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 Conservation and Diversity of Influenza A H1N1 HLA-Restricted T Cell Epitope Candidates for Epitope-Based Vaccines

PLoS ONE ◽  
2010 ◽  
Vol 5 (1) ◽  
pp. e8754 ◽  
Author(s):  
Paul ThiamJoo Tan ◽  
A. T. Heiny ◽  
Olivo Miotto ◽  
Jerome Salmon ◽  
Ernesto T. A. Marques ◽  
...  
Keyword(s):  
T Cell ◽  
Influenza A ◽  
Cell Epitope ◽  
T Cell Epitope ◽  
Influenza A H1n1

scholarly journals Narrowing of Human Influenza A Virus-Specific T Cell Receptor α and β Repertoires with Increasing Age

2015 ◽  
Vol 89 (8) ◽  
pp. 4102-4116 ◽  
Author(s):  
Anna Gil ◽  
Maryam B. Yassai ◽  
Yuri N. Naumov ◽  
Liisa K. Selin
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Influenza A Virus ◽  
Influenza A ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cell Receptor ◽  
Cross Reactivity ◽  
Older Individuals ◽  
Cell Responses

ABSTRACTAlterations in memory CD8 T cell responses may contribute to the high morbidity and mortality caused by seasonal influenza A virus (IAV) infections in older individuals. We questioned whether memory CD8 responses to this nonpersistent virus, to which recurrent exposure with new strains is common, changed over time with increasing age. Here, we show a direct correlation between increasing age and narrowing of the HLA-A2-restricted IAV Vα and Vβ T cell repertoires specific to M1 residues 58 to 66 (M158–66), which simultaneously lead to oligoclonal expansions, including the usage of a single identical VA12-JA29 clonotype in all eight older donors. The Vα repertoire of older individuals also had longer CDR3 regions with increased usage of G/A runs, whose molecular flexibility may enhance T cell receptor (TCR) promiscuity. Collectively, these results suggest that CD8 memory T cell responses to nonpersistent viruses like IAV in humans are dynamic, and with aging there is a reduced diversity but a preferential retention of T cell repertoires with features of enhanced cross-reactivity.IMPORTANCEWith increasing age, the immune system undergoes drastic changes, and older individuals have declined resistance to infections. Vaccinations become less effective, and infection with influenza A virus in older individuals is associated with higher morbidity and mortality. Here, we questioned whether T cell responses directed against the highly conserved HLA-A2-restricted M158–66peptide of IAV evolves with increasing age. Specifically, we postulated that CD8 T cell repertoires narrow with recurrent exposure and may thus be less efficient in response to new infections with new strains of IAV. Detailed analyses of the VA and VB TCR repertoires simultaneously showed a direct correlation between increasing age and narrowing of the TCR repertoire. Features of the TCRs indicated potentially enhanced cross-reactivity in all older donors. In summary, T cell repertoire analysis in older individuals may be useful as one of the predictors of protection after vaccination.

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.

scholarly journals Genetic Analysis Reveals Differences in CD8+ T Cell Epitope Regions That May Impact Cross-Reactivity of Vaccine-Induced T Cells against Wild-Type Mumps Viruses

Vaccines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 699
Author(s):  
Patricia Kaaijk ◽  
Maarten E. Emmelot ◽  
Jeroen Kerkhof ◽  
Cécile A.C.M. van Els ◽  
Hugo D. Meiring ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Critical Role ◽  
Cell Epitope ◽  
Human Leukocyte ◽  
Cd8 T Cell ◽  
Cross Reactivity ◽  
T Cell Epitope ◽  
Wild Type ◽  
Cell Immunity

Nowadays, mumps is re-emerging in highly vaccinated populations. Waning of vaccine-induced immunity plays a role, but antigenic differences between vaccine and mumps outbreak strains could also contribute to reduced vaccine effectiveness. CD8+ T cells play a critical role in immunity to viruses. However, limited data are available about sequence variability in CD8+ T cell epitope regions of mumps virus (MuV) proteins. Recently, the first set of naturally presented human leukocyte antigen Class I (HLA-I) epitopes of MuV was identified by us. In the present study, sequences of 40 CD8+ T cell epitope candidates, including previously and newly identified, obtained from Jeryl–Lynn mumps vaccine strains were compared with genomes from 462 circulating MuV strains. In 31 epitope candidates (78%) amino acid differences were detected, and in 17 (43%) of the epitope candidates the corresponding sequences in wild-type strains had reduced predicted HLA-I-binding compared to the vaccine strains. These findings suggest that vaccinated persons may have reduced T cell immunity to circulating mumps viruses due to antigenic differences.

scholarly journals The landscape of T cell epitope immunogenicity in sequence space

2017 ◽  
Author(s):  
Masato Ogishi ◽  
Hiroshi Yotsuyanagi
Keyword(s):  
T Cell ◽  
Cell Epitope ◽  
Cell Receptor ◽  
Single Amino Acid ◽  
Cell Reactivity ◽  
Human T Cell ◽  
Cell Immunity ◽  
Tcr Repertoire ◽  
Individualized Approach ◽  
T Cell Reactivity

SummaryThe existence of population-wide T cell immunity is widely recognized for multiple pathogen-derived immunodominant epitopes, despite the vast diversity and individualized nature of T cell receptor (TCR) repertoire. We thus hypothesized that population-wide epitope immunogenicity could be probabilistically defined by exploiting public TCR features. To gain a proof-of-concept, here we describe a machine learning framework yielding probabilistic estimates of immunogenicity, termed “immunogenicity scores”, by utilizing features designed to mimic thermodynamic interactions between peptides bound to major histocompatibility complex (MHC) and TCR repertoire. Immunogenicity score dynamics among observed and computationally simulated single amino acid mutants delineated the landscape of position- and residue-specific mutational impacts, and even quantitatively estimated escaping potentials of known epitopes with remarkable positional specificity. This study illustrates that the population-wide aspect of adaptive immunity is predictable via non-individualized approach, possibly indicating antigen-guided convergence of human T cell reactivity.

scholarly journals Vaccination against swine flu caused narcolepsy in several european countries

2020 ◽  
pp. 182-187
Author(s):  
I. Boström ◽  
◽  
O. Lindberger ◽  
M. Partinen ◽  
A.M. Landtblom ◽  
...  
Keyword(s):  
Influenza A ◽  
Strong Association ◽  
Diagnostic Delay ◽  
Sleep Onset ◽  
H1n1 Influenza ◽  
European Countries ◽  
Swine Flu ◽  
Increased Risk ◽  
2009 H1n1

Narcolepsy is a rare sleeping disorder that gives sleep onset rapid eye movement periods and excessive daytime sleepiness. It is divided into two subgroups, narcolepsy type 1 where there also is orexin deficiency and cataplexy and narcolepsy type 2 that lack these features. Narcolepsy type 1 is assumed to be an autoimmune disease with destruction of orexinproducing cells. The pathology behind is unclear. There is a strong association to a class II HLA allele, HLADQB1*06:02 and the H1N1-virus and streptococcal infections has also been associated with narcolepsy. The severity of narcolepsy differs between patients from those who can manage their disease without medication to those who has a severe impact on their everyday life. There is a diagnostic delay between the onset of symptoms and time for diagnosis that in some cases can be more than a decade. The global mean prevalence is 30 per 100 000 inhabitants. The incidence in children in northern Europe has risen since 2010. An early study of the 2009 H1N1 influenza A pandemic indicated a high mortality and prompted efforts to rapidly come up with a vaccine. One of these was Pandemrix that was the most widely used in Europe and 61 % of the inhabitants in Sweden was vaccinated. Studies have shown an increased incidence of narcolepsy type 1 in European countries that had used Pandemrix, but no increased risk was seen in countries that had used other vaccines than Pandemrix.

scholarly journals Vaccination against swine flu caused narcolepsy in several european countries

2020 ◽  
pp. 182-187
Author(s):  
I. Boström ◽  
◽  
O. Lindberger ◽  
M. Partinen ◽  
A.M. Landtblom ◽  
...  
Keyword(s):  
Influenza A ◽  
Strong Association ◽  
Diagnostic Delay ◽  
Sleep Onset ◽  
H1n1 Influenza ◽  
European Countries ◽  
Swine Flu ◽  
Increased Risk ◽  
2009 H1n1

Narcolepsy is a rare sleeping disorder that gives sleep onset rapid eye movement periods and excessive daytime sleepiness. It is divided into two subgroups, narcolepsy type 1 where there also is orexin deficiency and cataplexy and narcolepsy type 2 that lack these features. Narcolepsy type 1 is assumed to be an autoimmune disease with destruction of orexinproducing cells. The pathology behind is unclear. There is a strong association to a class II HLA allele, HLADQB1*06:02 and the H1N1-virus and streptococcal infections has also been associated with narcolepsy. The severity of narcolepsy differs between patients from those who can manage their disease without medication to those who has a severe impact on their everyday life. There is a diagnostic delay between the onset of symptoms and time for diagnosis that in some cases can be more than a decade. The global mean prevalence is 30 per 100 000 inhabitants. The incidence in children in northern Europe has risen since 2010. An early study of the 2009 H1N1 influenza A pandemic indicated a high mortality and prompted efforts to rapidly come up with a vaccine. One of these was Pandemrix that was the most widely used in Europe and 61 % of the inhabitants in Sweden was vaccinated. Studies have shown an increased incidence of narcolepsy type 1 in European countries that had used Pandemrix, but no increased risk was seen in countries that had used other vaccines than Pandemrix.

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 Balanced Cellular and Humoral Immune Responses Targeting Multiple Antigens in Adults Receiving a Quadrivalent Inactivated Influenza Vaccine

2021 ◽  
Author(s):  
Esther Dawen Yu ◽  
Alba Grifoni ◽  
Aaron Sutherland ◽  
Hannah Voic ◽  
Eric Wang ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Influenza Vaccine ◽  
Influenza A ◽  
Mononuclear Cells ◽  
Vaccine Development ◽  
Influenza B ◽  
Cell Reactivity ◽  
Cell Immunity ◽  
Influenza A H1n1

The role of T cell immunity has been acknowledged in recent vaccine development and evaluation. We tested the humoral and cellular immune responses to Flucelvax®, a quadrivalent inactivated seasonal influenza vaccine containing two influenza A (H1N1 Singapore/GP1908/2015 IVR-180 and H3N2 North Carolina/04/2016) and two influenza B (Iowa/06/2017 and Singapore/INFTT-16-0610/2016) virus strains, using peripheral blood mononuclear cells stimulated by pools of peptides overlapping all the individual influenza viral protein components. Baseline reactivity was detected against all four strains both at the level of CD4 and CD8 responses and targeting different proteins. CD4 T cell reactivity was mostly directed to HA/NA proteins in influenza B strains, and NP/M1/M2/NS1/NEP proteins in the case of the Influenza A strains. CD8 responses to both influenza A and B viruses preferentially targeted the more conserved core viral proteins. Following vaccination, both CD4 and CD8 responses against the various influenza antigens were increased in day 15 to day 91 post vaccination period and maintained a Th1 polarized profile. Importantly, no vaccine interference was detected, with the increased responses balanced across all 4 included viral strains for both CD4 and CD8 T cells, and targeting HA and multiple additional viral antigens.

scholarly journals Molecular basis for universal HLA-A*0201–restricted CD8+ T-cell immunity against influenza viruses

2016 ◽  
Vol 113 (16) ◽  
pp. 4440-4445 ◽  
Author(s):  
Sophie A. Valkenburg ◽  
Tracy M. Josephs ◽  
E. Bridie Clemens ◽  
Emma J. Grant ◽  
Thi H. O. Nguyen ◽  
...  
Keyword(s):  
T Cell ◽  
Influenza A ◽  
Molecular Mimicry ◽  
Ex Vivo ◽  
Cell Receptor ◽  
Influenza Viruses ◽  
Antigenic Peptides ◽  
Cell Immunity ◽  
Relative Conservation ◽  
Immune Efficacy

Memory CD8+ T lymphocytes (CTLs) specific for antigenic peptides derived from internal viral proteins confer broad protection against distinct strains of influenza A virus (IAV). However, immune efficacy can be undermined by the emergence of escape mutants. To determine how T-cell receptor (TCR) composition relates to IAV epitope variability, we used ex vivo peptide–HLA tetramer enrichment and single-cell multiplex analysis to compare TCRs targeted to the largely conserved HLA-A*0201-M158 and the hypervariable HLA-B*3501-NP418 antigens. The TCRαβs for HLA-B*3501-NP418+ CTLs varied among individuals and across IAV strains, indicating that a range of mutated peptides will prime different NP418-specific CTL sets. Conversely, a dominant public TRAV27/TRBV19+ TCRαβ was selected in HLA-A*0201+ donors responding to M158. This public TCR cross-recognized naturally occurring M158 variants complexed with HLA-A*0201. Ternary structures showed that induced-fit molecular mimicry underpins TRAV27/TRBV19+ TCR specificity for the WT and mutant M158 peptides, suggesting the possibility of universal CTL immunity in HLA-A*0201+ individuals. Combined with the high population frequency of HLA-A*0201, these data potentially explain the relative conservation of M158. Moreover, our results suggest that vaccination strategies aimed at generating broad protection should incorporate variant peptides to elicit cross-reactive responses against other specificities, especially those that may be relatively infrequent among IAV-primed memory CTLs.

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