scholarly journals Narcolepsy as an Immune-Mediated Disease

2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Alberto K. De la Herrán-Arita ◽  
Fabio García-García
Keyword(s):  
Influenza A ◽  
Molecular Mimicry ◽  
Strong Association ◽  
Human Leukocyte ◽  
Cell Receptor ◽  
H1n1 Vaccine ◽  
Leukocyte Antigen ◽  
Immune Mediated ◽  
Influenza A H1n1 ◽  
2009 H1n1

Narcolepsy is a neurological disorder characterized by excessive daytime sleepiness, cataplexy, hypnagonic hallucinations, sleep paralysis, and disturbed nocturnal sleep patterns. This disease is secondary to the specific loss of hypothalamic hypocretin (orexin)-producing neurons in the lateral hypothalamus. An autoimmune basis for the disease has long been suspected based on its strong association with the genetic marker DQB1*06:02, and current studies greatly support this hypothesis. Narcolepsy with hypocretin deficiency is associated with human leukocyte antigen (HLA) and T cell receptor (TCR) polymorphisms, suggesting that an autoimmune process targets a peptide unique to hypocretin-producing neurons via specific HLA-peptide-TCR interactions. This concept has gained a lot of notoriety after the increase 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 Scandinavia. The surge of narcolepsy cases subsequent to influenza A H1N1 infection and H1N1 vaccination suggests that processes such as molecular mimicry or bystander activation might be crucial for disease development.

2009 Pandemic Influenza A H1N1 Vaccination In the Patients with Hematologic Malignancies: Requirement for Repeated Dosing to Optimize Seroprotection

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 677-677
Author(s):  
Hugues de Lavallade ◽  
Paula Lorraine Garland ◽  
Takuya Sekine ◽  
Katja Hoschler ◽  
David Marin ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Influenza A ◽  
Hematologic Malignancies ◽  
B Cell Malignancies ◽  
H1n1 Vaccine ◽  
Influenza A H1n1 ◽  
Antibody Titers ◽  
2009 H1n1 ◽  
The Uk

Abstract Abstract 677 In 2009 the spread of influenza A (H1N1) satisfied the World Health Organization (WHO) criteria for a global pandemic and led to the initiation of a vaccination campaign to ensure protection for the most vulnerable patients. However, the immunogenicity of the 2009 H1N1 vaccine in immunocompromised patients has not been specifically evaluated. Furthermore, the number of doses of vaccine required for effective immunization against H1N1 has not been established. Whereas the European Medicines Agency (EMEA) and the UK Department of Health (DoH) recommended the injection of two doses of inactivated H1N1 vaccine 3 weeks apart in immunocompromised individuals, the Centers for Disease Control and Prevention recommended immunization with one dose of inactivated H1N1 vaccine for patients with cancer receiving chemotherapy, followed by a booster vaccine after completion of treatment if the pandemic continued. The aim of this study was to determine the safety and efficacy of the 2009 H1N1 vaccine in patients with hematologic malignancies. We prospectively evaluated the humoral and cellular immune responses to monovalent influenza A/California/2009(H1N1)v-like strain surface antigen vaccine in 97 adults with hematologic malignancies and 25 adult controls. Patients received two intramuscular injections of the vaccine 21 days apart and controls received one dose. Antibody titers, expressed as geometric mean, were measured using a hemagglutination-inhibition assay on days 0, 21 and 49 after injection of the first dose. The induction of virus-specific T-cell responses by H1N1 vaccination was assessed directly ex-vivo by flow cytometric enumeration of antigen-specific CD8+ and CD4+ T-lymphocytes using an intracellular cytokine assay for IFN-γ and TNF-α production on days 0 and 49. Of the 97 patients, 32 had chronic myeloid leukemia (CML) in chronic phase in complete cytogenetic response on the tyrosine kinase inhibitors imatinib or dasatinib, 39 had a B-cell malignancy in complete remission (CR) or untreated, and 26 were recipients of allogeneic hematopoietic stem cell transplantation (allo-SCT) in CR at least 6 months beyond transplant and without evidence of graft versus host disease. The vaccine was well tolerated, with no obvious difference in side effects for patients and controls. By day 21 post-vaccination, protective antibody titers of 1:32 or more were seen in 100% of controls compared to 39% of patients with B-cell malignancies (p<0.001), 46% of allo-SCT recipients (p<0.001) and 85% of CML patients (p=0.086). The effect of a booster dose was assessed with a paired sample analysis. After a second vaccine dose, the seroprotection rates increased to 68% (p=0.008), 73% (p=0.031), and 95% (p=0.5) in patients with B-cell malignancies, allo-SCT recipients and CML patients respectively. Patients vaccinated within 6 months of rituximab-based chemotherapy failed to mount a seroprotective antibody response. We also assessed the cellular response to H1N1 vaccine. Prior to vaccination, pre-existing T-cells against H1N1 could be detected in 10/23 controls compared to 2/25 allo-SCT recipients (p=0.007), 2/28 patients with B-cell malignancies (p=0.003) and 6/28 of CML patients (p=0.131). These pre-existing H1N1 T-cell responses may be related to previous exposure to 2009 H1N1 virus but more likely are due to the presence of cross-reactive seasonal and pandemic H1N1 specific T-cells. Following vaccination, H1N1-specific T-cells were induced in a significant proportion of allo-SCT recipient (10/25, p=0.008) and patients with B-cell malignancies (10/28; p=0.008), but not in CML patients or healthy controls. The limited ability of vaccines to significantly increase pre-existing influenza-specific T-cells has been previously reported although the mechanism for this phenomenon is not fully elucidated. These data demonstrate efficacy of H1N1 vaccine in the majority of patients with hematologic malignancies and unequivocally support the EMEA and the UK DoH official guidelines for the administration of 2 vaccine doses in immunocompromised patients to induce protective immune response against 2009 H1N1 influenza. Based on the WHO analyses, it is expected that the pandemic 2009 H1N1 virus will remain globally predominant in 2010–2011. These results may contribute towards the development of evidence-based guidelines for influenza vaccination in patients with hematologic malignancies. Disclosures: Marin: Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding.

Immunogenicity and safety of the 2009 non-adjuvanted influenza A/H1N1 vaccine in a large cohort of autoimmune rheumatic diseases

2011 ◽  
Vol 70 (6) ◽  
pp. 1068-1073 ◽  
Author(s):  
Carla G S Saad ◽  
Eduardo F Borba ◽  
Nadia E Aikawa ◽  
Clovis A Silva ◽  
Rosa M R Pereira ◽  
...  
Keyword(s):  
Lupus Erythematosus ◽  
Influenza A ◽  
Geometric Mean ◽  
Vaccine Safety ◽  
Primary Antiphospholipid Syndrome ◽  
H1n1 Vaccine ◽  
Link Type ◽  
Autoimmune Rheumatic Disease ◽  
Influenza A H1n1 ◽  
2009 H1n1

BackgroundDespite the WHO recommendation that the 2010–2011 trivalent seasonal flu vaccine must contain A/California/7/2009/H1N1-like virus there is no consistent data regarding its immunogenicity and safety in a large autoimmune rheumatic disease (ARD) population.Methods1668 ARD patients (systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), ankylosing spondylitis (AS), systemic sclerosis, psoriatic arthritis (PsA), Behçet's disease (BD), mixed connective tissue disease, primary antiphospholipid syndrome (PAPS), dermatomyositis (DM), primary Sjögren's syndrome, Takayasu's arteritis, polymyositis and Granulomatosis with polyangiitis (Wegener's) (GPA)) and 234 healthy controls were vaccinated with a non-adjuvanted influenza A/California/7/2009(H1N1) virus-like strain flu. Subjects were evaluated before vaccination and 21 days post-vaccination. The percentage of seroprotection, seroconversion and the factor increase in geometric mean titre (GMT) were calculated.ResultsAfter immunisation, seroprotection rates (68.5% vs 82.9% p<0.0001), seroconversion rates (63.4% vs 76.9%, p<0.001) and the factor increase in GMT (8.9 vs 13.2 p<0.0001) were significantly lower in ARD than controls. Analysis of specific diseases revealed that seroprotection significantly reduced in SLE (p<0.0001), RA (p<0.0001), PsA (p=0.0006), AS (p=0.04), BD (p=0.04) and DM (p=0.04) patients than controls. The seroconversion rates in SLE (p<0.0001), RA (p<0.0001) and PsA (p=0.0006) patients and the increase in GMTs in SLE (p<0.0001), RA (p<0.0001) and PsA (p<0.0001) patients were also reduced compared with controls. Moderate and severe side effects were not reported.ConclusionsThe novel recognition of a diverse vaccine immunogenicity profile in distinct ARDs supports the notion that a booster dose may be recommended for diseases with suboptimal immune responses. This large study also settles the issue of vaccine safety.(ClinicalTrials.gov #NCT01151644)

scholarly journals Immunogenicity Associated with the Routine Use of an Influenza A H1N1 Vaccine in Health Care Personnel in Guangzhou, China

2010 ◽  
Vol 17 (9) ◽  
pp. 1478-1480 ◽  
Author(s):  
Biao Di ◽  
Xinhong Xu ◽  
Tiegang Li ◽  
Enjie Lu ◽  
Jibin Wu ◽  
...  
Keyword(s):  
Health Care ◽  
Influenza A ◽  
Vaccination Campaign ◽  
Negative Control ◽  
Health Care Personnel ◽  
Seroprotection Rate ◽  
H1n1 Vaccine ◽  
Influenza A H1n1 ◽  
2009 H1n1 ◽  
Antibody Levels

ABSTRACT We present immunogenicity data on the routine vaccination of 103 health care personnel during the 2009 H1N1 national vaccination campaign. The seroprotection rate (percentage of samples with hemagglutination inhibition titers of ≥1:40) was 83.2% at 30 days postvaccination, lower than those obtained in previously published controlled trials. Low baseline antibody levels and an increase in seroprotection in a negative-control cohort suggest that the virus remains prevalent.

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

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
A. Vuorela ◽  
T. L. Freitag ◽  
K. Leskinen ◽  
H. Pessa ◽  
T. Härkönen ◽  
...  
Keyword(s):  
T Cell ◽  
Influenza A ◽  
Strong Association ◽  
Cell Epitope ◽  
Cell Receptor ◽  
Cross Reactivity ◽  
Cell Immunity ◽  
Increased Risk ◽  
Influenza A H1n1

AbstractNarcolepsy 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 (NA175–189) and nucleoprotein 214–228 (NP214–228), but also respond to a NA175–189-mimic, brain self-epitope, protein-O-mannosyltransferase 1 (POMT1675–689). 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 NA175–189 or POMT1675–689. 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.

scholarly journals Autoimmunity to hypocretin and molecular mimicry to flu antigens in Type 1 narcolepsy

2018 ◽  
Author(s):  
Guo Luo ◽  
Aditya Ambati ◽  
Ling Lin ◽  
Mélodie Bonvalet ◽  
Markku Partinen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Influenza A ◽  
Molecular Mimicry ◽  
Neuronal Loss ◽  
Human Leukocyte ◽  
Cell Receptor ◽  
Blood Monocytes ◽  
Genetic Components

AbstractType 1 narcolepsy (T1N) is caused by hypocretin (HCRT) neuronal loss. Association with the Human Leukocyte Antigen (HLA)-DQB1*06:02/DQA1*01:02 (98% vs 25%) heterodimer (DQ0602), T cell receptor (TCR) and other immune loci suggest autoimmunity but autoantigen(s) are unknown. Onset is seasonal and associated with influenza A, notably pandemic 2009 H1N1 (pH1N1). An extensive unbiased DQ0602 binding peptide screen was performed encompassing peptides derived from Pandemrix® X-179-A pH1N1 influenza-A vaccine, a known T1N trigger, other H1N1 strains, and potential human autoantigens HCRT and RFX4, identifying 109 binders. The presence of cognate tetramer-peptide specific CD4+ T cells was studied in 35 narcolepsy cases and 22 DQ0602 controls after expansion of antigen-specific cells in Peripheral Blood Monocytes Cell (PBMC) cultures. Higher reactivity to influenza epitopes pHA273-287 (pH1N1 specific) and PR8 (H1N1 pre 2009)-specific NP17-31 were observed in T1N. Extensive reactivity to C-amidated but not native version of HCRT54-66 and HCRT86-97, which are two highly homologous peptides (HCRTNH2) was observed with higher frequencies of specific T cells in T1N. TCRα/β CDR3 sequences found in pHA273-287, NP17-31 and HCRTNH2 tetramer positive CD4+ cells were also retrieved in single INFγ-secreting CD4+ sorted cells stimulated with Pandemrix®, confirming immunodominance and functional significance in DQ0602-mediated responses and molecular mimicry. TCRα/β CDR3 motifs of HCRT54-66 and HCRT86-97 tetramers were extensively shared. Particularly notable was sharing across subjects of an CDR3α, CAVETDSWGKLQF (in association with various CDR3β that used TRAJ24, a chain modulated by Single Nucleotide Polymorphism (SNPs) rs1154155 and rs1483979 associated with T1N. Sharing of CDR3β CASSQETQGRNYGYTF (in association with various CDR3α was also observed with HCRTNH2 and pHA273-287-tetramers across subjects. This segment uses TRBV4-2, a segment modulated by narcolepsy-associated SNP rs1008599. Higher HCRTNH2 positive CD4+ T cell numbers in T1N together with sharing of J24 CAVETDSWGKLQF in HCRTNH2 autoimmune responses, indicates causal DQ0602-mediated CD4+ autoreactivity to HCRT in T1N. Our results provide evidence for autoimmunity and molecular mimicry with flu antigens modulated by genetic components in the pathophysiology of T1N.

scholarly journals Juvenile Spondyloarthritis: What More Do We Know About HLA-B27, Enthesitis, and New Bone Formation?

2021 ◽  
Vol 8 ◽  
Author(s):  
Shi Huan Tay ◽  
Joo Guan Yeo ◽  
Jing Yao Leong ◽  
Salvatore Albani ◽  
Thaschawee Arkachaisri
Keyword(s):  
Bone Formation ◽  
Treatment Options ◽  
Strong Association ◽  
Human Leukocyte ◽  
Childhood And Adolescence ◽  
Hla B27 ◽  
New Bone Formation ◽  
Leukocyte Antigen ◽  
Immune Mediated ◽  
Juvenile Spondyloarthritis

Juvenile spondyloarthritis (JSpA) refers to a diverse spectrum of immune-mediated inflammatory arthritides whose onset occurs in late childhood and adolescence. Like its adult counterpart, JSpA is typified by a strong association with human leukocyte antigen-B27 (HLA-B27) and potential axial involvement, while lacking rheumatoid factor (RF) and distinguishing autoantibodies. A characteristic manifestation of JSpA is enthesitis (inflammation of insertion sites of tendons, ligaments, joint capsules or fascia to bone), which is commonly accompanied by bone resorption and new bone formation at affected sites. In this Review, advances in the role of HLA-B27, enthesitis and its associated osteoproliferation in JSpA pathophysiology and treatment options will be discussed. A deeper appreciation of how these elements contribute to the JSpA disease mechanism will better inform diagnosis, prognosis and therapy, which in turn translates to an improved quality of life for patients.

scholarly journals Spectrum of cutaneous adverse reactions to aromatic antiepileptic drugs and human leukocyte antigen genotypes in Thai patients and meta-analysis

2021 ◽  
Author(s):  
Chonlaphat Sukasem ◽  
Suthida Sririttha ◽  
Chonlawat Chaichan ◽  
Thapanat Nakkrut ◽  
Patompong Satapornpong ◽  
...  
Keyword(s):  
Human Leukocyte Antigen ◽  
Antiepileptic Drugs ◽  
Meta Analysis ◽  
Strong Association ◽  
Human Leukocyte ◽  
Stevens Johnson Syndrome ◽  
Thai Population ◽  
Leukocyte Antigen ◽  
Maculopapular Eruption ◽  
Sequence Specific Oligonucleotide Probe

AbstractAromatic antiepileptic drugs (AEDs)-induced cutaneous adverse drug reactions (cADRs) add up to the limited use of the AEDs in the treatment and prevention of seizures. Human leukocyte antigen-B (HLA-B) alleles have been linked to AEDs-induced cADRs. We investigated the association between cADRs (including Stevens–Johnson syndrome; SJS/toxic epidermal necrolysis; TEN, drug reaction with eosinophilia and systemic symptoms; DRESS, and Maculopapular eruption; MPE) caused by AEDs (phenytoin, carbamazepine, lamotrigine, phenobarbital and oxcarbazepine) and HLA-B alleles in Thai population. Through the case-control study, 166 patients with AEDs-induced cADRs, 426 AEDs-tolerant patients (AEDs-tolerant controls), and 470 healthy subjects (Thai population) were collected. The HLA genotypes were detected using the polymerase chain reaction-sequence specific oligonucleotide probe (PCR-SSOP) method. We also performed a meta-analysis with these data and other populations. The carrier rate of HLA-B*15:02 was significantly different between AEDs-induced cADRs group and AEDs-tolerant group (Odds ratio; OR 4.28, 95% Confidence interval; CI 2.64–6.95, p < 0.001), AEDs-induced cADRs group and Thai population (OR 2.15, 95%CI 1.41–3.29, p < 0.001). In meta-analysis showed the strong association HLA-B*15:02 with AEDs-induced cADRs (OR 4.77, 95%CI 1.79–12.73, p < 0.001). Furthermore, HLA-B*15:02 was associated with SJS/TEN induced by AEDs (OR 10.28, 95%CI 6.50–16.28, p < 0.001) Phenytoin (OR 4.12, 95%CI 1.77–9.59, p = 0.001) and carbamazepine (OR 137.69, 95%CI 50.97–371.98, p < 0.001). This study demonstrated that genetic association for AEDs-induced cADRs was phenotype-specific. A strong association between HLA-B*15:02 and AEDs-induced SJS/TEN was demonstrated with an OR of 10.79 (95%CI 5.50–21.16, p < 0.001) when compared with AEDs-tolerant group. On the other hand, the carrier rates of HLA-B*08:01, HLA-B*13:01, and HLA-B*56:02 were significantly higher in the DRESS group compared with the AEDs-tolerant group (p = 0.029, 0.007, and 0.017, respectively). The HLA-B*15:02 allele may represent a risk factor for AEDs-induced cADRs.

Epidemiological analysis of critically ill adult patients with pandemic influenza A(H1N1) in South Korea

2012 ◽  
Vol 141 (5) ◽  
pp. 1070-1079 ◽  
Author(s):  
S. B. HONG ◽  
E. Y. CHOI ◽  
S. H. KIM ◽  
G. Y. SUH ◽  
M. S. PARK ◽  
...  
Keyword(s):  
South Korea ◽  
Influenza A ◽  
Multivariate Logistic Regression Analysis ◽  
H1n1 Influenza ◽  
Epidemiological Analysis ◽  
Influenza A H1n1 ◽  
Failure Assessment ◽  
2009 H1n1 ◽  
Independent Risk Factors ◽  
Chronic Comorbidities

SUMMARYA total of 245 patients with confirmed 2009 H1N1 influenza were admitted to the intensive-care units of 28 hospitals (South Korea). Their mean age was 55·3 years with 68·6% aged >50 years, and 54·7% male. Nine were obese and three were pregnant. One or more comorbidities were present in 83·7%, and nosocomial acquisition occurred in 14·3%. In total, 107 (43·7%) patients received corticosteroids and 66·1% required mechanical ventilation. Eighty (32·7%) patients died within 30 days after onset of symptoms and 99 (40·4%) within 90 days. Multivariate logistic regression analysis showed that the clinician's decision to prescribe corticosteroids, older age, Sequential Organ Failure Assessment score and nosocomial bacterial pneumonia were independent risk factors for 90-day mortality. In contrast with Western countries, critical illness in Korea in relation to 2009 H1N1 was most common in older patients with chronic comorbidities; nosocomial acquisition occurred occasionally but disease in obese or pregnant patients was uncommon.

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