Displaying publications 1 - 20 of 81 in total

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  1. Zepeda-Ortega B, Goh A, Xepapadaki P, Sprikkelman A, Nicolaou N, Hernandez REH, et al.
    Front Immunol, 2021;12:608372.
    PMID: 34177882 DOI: 10.3389/fimmu.2021.608372
    The prevalence of food allergy has increased over the last 20-30 years, including cow milk allergy (CMA) which is one of the most common causes of infant food allergy. International allergy experts met in 2019 to discuss broad topics in allergy prevention and management of CMA including current challenges and future opportunities. The highlights of the meeting combined with recently published developments are presented here. Primary prevention of CMA should start from pre-pregnancy with a focus on a healthy lifestyle and food diversity to ensure adequate transfer of inhibitory IgG- allergen immune complexes across the placenta especially in mothers with a history of allergic diseases and planned c-section delivery. For non-breastfed infants, there is controversy about the preventive role of partially hydrolyzed formulae (pHF) despite some evidence of health economic benefits among those with a family history of allergy. Clinical management of CMA consists of secondary prevention with a focus on the development of early oral tolerance. The use of extensive Hydrolysate Formulae (eHF) is the nutrition of choice for the majority of non-breastfed infants with CMA; potentially with pre-, probiotics and LCPUFA to support early oral tolerance induction. Future opportunities are, among others, pre- and probiotics supplementation for mothers and high-risk infants for the primary prevention of CMA. A controlled prospective study implementing a step-down milk formulae ladder with various degrees of hydrolysate is proposed for food challenges and early development of oral tolerance. This provides a more precise gradation of milk protein exposure than those currently recommended.
  2. Yıldırım-Buharalıoğlu G, Bond M, Sala-Newby GB, Hindmarch CC, Newby AC
    Front Immunol, 2017;8:92.
    PMID: 28228757 DOI: 10.3389/fimmu.2017.00092
    BACKGROUND: Interferon-γ (IFN-γ) or interleukin-4 (IL-4) drives widely different transcriptional programs in macrophages. However, how IFN-γ and IL-4 alter expression of histone-modifying enzymes involved in epigenetic regulation and how this affects the resulting phenotypic polarization is incompletely understood.

    METHODS AND RESULTS: We investigated steady-state messenger RNA levels of 84 histone-modifying enzymes and related regulators in colony-stimulating factor-1 differentiated primary human macrophages using quantitative polymerase chain reaction. IFN-γ or IL-4 treatment for 6-48 h changed 11 mRNAs significantly. IFN-γ increased CIITA, KDM6B, and NCOA1, and IL-4 also increased KDM6B by 6 h. However, either cytokine decreased AURKB, ESCO2, SETD6, SUV39H1, and WHSC1, whereas IFN-γ alone decreased KAT2A, PRMT7, and SMYD3 mRNAs only after 18 h, which coincided with decreased cell proliferation. Rendering macrophages quiescent by growth factor starvation or adenovirus-mediated overexpression of p27(kip1) inhibited expression of AURKB, ESCO2, SUV39H1, and WHSC1, and mRNA levels were restored by overexpressing the S-phase transcription factor E2F1, implying their expression, at least partly, depended on proliferation. However, CIITA, KDM6B, NCOA1, KAT2A, PRMT7, SETD6, and SMYD3 were regulated independently of effects on proliferation. Silencing KDM6B, the only transcriptional activator upregulated by both IFN-γ and IL-4, pharmacologically or with short hairpin RNA, blunted a subset of responses to each cytokine.

    CONCLUSION: These findings demonstrate that IFN-γ or IL-4 can regulate the expression of histone acetyl transferases and histone methyl transferases independently of effects on proliferation and that upregulation of the histone demethylase, KDM6B, assists phenotypic polarization by both cytokines.

  3. Yong YK, Saeidi A, Tan HY, Rosmawati M, Enström PF, Batran RA, et al.
    Front Immunol, 2018;9:472.
    PMID: 29616020 DOI: 10.3389/fimmu.2018.00472
    Mucosal-associated invariant T (MAIT) cells, defined as CD161++TCR iVα7.2+ T cells, play an important role in the innate defense against bacterial infections, and their functionality is impaired in chronic viral infections. Here, we investigated the frequency and functional role of MAIT cells in chronic hepatitis B virus (HBV) infection. The peripheral CD3+CD161++TCR iVα7.2+ MAIT cells in chronic HBV-infected patients and healthy controls were phenotypically characterized based on CD57, PD-1, TIM-3, and CTLA-4, as well as HLA-DR and CD38 expression. The frequency of MAIT cells was significantly decreased among chronic HBV-infected individuals as compared to controls. Expression of CD57, PD-1, CTLA-4, as well as HLA-DR and CD38 on MAIT cells was significantly elevated in chronic HBV-infected individuals relative to controls. The percentage of T cell receptor (TCR) iVα7.2+ CD161+ MAIT cells did not correlate with HBV viral load but inversely with HLA-DR on CD4+ T cells and MAIT cells and with CD57 on CD8+ T cells suggesting that decrease of MAIT cells may not be attributed to direct infection by HBV but driven by HBV-induced chronic immune activation. The percentage and expression levels of PD-1 as well as CTLA-4 on MAIT cells inversely correlated with plasma HBV-DNA levels, which may suggest either a role for MAIT cells in the control of HBV infection or the effect of HBV replication in the liver on MAIT cell phenotype. We report that decrease of TCR iVα7.2+ MAIT cells in the peripheral blood and their functions were seemingly impaired in chronic HBV-infected patients likely because of the increased expression of PD-1.
  4. Yong YK, Wong WF, Vignesh R, Chattopadhyay I, Velu V, Tan HY, et al.
    Front Immunol, 2022;13:889196.
    PMID: 35874775 DOI: 10.3389/fimmu.2022.889196
    The dynamics of host-virus interactions, and impairment of the host's immune surveillance by dengue virus (DENV) serotypes largely remain ambiguous. Several experimental and preclinical studies have demonstrated how the virus brings about severe disease by activating immune cells and other key elements of the inflammatory cascade. Plasmablasts are activated during primary and secondary infections, and play a determinative role in severe dengue. The cross-reactivity of DENV immune responses with other flaviviruses can have implications both for cross-protection and severity of disease. The consequences of a cross-reactivity between DENV and anti-SARS-CoV-2 responses are highly relevant in endemic areas. Here, we review the latest progress in the understanding of dengue immunopathogenesis and provide suggestions to the development of target strategies against dengue.
  5. Wang C, Zainal NS, Chai SJ, Dickie J, Gan CP, Zulaziz N, et al.
    Front Immunol, 2021;12:763086.
    PMID: 34733290 DOI: 10.3389/fimmu.2021.763086
    HPV-independent head and neck squamous cell carcinoma (HNSCC) is a common cancer globally. The overall response rate to anti-PD1 checkpoint inhibitors (CPIs) in HNSCC is ~16%. One major factor influencing the effectiveness of CPI is the level of tumor infiltrating T cells (TILs). Converting TILlow tumors to TILhigh tumors is thus critical to improve clinical outcome. Here we describe a novel DNA vaccines to facilitate the T-cell infiltration and control tumor growth. We evaluated the expression of target antigens and their respective immunogenicity in HNSCC patients. The efficacy of DNA vaccines targeting two novel antigens were evaluated with or without CPI using a syngeneic model. Most HNSCC patients (43/44) co-expressed MAGED4B and FJX1 and their respective tetramer-specific T cells were in the range of 0.06-0.12%. In a preclinical model, antigen-specific T cells were induced by DNA vaccines and increased T cell infiltration into the tumor, but not MDSC or regulatory T cells. The vaccines inhibited tumor growth and improved the outcome alone and upon combination with anti-PD1 and resulted in tumor clearance in approximately 75% of mice. Pre-existence of MAGED4B and FJX1-reactive T cells in HNSCC patients suggests that these widely expressed antigens are highly immunogenic and could be further expanded by vaccination. The DNA vaccines targeting these antigens induced robust T cell responses and with the anti-PD1 antibody conferring excellent tumor control. This opens up an opportunity for combination immunotherapy that might benefit a wider population of HNSCC patients in an antigen-specific manner.
  6. Tong DL, Kempsell KE, Szakmany T, Ball G
    Front Immunol, 2020;11:380.
    PMID: 32318053 DOI: 10.3389/fimmu.2020.00380
    Sepsis is defined as dysregulated host response caused by systemic infection, leading to organ failure. It is a life-threatening condition, often requiring admission to an intensive care unit (ICU). The causative agents and processes involved are multifactorial but are characterized by an overarching inflammatory response, sharing elements in common with severe inflammatory response syndrome (SIRS) of non-infectious origin. Sepsis presents with a range of pathophysiological and genetic features which make clinical differentiation from SIRS very challenging. This may reflect a poor understanding of the key gene inter-activities and/or pathway associations underlying these disease processes. Improved understanding is critical for early differential recognition of sepsis and SIRS and to improve patient management and clinical outcomes. Judicious selection of gene biomarkers suitable for development of diagnostic tests/testing could make differentiation of sepsis and SIRS feasible. Here we describe a methodologic framework for the identification and validation of biomarkers in SIRS, sepsis and septic shock patients, using a 2-tier gene screening, artificial neural network (ANN) data mining technique, using previously published gene expression datasets. Eight key hub markers have been identified which may delineate distinct, core disease processes and which show potential for informing underlying immunological and pathological processes and thus patient stratification and treatment. These do not show sufficient fold change differences between the different disease states to be useful as primary diagnostic biomarkers, but are instrumental in identifying candidate pathways and other associated biomarkers for further exploration.
  7. Tan LY, Komarasamy TV, Rmt Balasubramaniam V
    Front Immunol, 2021;12:742941.
    PMID: 34659238 DOI: 10.3389/fimmu.2021.742941
    The coronavirus disease-19 (COVID-19) elicited by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused devastating health, economic and social impact worldwide. Its clinical spectrum ranges from asymptomatic to respiratory failure and multi-organ failure or death. The pathogenesis of SARS-CoV-2 infection is attributed to a complex interplay between virus and host immune response. It involves activation of multiple inflammatory pathways leading to hyperinflammation and cytokine storm, resulting in tissue damage, acute respiratory distress syndrome (ARDS) and multi-organ failure. Accumulating evidence has raised concern over the long-term health effects of COVID-19. Importantly, the neuroinvasive potential of SARS-CoV-2 may have devastating consequences in the brain. This review provides a conceptual framework on how the virus tricks the host immune system to induce infection and cause severe disease. We also explore the key differences between mild and severe COVID-19 and its short- and long-term effects, particularly on the human brain.
  8. Tan K, Zhang H, Lim LS, Ma H, Li S, Zheng H
    Front Immunol, 2019;10:3041.
    PMID: 32010132 DOI: 10.3389/fimmu.2019.03041
    Carotenoids are biologically active pigments that are well-known to enhance the defense and immunity of the vertebrate system. However, in invertebrates, the role of carotenoids in immunity is not clear. Therefore, this study aims to review the scientific evidence for the role of carotenoids in invertebrate immunization. From the analysis of published literatures and recent studies from our laboratory, it is obvious that carotenoids are involved in invertebrate immunity in two ways. On the one hand, carotenoids can act as antioxidant enzymes to remove singlet oxygen, superoxide anion radicals, and hydroxyl radicals, thereby reducing SOD activity and reducing the cost of immunity. In some organisms, carotenoids have been shown to promote SOD activity by up-regulating the expression of the ZnCuSOD gene. Carotenoids, on the other hand, play a role in the expression and regulation of many genes involved in invertebrate immunity, including thioredoxins (TRX), peptidoglycan recognition receptor proteins (PGRPs), ferritins, prophenoloxidase (ProPO), vitellogenin (Vg), toll-like receptor (TLRs), heat shock proteins (HSPs), and CuZnSOD gene. The information in this review is very useful for updating our understanding of the progress of carotenoid research in invertebrate immunology and to help identify topics for future topics.
  9. Szakmany T, Fitzgerald E, Garlant HN, Whitehouse T, Molnar T, Shah S, et al.
    Front Immunol, 2023;14:1308530.
    PMID: 38332914 DOI: 10.3389/fimmu.2023.1308530
    INTRODUCTION: Early diagnosis of sepsis and discrimination from SIRS is crucial for clinicians to provide appropriate care, management and treatment to critically ill patients. We describe identification of mRNA biomarkers from peripheral blood leukocytes, able to identify severe, systemic inflammation (irrespective of origin) and differentiate Sepsis from SIRS, in adult patients within a multi-center clinical study.

    METHODS: Participants were recruited in Intensive Care Units (ICUs) from multiple UK hospitals, including fifty-nine patients with abdominal sepsis, eighty-four patients with pulmonary sepsis, forty-two SIRS patients with Out-of-Hospital Cardiac Arrest (OOHCA), sampled at four time points, in addition to thirty healthy control donors. Multiple clinical parameters were measured, including SOFA score, with many differences observed between SIRS and sepsis groups. Differential gene expression analyses were performed using microarray hybridization and data analyzed using a combination of parametric and non-parametric statistical tools.

    RESULTS: Nineteen high-performance, differentially expressed mRNA biomarkers were identified between control and combined SIRS/Sepsis groups (FC>20.0, p<0.05), termed 'indicators of inflammation' (I°I), including CD177, FAM20A and OLAH. Best-performing minimal signatures e.g. FAM20A/OLAH showed good accuracy for determination of severe, systemic inflammation (AUC>0.99). Twenty entities, termed 'SIRS or Sepsis' (S°S) biomarkers, were differentially expressed between sepsis and SIRS (FC>2·0, p-value<0.05).

    DISCUSSION: The best performing signature for discriminating sepsis from SIRS was CMTM5/CETP/PLA2G7/MIA/MPP3 (AUC=0.9758). The I°I and S°S signatures performed variably in other independent gene expression datasets, this may be due to technical variation in the study/assay platform.

  10. Saeidi A, Zandi K, Cheok YY, Saeidi H, Wong WF, Lee CYQ, et al.
    Front Immunol, 2018;9:2569.
    PMID: 30473697 DOI: 10.3389/fimmu.2018.02569
    T-cell exhaustion is a phenomenon of dysfunction or physical elimination of antigen-specific T cells reported in human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) infections as well as cancer. Exhaustion appears to be often restricted to CD8+ T cells responses in the literature, although CD4+ T cells have also been reported to be functionally exhausted in certain chronic infections. Although our understanding of the molecular mechanisms associated with the transcriptional regulation of T-cell exhaustion is advancing, it is imperative to also explore the central mechanisms that control the altered expression patterns. Targeting metabolic dysfunctions with mitochondrion-targeted antioxidants are also expected to improve the antiviral functions of exhausted virus-specific CD8+ T cells. In addition, it is crucial to consider the contributions of mitochondrial biogenesis on T-cell exhaustion and how mitochondrial metabolism of T cells could be targeted whilst treating chronic viral infections. Here, we review the current understanding of cardinal features of T-cell exhaustion in chronic infections, and have attempted to focus on recent discoveries, potential strategies to reverse exhaustion and reinvigorate optimal protective immune responses in the host.
  11. Ripen AM, Chiow MY, Rama Rao PR, Mohamad SB
    Front Immunol, 2021;12:778133.
    PMID: 34804071 DOI: 10.3389/fimmu.2021.778133
    Blended phenotypes exhibited by a patient may present a challenge to the establishment of diagnosis. In this study, we report a seven-year-old Murut girl with unusual features of Williams-Beuren syndrome (WBS), including recurrent infections and skin abscesses. Considering the possibility of a second genetic disorder, a mutation screening for genes associated with inborn errors of immunity (IEI) was conducted using whole exome sequencing (WES). Analysis of copy number variations (CNVs) from the exome data revealed a 1.53Mb heterozygous deletion on chromosome 7q11.23, corresponding to the known WBS. We also identified a biallelic loss of NCF1, which indicated autosomal recessive chronic granulomatous disease (CGD). Dihydrorhodamine (DHR) flow cytometric assay demonstrated abnormally low neutrophil oxidative burst activity. Coamplification of NCF1 and its pseudogenes identified a GT-deletion (ΔGT) at the start of exon 2 in NCF1 (NM_000265.7: c.75_76delGT: p.Tyr26Hisfs*26). Estimation of NCF1-to-NCF1 pseudogenes ratio using ΔGT and 20-bp gene scans affirmed nil copies of NCF1 in the patient. While the father had a normal ratio of 2:4, the mother had a ratio of 1:5, implicating the carrier of ΔGT-containing NCF1. Discovery of a 7q11.23 deletion involving one NCF1 allele and a ΔGT in the second NCF1 allele explained the coexistence of WBS and CGD in our patient. This study highlights the capability of WES to establish a molecular diagnosis for a case with blended phenotypes, enabling the provision of appropriate prophylactic treatment.
  12. Rich AM, Hussaini HM, Parachuru VP, Seymour GJ
    Front Immunol, 2014;5:464.
    PMID: 25309546 DOI: 10.3389/fimmu.2014.00464
    It is becoming increasingly apparent that the tumor microenvironment plays an important role in the progression of cancer. The microenvironment may promote tumor cell survival and proliferation or, alternatively may induce tumor cell apoptosis. Toll-like receptors (TLRs) are transmembrane proteins, expressed on immune cells and epithelial cells, that recognize exogenous and endogenous macromolecules. Once activated, they initiate signaling pathways leading to the release of cytokines and chemokines, which recruit immune cells inducing further cytokine production, the production of angiogenic mediators and growth factors, all of which may influence tumor progression. This paper examines the actions of TLRs in carcinogenesis with particular emphasis on their role in oral squamous cell carcinoma.
  13. Rasheed ZBM, Lee YS, Kim SH, Rai RK, Ruano CSM, Anucha E, et al.
    Front Immunol, 2020;11:1899.
    PMID: 32983111 DOI: 10.3389/fimmu.2020.01899
    Background: Infection/inflammation is an important causal factor in spontaneous preterm birth (sPTB). Most mechanistic studies have concentrated on the role of bacteria, with limited focus on the role of viruses in sPTB. Murine studies support a potential multi-pathogen aetiology in which a double or sequential hit of both viral and bacterial pathogens leads to a higher risk preterm labour. This study aimed to determine the effect of viral priming on bacterial induced inflammation in human in vitro models of ascending and haematogenous infection. Methods: Vaginal epithelial cells, and primary amnion epithelial cells and myocytes were used to represent cell targets of ascending infection while interactions between peripheral blood mononuclear cells (PBMCs) and placental explants were used to model systemic infection. To model the effect of viral priming upon the subsequent response to bacterial stimuli, each cell type was stimulated first with a TLR3 viral agonist, and then with either a TLR2 or TLR2/6 agonist, and responses compared to those of each agonist alone. Immunoblotting was used to detect cellular NF-κB, AP-1, and IRF-3 activation. Cellular TLR3, TLR2, and TLR6 mRNA was quantified by RT-qPCR. Immunoassays were used to measure supernatant cytokine, chemokine and PGE2 concentrations. Results: TLR3 ("viral") priming prior to TLR2/6 agonist ("bacterial") exposure augmented the pro-inflammatory, pro-labour response in VECs, AECs, myocytes and PBMCs when compared to the effects of agonists alone. In contrast, enhanced anti-inflammatory cytokine production (IL-10) was observed in placental explants. Culturing placental explants in conditioned media derived from PBMCs primed with a TLR3 agonist enhanced TLR2/6 agonist stimulated production of IL-6 and IL-8, suggesting a differential response by the placenta to systemic inflammation compared to direct infection as a result of haematogenous spread. TLR3 agonism generally caused increased mRNA expression of TLR3 and TLR2 but not TLR6. Conclusion: This study provides human in vitro evidence that viral infection may increase the susceptibility of women to bacterial-induced sPTB. Improved understanding of interactions between viral and bacterial components of the maternal microbiome and host immune response may offer new therapeutic options, such as antivirals for the prevention of PTB.
  14. Paul A, Tang TH, Ng SK
    Front Immunol, 2018;9:1831.
    PMID: 30147694 DOI: 10.3389/fimmu.2018.01831
    Interferon regulatory factor 9 (IRF9) is an integral transcription factor in mediating the type I interferon antiviral response, as part of the interferon-stimulated gene factor 3. However, the role of IRF9 in many important non-communicable diseases has just begun to emerge. The duality of IRF9's role in conferring protection but at the same time exacerbates diseases is certainly puzzling. The regulation of IRF9 during these conditions is not well understood. The high homology of IRF9 DNA-binding domain to other IRFs, as well as the recently resolved IRF9 IRF-associated domain structure can provide the necessary insights for progressive inroads on understanding the regulatory mechanism of IRF9. This review sought to outline the structural basis of IRF9 that guides its regulation and interaction in antiviral immunity and other diseases.
  15. Othman N, Jamal R, Abu N
    Front Immunol, 2019;10:2103.
    PMID: 31555295 DOI: 10.3389/fimmu.2019.02103
    Exosomes, a category of small lipid bilayer extracellular vesicles that are naturally secreted by many cells (both healthy and diseased), carry cargo made up of proteins, lipids, DNAs, and RNAs; all of which are functional when transferred to their recipient cells. Numerous studies have demonstrated the powerful role that exosomes play in the mediation of cell-to-cell communication to induce a pro-tumoral environment to encourage tumor progression and survival. Recently, considerable interest has developed in regard to the role that exosomes play in immunity; with studies demonstrating the ability of exosomes to either metabolically alter immune players such as dendritic cells, T cells, macrophages, and natural killer cells. In this review, we summarize the recent literature on the function of exosomes in regulating a key process that has long been associated with the progression of cancer-inflammation and immunity.
  16. Nur Husna SM, Tan HT, Md Shukri N, Mohd Ashari NS, Wong KK
    Front Immunol, 2021;12:663626.
    PMID: 34093555 DOI: 10.3389/fimmu.2021.663626
    Allergic rhinitis (AR) is a common disorder affecting up to 40% of the population worldwide and it usually persists throughout life. Nasal epithelial barrier constitutes the first line of defense against invasion of harmful pathogens or aeroallergens. Cell junctions comprising of tight junctions (TJs), adherens junctions, desmosomes and hemidesmosomes form the nasal epithelial barrier. Impairment of TJ molecules plays causative roles in the pathogenesis of AR. In this review, we describe and discuss the components of TJs and their disruption leading to development of AR, as well as regulation of TJs expression by epigenetic changes, neuro-immune interaction, epithelial-derived cytokines (thymic stromal lymphopoietin, IL-25 and IL-33), T helper 2 (Th2) cytokines (IL-4, IL-5, IL-6 and IL-13) and innate lymphoid cells. These growing evidence support the development of novel therapeutic approaches to restore nasal epithelial TJs expression in AR patients.
  17. Nordin J, Solís L, Prévot J, Mahlaoui N, Chapel H, Sánchez-Ramón S, et al.
    Front Immunol, 2021;12:780140.
    PMID: 34868053 DOI: 10.3389/fimmu.2021.780140
    A global gold standard framework for primary immunodeficiency (PID) care, structured around six principles, was published in 2014. To measure the implementation status of these principles IPOPI developed the PID Life Index in 2020, an interactive tool aggregating national PID data. This development was combined with a revision of the principles to consider advances in the field of health and science as well as political developments since 2014. The revision resulted in the following six principles: PID diagnosis, treatments, universal health coverage, specialised centres, national patient organisations and registries for PIDs. A questionnaire corresponding to these principles was sent out to IPOPI's national member organisations and to countries in which IPOPI had medical contacts, and data was gathered from 60 countries. The data demonstrates that, regardless of global scientific progress on PIDs with a growing number of diagnostic tools and better treatment options becoming available, the accessibility and affordability of these remains uneven throughout the world. It is not only visible between regions, but also between countries within the same region. One of the most urgent needs is medical education. In countries without immunologists, patients with PID suffer the risk of remaining undiagnosed or misdiagnosed, resulting in health implications or even death. Many countries also lack the infrastructure needed to carry out more advanced diagnostic tests and perform treatments such as hematopoietic stem cell transplantation or gene therapy. The incapacity to secure appropriate diagnosis and treatments affects the PID environment negatively in these countries. Availability and affordability also remain key issues, as diagnosis and treatments require coverage/reimbursement to ensure that patients with PID can access them in practice, not only in theory. This is still not the case in many countries of the world according to the PID Life Index. Although some countries do perform better than others, to date no country has fully implemented the PID principles of care, confirming the long way ahead to ensure an optimal environment for patients with PID in every country.
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