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The Proximal Airway Is a Reservoir for Adaptive Immunologic Memory in Idiopathic Subglottic Stenosis.
Gelbard A, Wanjalla C, Wootten CT, Drake WP, Lowery AS, Wheeler DA, Cardenas MF, Sikora AG, Pathak RR, McDonnell W, Mallal S, Pilkinton M
(2021) Laryngoscope 131: 610-617
MeSH Terms: Adult, Aged, Airway Obstruction, Antigens, CD, Antigens, Differentiation, T-Lymphocyte, CD8 Antigens, Cicatrix, Constriction, Pathologic, Female, Glottis, Humans, Immunohistochemistry, Immunologic Memory, Integrin alpha Chains, Laryngostenosis, Lectins, C-Type, Male, Middle Aged, T-Lymphocyte Subsets
Show Abstract · Added July 30, 2020
OBJECTIVES/HYPOTHESIS - Characterization of the localized adaptive immune response in the airway scar of patients with idiopathic subglottic stenosis (iSGS).
STUDY DESIGN - Basic Science.
METHODS - Utilizing 36 patients with subglottic stenosis (25 idiopathic subglottic stenosis [iSGS], 10 iatrogenic post-intubation stenosis [iLTS], and one granulomatosis with polyangiitis [GPA]) we applied immunohistochemical and immunologic techniques coupled with RNA sequencing.
RESULTS - iSGS, iLTS, and GPA demonstrate a significant immune infiltrate in the subglottic scar consisting of adaptive cell subsets (T cells along with dendritic cells). Interrogation of T cell subtypes showed significantly more CD69 CD103 CD8 tissue resident memory T cells (T ) in the iSGS airway scar than iLTS specimens (iSGS vs. iLTS; 50% vs. 28%, P = .0065). Additionally, subglottic CD8 clones possessed T-cell receptor (TCR) sequences with known antigen specificity for viral and intracellular pathogens.
CONCLUSIONS - The human subglottis is significantly enriched for CD8 tissue resident memory T cells in iSGS, which possess TCR sequences proven to recognize viral and intracellular pathogens. These results inform our understanding of iSGS, provide a direction for future discovery, and demonstrate immunologic function in the human proximal airway. Laryngoscope, 131:610-617, 2021.
© 2020 The American Laryngological, Rhinological and Otological Society, Inc.
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19 MeSH Terms
Bacterial CagA protein compromises tumor suppressor mechanisms in gastric epithelial cells.
Palrasu M, Zaika E, El-Rifai W, Garcia-Buitrago M, Piazuelo MB, Wilson KT, Peek RM, Zaika AI
(2020) J Clin Invest 130: 2422-2434
MeSH Terms: Antigens, Bacterial, Apoptosis Regulatory Proteins, Bacterial Proteins, Epithelial Cells, Gastric Mucosa, HCT116 Cells, Helicobacter pylori, Humans, Neoplasm Proteins, Proteolysis, Stomach Neoplasms, Ubiquitination, X-Linked Inhibitor of Apoptosis Protein
Show Abstract · Added April 7, 2020
Approximately half of the world's population is infected with the stomach pathogen Helicobacter pylori. Infection with H. pylori is the main risk factor for distal gastric cancer. Bacterial virulence factors, such as the oncoprotein CagA, augment cancer risk. Yet despite high infection rates, only a fraction of H. pylori-infected individuals develop gastric cancer. This raises the question of defining the specific host and bacterial factors responsible for gastric tumorigenesis. To investigate the tumorigenic determinants, we analyzed gastric tissues from human subjects and animals infected with H. pylori bacteria harboring different CagA status. For laboratory studies, well-defined H. pylori strain B128 and its cancerogenic derivative strain 7.13, as well as various bacterial isogenic mutants were employed. We found that H. pylori compromises key tumor suppressor mechanisms: the host stress and apoptotic responses. Our studies showed that CagA induces phosphorylation of XIAP E3 ubiquitin ligase, which enhances ubiquitination and proteasomal degradation of the host proapoptotic factor Siva1. This process is mediated by the PI3K/Akt pathway. Inhibition of Siva1 by H. pylori increases survival of human cells with damaged DNA. It occurs in a strain-specific manner and is associated with the ability to induce gastric tumor.
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New genetic predictors for abacavir tolerance in HLA-B*57:01 positive individuals.
Pavlos R, Deshpande P, Chopra A, Leary S, Strautins K, Nolan D, Thorborn D, Shaefer M, Rauch A, Dunn D, Montaner J, Rachlis A, Almeida CA, Choo L, James I, Redwood AJ, Li Y, Gaudieri S, Mallal SA, Phillips EJ
(2020) Hum Immunol 81: 300-304
MeSH Terms: Allergens, Aminopeptidases, Anti-HIV Agents, Dideoxynucleosides, Drug Hypersensitivity Syndrome, Drug-Related Side Effects and Adverse Reactions, Female, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, HIV Infections, HIV-1, HLA-B Antigens, Humans, Lipopolysaccharide Receptors, Male, Minor Histocompatibility Antigens, Phenotype, Retrospective Studies
Show Abstract · Added March 30, 2020
Abacavir hypersensitivity syndrome (ABC HSS) is strongly associated with carriage of human leukocyte antigen (HLA)-B*57:01, which has a 100% negative predictive value for the development of ABC HSS. However, 45% of individuals who carry HLA-B*57:01 can tolerate ABC. We investigated immune and non-immune related genes in ABC HSS (n = 95) and ABC tolerant (n = 43) HLA-B*57:01 + patients to determine other factors required for the development of ABC HSS. Assignment of phenotype showed that ABC HSS subjects were significantly less likely than tolerants to carry only ERAP1 hypoactive trimming allotypes (p = 0.02). An altered self-peptide repertoire model by which abacavir activates T cells is in keeping with observation that endoplasmic reticulum aminopeptidase 1 (ERAP1) allotypes that favour efficient peptide trimming are more common in ABC HSS patients compared to patients who tolerate ABC. Independently, non-specific immune activation via soluble cluster of differentiation antigen 14 (sCD14) may also influence susceptibility to ABC HSS.
Copyright © 2020 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.
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Bacterial Energetic Requirements for Helicobacter pylori Cag Type IV Secretion System-Dependent Alterations in Gastric Epithelial Cells.
Lin AS, Dooyema SDR, Frick-Cheng AE, Harvey ML, Suarez G, Loh JT, McDonald WH, McClain MS, Peek RM, Cover TL
(2020) Infect Immun 88:
MeSH Terms: Antigens, Bacterial, Bacterial Proteins, Biological Transport, DNA, Bacterial, Epithelial Cells, Helicobacter pylori, Humans, Interleukin-8, Lipopolysaccharides, NF-kappa B, Peptidoglycan, Toll-Like Receptor 9, Type IV Secretion Systems, Virulence Factors
Show Abstract · Added March 3, 2020
colonizes the stomach in about half of the world's population. strains containing the pathogenicity island ( PAI) are associated with a higher risk of gastric adenocarcinoma or peptic ulcer disease than PAI-negative strains. The PAI encodes a type IV secretion system (T4SS) that mediates delivery of the CagA effector protein as well as nonprotein bacterial constituents into gastric epithelial cells. -induced nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation and interleukin-8 (IL-8) secretion are attributed to T4SS-dependent delivery of lipopolysaccharide metabolites and peptidoglycan into host cells, and Toll-like receptor 9 (TLR9) activation is attributed to delivery of bacterial DNA. In this study, we analyzed the bacterial energetic requirements associated with these cellular alterations. Mutant strains lacking Cagα, Cagβ, or CagE (putative ATPases corresponding to VirB11, VirD4, and VirB4 in prototypical T4SSs) were capable of T4SS core complex assembly but defective in CagA translocation into host cells. Thus, the three Cag ATPases are not functionally redundant. Cagα and CagE were required for -induced NF-κB activation, IL-8 secretion, and TLR9 activation, but Cagβ was dispensable for these responses. We identified putative ATP-binding motifs (Walker-A and Walker-B) in each of the ATPases and generated mutant strains in which these motifs were altered. Each of the Walker box mutant strains exhibited properties identical to those of the corresponding deletion mutant strains. These data suggest that Cag T4SS-dependent delivery of nonprotein bacterial constituents into host cells occurs through mechanisms different from those used for recruitment and delivery of CagA into host cells.
Copyright © 2020 American Society for Microbiology.
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MeSH Terms
Histone deacetylase 3 controls a transcriptional network required for B cell maturation.
Stengel KR, Bhaskara S, Wang J, Liu Q, Ellis JD, Sampathi S, Hiebert SW
(2019) Nucleic Acids Res 47: 10612-10627
MeSH Terms: Animals, Antigens, CD19, B-Lymphocytes, Base Sequence, Cell Differentiation, Gene Expression Regulation, Gene Regulatory Networks, Histone Deacetylase Inhibitors, Histone Deacetylases, Lipopolysaccharides, Lymphocyte Activation, Mice, Inbred C57BL, Plasma Cells, Positive Regulatory Domain I-Binding Factor 1, Proto-Oncogene Proteins c-bcl-6, Repressor Proteins, Transcription, Genetic, Up-Regulation
Show Abstract · Added October 25, 2019
Histone deacetylase 3 (Hdac3) is a target of the FDA approved HDAC inhibitors, which are used for the treatment of lymphoid malignancies. Here, we used Cd19-Cre to conditionally delete Hdac3 to define its role in germinal center B cells, which represent the cell of origin for many B cell malignancies. Cd19-Cre-Hdac3-/- mice showed impaired germinal center formation along with a defect in plasmablast production. Analysis of Hdac3-/- germinal centers revealed a reduction in dark zone centroblasts and accumulation of light zone centrocytes. RNA-seq revealed a significant correlation between genes up-regulated upon Hdac3 loss and those up-regulated in Foxo1-deleted germinal center B cells, even though Foxo1 typically activates transcription. Therefore, to determine whether gene expression changes observed in Hdac3-/- germinal centers were a result of direct effects of Hdac3 deacetylase activity, we used an HDAC3 selective inhibitor and examined nascent transcription in germinal center-derived cell lines. Transcriptional changes upon HDAC3 inhibition were enriched for light zone gene signatures as observed in germinal centers. Further comparison of PRO-seq data with ChIP-seq/exo data for BCL6, SMRT, FOXO1 and H3K27ac identified direct targets of HDAC3 function including CD86, CD83 and CXCR5 that are likely responsible for driving the light zone phenotype observed in vivo.
© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.
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18 MeSH Terms
Single-cell transcriptomics reveal polyclonal memory T-cell responses in skin with positive abacavir patch test results.
Redwood AJ, Rwandamuriye F, Chopra A, Leary S, Ram R, McDonnell W, Konvinse K, White K, Pavlos R, Koelle DM, Mallal S, Phillips EJ
(2019) J Allergy Clin Immunol 144: 1413-1416.e7
MeSH Terms: Aged, Anti-HIV Agents, Arthralgia, CD8-Positive T-Lymphocytes, Dideoxynucleosides, Drug Hypersensitivity, Drug-Related Side Effects and Adverse Reactions, Gene Expression Profiling, HLA-B Antigens, Headache, Humans, Immunologic Memory, Lymphocyte Activation, Male, Myalgia, Patch Tests, Single-Cell Analysis, Skin
Added March 30, 2020
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18 MeSH Terms
Editorial: Role of CD1- and MR1-Restricted T Cells in Immunity and Disease.
Iwabuchi K, Van Kaer L
(2019) Front Immunol 10: 1837
MeSH Terms: Animals, Antigens, CD1, Histocompatibility Antigens Class I, Humans, Minor Histocompatibility Antigens, Mucosal-Associated Invariant T Cells, Natural Killer T-Cells, Receptors, Antigen, T-Cell, T-Lymphocytes
Added March 3, 2020
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9 MeSH Terms
Characterization of Magnitude and Antigen Specificity of HLA-DP, DQ, and DRB3/4/5 Restricted DENV-Specific CD4+ T Cell Responses.
Grifoni A, Moore E, Voic H, Sidney J, Phillips E, Jadi R, Mallal S, De Silva AD, De Silva AM, Peters B, Weiskopf D, Sette A
(2019) Front Immunol 10: 1568
MeSH Terms: Alleles, Antibody Specificity, CD4-Positive T-Lymphocytes, Dengue, Dengue Virus, Epitopes, T-Lymphocyte, HLA-DP Antigens, HLA-DRB1 Chains, Humans, Interferon-gamma
Show Abstract · Added March 30, 2020
Dengue Virus (DENV) associated disease is a major public health problem. Assessment of HLA class II restricted DENV-specific responses is relevant for immunopathology and definition of correlates of protection. While previous studies characterized responses restricted by the HLA-DRB1 locus, the responses associated with other class II loci have not been characterized to date. Accordingly, we mapped HLA-DP, DQ, and DRB3/4/5 restricted DENV-specific CD4 T cell epitopes in PBMCs derived from the DENV endemic region Sri Lanka. We studied 12 DP, DQ, and DRB3/4/5 alleles that are commonly expressed and provide worldwide coverage >82% for each of the loci analyzed and >99% when combined. CD4+ T cells purified by negative selection were stimulated with pools of HLA-predicted binders for 2 weeks with autologous APC. Epitope reactive T cells were enumerated using IFNγ ELISPOT assay. This strategy was previously applied to identify DRB1 restricted epitopes. In parallel, membrane expression levels of HLA-DR, DP, and DQ proteins was assessed using flow cytometry. Epitopes were identified for all DP, DQ, and DRB3/4/5 allelic variants albeit with magnitudes significantly lower than the ones previously observed for the DRB1 locus. This was in line with lower membrane expression of HLA-DP and DQ molecules on the PBMCs tested, as compared to HLA-DR. Significant differences between loci were observed in antigen immunodominance. Capsid responses were dominant for DRB1/3/4/5 and DP alleles but negligible for the DQ alleles. NS3 responses were dominant in the case of DRB1/3/4/5 and DQ but absent in the case of DP. NS1 responses were prominent in the case of the DP alleles, but negligible in the case of DR and DQ. In terms of epitope specificity, repertoire was largely overlapping between DRB1 and DRB3/4/5, while DP and DQ loci recognized largely distinct epitope sets. The HLA-DP, DQ, and DRB3/4/5 loci mediate DENV-CD4 specific immune responses of lower magnitude as compared to HLA-DRB1, consistent with their lower levels of expression. The responses are associated with distinct and characteristic patterns of immunodominance, and variable epitope overlap across loci.
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10 MeSH Terms
High and variable population prevalence of HLA-B*56:02 in indigenous Australians and relation to phenytoin-associated drug reaction with eosinophilia and systemic symptoms.
Somogyi AA, Barratt DT, Phillips EJ, Moore K, Ilyas F, Gabb GM
(2019) Br J Clin Pharmacol 85: 2163-2169
MeSH Terms: Adolescent, Adult, Aged, Australia, Biological Variation, Population, Cohort Studies, Cytochrome P-450 CYP2C9, Drug Hypersensitivity Syndrome, Female, Gene Frequency, Genetic Predisposition to Disease, Genotyping Techniques, HLA-B Antigens, Humans, Indigenous Peoples, Male, Middle Aged, Phenytoin, Young Adult
Show Abstract · Added March 30, 2020
Phenytoin drug reaction with eosinophilia and systemic symptoms (DRESS) in 3 Aboriginal Australians positive for HLA-B*56:02 has been previously reported. We report the allele frequency of HLA-B*56:02 in 2 South Australian populations, 1 Aboriginal (4.8%, 95% confidence interval 2.4-7.8%) and the other European (0%). We compared the frequency with publicly available information on HLA-B*56:02 status in other Indigenous Australian (n = 4) and European Australian cohorts (n = 1). In the Indigenous Australian cohorts, HLA-B*56:02 allele frequency ranged from 1.3 to 19%. We also describe an additional case of phenytoin DRESS (RegiSCAR DRESS score 7) in an Aboriginal Australian that was associated with HLA-B*56:02 and with CYP2C9*1/*3 genotype. In Aboriginal Australians, phenytoin DRESS appears distinctly linked to HLA-B*56:02 with an allele carriage rate substantially higher than in Europeans, but also with considerable regional variation. Investigations of human leucocyte antigen and other contributing genes and severe adverse drug reactions in understudied non-European populations are required to optimize safe medication use and inform risk mitigation strategies.
© 2019 The British Pharmacological Society.
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19 MeSH Terms
Systematic review with meta-analysis: association between Helicobacter pylori CagA seropositivity and odds of inflammatory bowel disease.
Tepler A, Narula N, Peek RM, Patel A, Edelson C, Colombel JF, Shah SC
(2019) Aliment Pharmacol Ther 50: 121-131
MeSH Terms: Adolescent, Adult, Antibodies, Bacterial, Antigens, Bacterial, Bacterial Proteins, Colitis, Ulcerative, Comorbidity, Crohn Disease, Female, Helicobacter Infections, Helicobacter pylori, Humans, Inflammatory Bowel Diseases, Male, Middle Aged, Seroepidemiologic Studies, Young Adult
Show Abstract · Added March 3, 2020
BACKGROUND - Accumulating data support a protective role of Helicobacter pylori against inflammatory bowel diseases (IBD), which might be mediated by strain-specific constituents, specifically cagA expression.
AIM - To perform a systematic review and meta-analysis to more clearly define the association between CagA seropositivity and IBD.
METHODS - We identified comparative studies that included sufficient detail to determine the odds or risk of IBD, Crohn's disease (CD) or ulcerative colitis (UC) amongst individuals with vs without evidence of cagA expression (eg CagA seropositivity). Estimates were pooled using a random effects model.
RESULTS - Three clinical studies met inclusion criteria. cagA expression was represented by CagA seropositivity in all studies. Compared to CagA seronegativity overall, CagA seropositivity was associated with lower odds of IBD (OR 0.31, 95% CI 0.21-0.44) and CD (OR 0.25, 95% CI 0.17-0.38), and statistically nonsignificant lower odds for UC (OR 0.68, 95% CI 0.35-1.32). Similarly, compared to H pylori non-exposed individuals, H pylori exposed, CagA seropositive individuals had lower odds of IBD (OR 0.26, 95% CI 0.16-0.41) and CD (OR 0.23, 95% CI 0.15-0.35), but not UC (OR 0.66, 0.34-1.27). However, there was no significant difference in the odds of IBD, CD or UC between H pylori exposed, CagA seronegative and H pylori non-exposed individuals.
CONCLUSION - We found evidence for a significant association between CagA seropositive H pylori exposure and reduced odds of IBD, particularly CD, but not for CagA seronegative H pylori exposure. Additional studies are needed to confirm these findings and define underlying mechanisms.
© 2019 John Wiley & Sons Ltd.
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17 MeSH Terms