human leukocyte antigen (HLA) DQB1*06:02 but full high-resolution HLA-typing of all loci in vaccine-induced NT1 remains to be done. Therefore, here we performed HLA typing by sequencing HLA-DRB3, DRB4, DRB5, DRB1, DQA1, DQB1, DPA1 and DPB1 in 31 vaccine-associated NT1 patients and 66 of their first-degree relatives (FDR), and compared these data to 636 Swedish general population controls (GP). Previously reported disease-related alleles in the HLA-DRB5*01:01:01-DRB1*15:01:01-DQA1*01:02:01-DQB1*06:02:01 extended haplotype were increased in NT1 patients (34/62 haplotypes, 54.8%) compared to GP (194/1272 haplotypes, 15.3%, p = 6.17E-16). Indeed, this extended haplotype was found in 30/31 patients (96.8%) and 178/636 GP (28.0%). In total, 15 alleles, four extended haplotypes, and six genotypes were found to be increased or decreased in frequency among NT1 patients compared to GP. Among subjects with the HLA-DRB5*01:01:01-DRB1*15:01:01-DQA1*01:02-DQB1*06:02 haplotype, a second DRB4*01:03:01-DRB1*04:01:01-DQA1*03:02//*03:03:01-DQB1*03:01:01 haplotype (p = 2.02E-2), but not homozygosity for DRB1*15:01:01-DQB1*06:02:01 (p = 7.49E-1) conferred association to NT1. Alleles with increased frequency in DQA1*01:02:01 (p = 1.07E-2) and DQA1*03:02//*03:03:01 (p = 3.26E-2), as well as with decreased frequency in DRB3*01:01:02 (p = 8.09E-3), DRB1*03:01:01 (p = 1.40E-2), and DQB1*02:01:01 (p = 1.40E-2) were found among patients compared to their FDR. High-resolution HLA sequencing in Pandemrix-associated NT1 confirmed the strong association with the DQB1*06:02:01-containing haplotype but also revealed an increased association to the not previously reported extended HLA-DRB4*01:03:01-DRB1*04:01:01-DQA1*03:02//*03:03:01-DQB1*03:01:01 haplotype. High-resolution HLA typing should prove useful in dissecting the immunological mechanisms of vaccination-associated NT1.

Project description:BackgroundA recent publication suggested molecular mimicry of a nucleoprotein (NP) sequence from A/Puerto Rico/8/1934 (PR8) strain, the backbone used in the construction of the reassortant strain X-179A that was used in Pandemrix® vaccine, and reported on anti-hypocretin (HCRT) receptor 2 (anti-HCRTR2) autoantibodies in narcolepsy, mostly in post Pandemrix® narcolepsy cases (17 of 20 sera). In this study, we re-examined this hypothesis through mass spectrometry (MS) characterization of Pandemrix®, and two other pandemic H1N1 (pH1N1)-2009 vaccines, Arepanrix® and Focetria®, and analyzed anti-HCRTR2 autoantibodies in narcolepsy patients and controls using three independent strategies.MethodsMS characterization of Pandemrix® (2 batches), Arepanrix® (4 batches) and Focetria® (1 batch) was conducted with mapping of NP 116I or 116M spectrogram. Two sets of narcolepsy cases and controls were used: 40 post Pandemrix® narcolepsy (PP-N) cases and 18 age-matched post Pandemrix® controls (PP-C), and 48 recent (≤6 months) early onset narcolepsy (EO-N) cases and 70 age-matched other controls (O-C). Anti-HCRTR2 autoantibodies were detected using three strategies: (1) Human embryonic kidney (HEK) 293T cells with transient expression of HCRTR2 were stained with human sera and then analyzed by flow cytometer; (2) In vitro translation of [35S]-radiolabelled HCRTR2 was incubated with human sera and immune complexes of autoantibody and [35S]-radiolabelled HCRTR2 were quantified using a radioligand-binding assay; (3) Optical density (OD) at 450 nm (OD450) of human serum immunoglobulin G (IgG) binding to HCRTR2 stably expressed in Chinese hamster ovary (CHO)-K1 cell line was measured using an in-cell enzyme-linked immunosorbent assay (ELISA).ResultsNP 116M mutations were predominantly present in all batches of Pandemrix®, Arepanrix® and Focetria®. The wild-type NP109-123 (ILYDKEEIRRIWRQA), a mimic to HCRTR234-45 (YDDEEFLRYLWR), was not found to bind to DQ0602. Three or four subjects were found positive for anti-HCRTR2 autoantibodies using two strategies or the third one, respectively. None of the post Pandemrix® narcolepsy cases (0 of 40 sera) was found positive with all three strategies.ConclusionAnti-HCRTR2 autoantibody is not a significant biological feature of narcolepsy or of post Pandemrix® autoimmune responses.

Project description:BackgroundThe incidence of narcolepsy rose sharply after the swine influenza A (H1N1) vaccination campaign with Pandemrix. Narcolepsy is an immune-related disorder with excessive daytime sleepiness. The most frequent form is strongly associated with HLA-DQB1*06:02, but only a minority of carriers develop narcolepsy. We aimed to identify genetic markers that predispose to Pandemrix-induced narcolepsy.MethodsWe tested for genome-wide and candidate gene associations in 42 narcolepsy cases and 4981 controls. Genotyping was performed on Illumina arrays, HLA alleles were imputed using SNP2HLA, and single nucleotide polymorphisms were imputed using the haplotype reference consortium panel. The genome-wide significance threshold was p < 5 × 10-8, and the nominal threshold was p < 0.05. Results were replicated in 32 cases and 7125 controls. Chromatin data was used for functional annotation.FindingsCarrying HLA-DQB1*06:02 was significantly associated with narcolepsy, odds ratio (OR) 39.4 [95% confidence interval (CI) 11.3, 137], p = 7.9 × 10-9. After adjustment for HLA, GDNF-AS1 (rs62360233) was significantly associated, OR = 8.7 [95% CI 4.2, 17.5], p = 2.6 × 10-9, and this was replicated, OR = 3.4 [95% CI 1.2-9.6], p = 0.022. Functional analysis revealed variants in high LD with rs62360233 that might explain the detected association. The candidate immune-gene locus TRAJ (rs1154155) was nominally associated in both the discovery and replication cohorts, meta-analysis OR = 2.0 [95% CI 1.4, 2.8], p = 0.0002.InterpretationWe found a novel association between Pandemrix-induced narcolepsy and the non-coding RNA gene GDNF-AS1, which has been shown to regulate expression of the essential neurotrophic factor GDNF. Changes in regulation of GDNF have been associated with neurodegenerative diseases. This finding may increase the understanding of disease mechanisms underlying narcolepsy. Associations between Pandemrix-induced narcolepsy and immune-related genes were replicated.

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Enhanced influenza A H1N1 T cell epitope recognition and cross-reactivity to protein-O-mannosyltransferase 1 in Pandemrix-associated narcolepsy type 1.

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