Publications by authors named "Evangelos Andreakos"

63 Publications

Differential maturation trajectories of innate antiviral immunity in health and atopy.

Pediatr Allergy Immunol 2021 Jul 20. Epub 2021 Jul 20.

Allergy and Clinical Immunology Unit, Second Department of Pediatrics, National and Kapodistrian University of Athens, Athens, Greece.

Background: The maturation of innate immune responses in health and atopy is still incompletely understood.

Methods: We aimed to evaluate age-related trajectories of the TLR3 and TLR7/8 pathways from birth to adulthood and whether these differ between healthy and atopic individuals. Peripheral blood mononuclear cells (PBMCs) were isolated from 39 otherwise healthy, atopic and 39 non-atopic subjects, aged 0-45 years. Selected cytokines involved in antiviral responses were measured by Luminex in culture supernatants of poly(I:C)- and R848-stimulated PBMCs. The non-parametric correlation between age and cytokine expression and differences in developmental trajectories between healthy and atopic subjects were estimated. Patterns of cytokine development were identified with principal component analysis.

Results: Normal innate immune maturation entails significant and progressive age-related changes in the production of IL-1β, TNF-α, MIP-1β, MCP-3, IP-10, IL-10, IL-12p70, and IFN-γ upon TLR3 and/or TLR7/8 stimulation. Individual cytokines made small contributions to the observed variability; chemokines MCP-3 and IP-10 were key contributors. The development of these pathways deviated in atopic subjects with significant differences observed in the trajectories of IL-1β, MIP-1β, and IL-10 syntheses.

Conclusion: TLR3 and TLR7/8 pathways mature during childhood, while atopy is associated with an abnormal maturation pattern. Suboptimal responses in Th1, inflammatory cytokine, and chemokine production may be implicated in poor antiviral immunity in atopics. Moreover, the deficient maturation of IL-10 synthesis may be implicated in the breaking of tolerance, characterizing the onset of atopic disease.
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http://dx.doi.org/10.1111/pai.13601DOI Listing
July 2021

Genetic regulation of nonsense-mediated decay underlies association with risk of severe COVID-19.

medRxiv 2021 Jul 13. Epub 2021 Jul 13.

Genomic regions have been associated with COVID-19 susceptibility and outcomes, including the chr12q24.13 locus encoding antiviral proteins OAS1-3. Here, we report genetic, functional, and clinical insights into genetic associations within this locus. In Europeans, the risk of hospitalized vs. non-hospitalized COVID-19 was associated with a single 19Kb-haplotype comprised of 76 variants included in a 95% credible set within a large genomic fragment introgressed from Neandertals. The risk haplotype was also associated with impaired spontaneous but not treatment-induced SARS-CoV-2 clearance in a clinical trial with pegIFN-λ1. We demonstrate that two exonic variants, rs10774671 and rs1131454, affect splicing and nonsense-mediated decay of . We suggest that genetically-regulated loss of expression contributes to impaired spontaneous clearance of SARS-CoV-2 and elevated risk of hospitalization for COVID-19. Our results provide the rationale for further clinical studies using interferons to compensate for impaired spontaneous SARS-CoV-2 clearance, particularly in carriers of the risk haplotypes.
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http://dx.doi.org/10.1101/2021.07.09.21260221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288155PMC
July 2021

COVID-19 enters the expanding network of apolipoprotein E4-related pathologies.

Redox Biol 2021 05 10;41:101938. Epub 2021 Mar 10.

Department of Biology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece; Biomedical Research Foundation of the Academy of Athens, Athens, Greece; Center for New Biotechnologies and Precision Medicine, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece. Electronic address:

COVID-19 incidence and case fatality rates (CFR) differ among ethnicities, stimulating efforts to pinpoint genetic factors that could explain these phenomena. In this regard, the multiallelic apolipoprotein E (APOE) gene has recently been interrogated in the UK biobank cohort, demonstrating associations of the APOE ε4/ε4 genotype with COVID-19 severity and mortality. The frequency of the ε4 allele and thus the distribution of APOE ε4/ε4 genotype may differ among populations. We have assessed APOE genotypes in 1638 Greek individuals, based on haplotypes derived from SNP rs7412 and rs429358 and found reduced frequency of ε4/ε4 compared to the British cohort. Herein we discuss this finding in relation to CFR and hypothesize on the potential mechanisms linking APOE ε4/ε4 to severe COVID-19. We postulate that the metabolic deregulation ensued by APOE4, manifested by elevated cholesterol and oxidized lipoprotein levels, may be central to heightened pneumocyte susceptibility to infection and to exaggerated lung inflammation associated with the ε4/ε4 genotype. We also discuss putative dietary and pharmacological approaches for the prevention and management of COVID-19 in APOE ε4/ε4 individuals.
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http://dx.doi.org/10.1016/j.redox.2021.101938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943392PMC
May 2021

Untuned antiviral immunity in COVID-19 revealed by temporal type I/III interferon patterns and flu comparison.

Nat Immunol 2021 01 4;22(1):32-40. Epub 2020 Dec 4.

Laboratory of Immunobiology, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.

A central paradigm of immunity is that interferon (IFN)-mediated antiviral responses precede pro-inflammatory ones, optimizing host protection and minimizing collateral damage. Here, we report that for coronavirus disease 2019 (COVID-19) this paradigm does not apply. By investigating temporal IFN and inflammatory cytokine patterns in 32 moderate-to-severe patients with COVID-19 hospitalized for pneumonia and longitudinally followed for the development of respiratory failure and death, we reveal that IFN-λ and type I IFN production were both diminished and delayed, induced only in a fraction of patients as they became critically ill. On the contrary, pro-inflammatory cytokines such as tumor necrosis factor (TNF), interleukin (IL)-6 and IL-8 were produced before IFNs in all patients and persisted for a prolonged time. This condition was reflected in blood transcriptomes wherein prominent IFN signatures were only seen in critically ill patients who also exhibited augmented inflammation. By comparison, in 16 patients with influenza (flu) hospitalized for pneumonia with similar clinicopathological characteristics to those of COVID-19 and 24 nonhospitalized patients with flu with milder symptoms, IFN-λ and type I IFN were robustly induced earlier, at higher levels and independently of disease severity, whereas pro-inflammatory cytokines were only acutely produced. Notably, higher IFN-λ concentrations in patients with COVID-19 correlated with lower viral load in bronchial aspirates and faster viral clearance and a higher IFN-λ to type I IFN ratio correlated with improved outcome for critically ill patients. Moreover, altered cytokine patterns in patients with COVID-19 correlated with longer hospitalization and higher incidence of critical disease and mortality compared to flu. These data point to an untuned antiviral response in COVID-19, contributing to persistent viral presence, hyperinflammation and respiratory failure.
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http://dx.doi.org/10.1038/s41590-020-00840-xDOI Listing
January 2021

Dexamethasone, pro-resolving lipid mediators and resolution of inflammation in COVID-19.

Allergy 2021 03;76(3):626-628

Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Center for Experimental Therapeutics and Reperfusion Injury, Boston, MA, USA.

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http://dx.doi.org/10.1111/all.14595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537007PMC
March 2021

The TAXINOMISIS Project: A multidisciplinary approach for the development of a new risk stratification model for patients with asymptomatic carotid artery stenosis.

Eur J Clin Invest 2020 Dec 2;50(12):e13411. Epub 2020 Oct 2.

Department of Materials Science and Engineering, Unit of Medical Technology and Intelligent Information Systems, University of Ioannina, Ioannina, Greece.

Introduction: Asymptomatic carotid artery stenosis (ACAS) may cause future stroke and therefore patients with ACAS require best medical treatment. Patients at high risk for stroke may opt for additional revascularization (either surgery or stenting) but the future stroke risk should outweigh the risk for peri/post-operative stroke/death. Current risk stratification for patients with ACAS is largely based on outdated randomized-controlled trials that lack the integration of improved medical therapies and risk factor control. Furthermore, recent circulating and imaging biomarkers for stroke have never been included in a risk stratification model. The TAXINOMISIS Project aims to develop a new risk stratification model for cerebrovascular complications in patients with ACAS and this will be tested through a prospective observational multicentre clinical trial performed in six major European vascular surgery centres.

Methods And Analysis: The risk stratification model will compromise clinical, circulating, plaque and imaging biomarkers. The prospective multicentre observational study will include 300 patients with 50%-99% ACAS. The primary endpoint is the three-year incidence of cerebrovascular complications. Biomarkers will be retrieved from plasma samples, brain MRI, carotid MRA and duplex ultrasound. The TAXINOMISIS Project will serve as a platform for the development of new computer tools that assess plaque progression based on radiology images and a lab-on-chip with genetic variants that could predict medication response in individual patients.

Conclusion: Results from the TAXINOMISIS study could potentially improve future risk stratification in patients with ACAS to assist personalized evidence-based treatment decision-making.
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http://dx.doi.org/10.1111/eci.13411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757200PMC
December 2020

COVID-19: lambda interferon against viral load and hyperinflammation.

EMBO Mol Med 2020 06 25;12(6):e12465. Epub 2020 May 25.

4th Department of Internal Medicine, Attikon University Hospital, University of Athens Medical School, Athens, Greece.

Coronavirus disease 2019 (COVID-19), triggered by the betacoronavirus SARS-CoV-2, has become one of the worst pandemics of our time that has already caused more than 250,000 deaths (JHU data-05/06/2020, https://coronavirus.jhu.edu/). Effective therapeutic approaches are urgently needed to reduce the spread of the virus and its death toll. Here, we assess the possibility of using interferon-lambda (IFNλ), a third type of interferon sharing low homology with type I IFNs and IL-10, for treating COVID-19 patients. We discuss the unique role of IFNλ in fine-tuning antiviral immunity in the respiratory tract to achieve optimal protection and minimal host damage and review early evidence that SARS-CoV-2 may impair IFNλ induction, leading to a delayed type I IFN-dominated response that triggers hyperinflammation and severe disease. We also consider the potential windows of opportunity for therapeutic intervention with IFNλ and potential safety considerations. We conclude that IFNλ constitutes a promising therapeutic agent for reducing viral presence and hyperinflammation in a single shot to prevent the devastating consequences of COVID-19 such as pneumonia and acute respiratory distress syndrome (ARDS).
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http://dx.doi.org/10.15252/emmm.202012465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7267110PMC
June 2020

Increased autophagy/mitophagy levels in primary tumours of patients with pancreatic neuroendocrine neoplasms.

Endocrine 2020 05 29;68(2):438-447. Epub 2020 Feb 29.

Laboratory of Molecular Genetics, Department of Immunology, Hellenic Pasteur Institute, Athens, Greece.

Background/aims: We assessed the levels of autophagy and mitophagy, that are linked to cancer development and drug resistance, in well differentiated pancreatic neuroendocrine neoplasms (PanNENs) and correlated them with clinico-pathological parameters.

Methods: Fluorescent immunostaining for the autophagy markers LC3Β and p62/or LAMP1 was performed on 22 PanNENs and 11 controls of normal pancreatic tissues and validated through Western blotting. Autophagy quantitative scoring was generated for LC3B-positive puncta and analysed in relation to clinico-pathological parameters. TOMM20/LC3B qualitative assessment of mitophagy levels was undertaken by fluorescent immunostaining. The presence of autophagy/mitophagy was validated by transmission electron microscopy.

Results: Autophagy levels (LC3B-positive puncta/cell) were discriminative for normal vs. NEN pancreatic tissue (p = 0.007). A significant association was observed between autophagy levels and tumour grade (Ki67 < 3% vs. Ki67 ≥ 3%; p = 0.021), but not functionality (p = 0.266) size (cut-off of 20 mm; p = 0.808), local invasion (p = 0.481), lymph node- (p = 0.849) and distant metastases (p = 0.699). Qualitative assessment of TOMM20/LC3B demonstrated strong mitophagy levels in PanNENs by fluorescent immunostaining as compared with normal tissue. Transmission electron microscopy revealed enhanced autophagy and mitophagy in PanNEN tissue. Response to molecular targeted therapies in metastatic cases (n = 4) did not reveal any patterns of association to autophagy levels.

Conclusions: Increased autophagy levels are present in primary tumours of patients with PanNENs and are partially attributed to upregulated mitophagy. Grade was the only clinico-pathological parameter associated with autophagy scores.
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http://dx.doi.org/10.1007/s12020-020-02228-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7266843PMC
May 2020

Human and translational immunology in the third millennium: progress, challenges and opportunities.

Nat Immunol 2019 12;20(12):1568-1573

Laboratory of Immunobiology, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.

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http://dx.doi.org/10.1038/s41590-019-0543-6DOI Listing
December 2019

Independent association of low IFNλ1 gene expression and type I IFN score/IFNλ1 ratio with obstetric manifestations and triple antiphospholipid antibody positivity in primary antiphospholipid syndrome.

Clin Immunol 2019 12 19;209:108265. Epub 2019 Oct 19.

First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece; Joint Academic Rheumatology Program, National and Kapodistrian University of Athens, Athens, Greece. Electronic address:

Recent data suggest an important role of type I interferons (IFN) in antiphospholipid syndrome (APS). Here we aimed to evaluate the interplay of type I and type III (or IFNλs) IFNs in APS and potential clinical and serological associations. Our findings suggest that patients with primary APS (PAPS) and systemic lupus erythematosus (SLE)/APS displayed increased type I IFN scores but decreased IFNλ1 gene expression levels compared to healthy individuals, as assessed with real-time qPCR analysis in isolated peripheral blood mononuclear cells (PBMCs). Type I IFN score/IFNλ1 ratio was remarkably higher in patients with PAPS and SLE/APS as well as in SLE patients with or without antiphospholipid antibodies (aPL) vs controls. In conclusion, our results reveal an association between low IFNλ1 expression and obstetric APS. Moreover, the type I IFN score/IFNλ1 ratio seems to be a potential marker of high risk APS given its associations with triple aPL positivity.
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http://dx.doi.org/10.1016/j.clim.2019.108265DOI Listing
December 2019

Lambda interferons in immunity and autoimmunity.

J Autoimmun 2019 11 31;104:102319. Epub 2019 Aug 31.

Laboratory of Immunobiology, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, 11527, Athens, Greece. Electronic address:

Type I IFNs are well known players in immunity and autoimmunity. They induce potent innate and adaptive immune responses essential for mediating host defenses against viral and bacterial infections but also driving inflammation during chronic inflammatory and autoimmune diseases. Lambda interferons (IFNλs) or type III IFNs, on the other hand, comprise a relatively new family of cytokines sharing homology and functional resemblance with type I IFNs but whose spectrum of activities remains poorly understood. Although IFNλs induce antiviral responses similar to type I IFNs, their restricted pattern of expression suggested that may have more specialized functions at specific body sites such as barrier surfaces. However, recent developments in the field have revealed broader roles of IFNλs in immunity against a diverse range of pathogens including viral, bacterial and fungal infections, and have highlighted unique non-redundant functions of IFNλs that cannot be compensated by type I IFNs. They have also positioned IFNλs as a non-inflammatory or immunoregulatory form of IFNs that possesses the antimicrobial functions of type I IFNs but lacks their pro-inflammatory effects, playing a crucial role in the fine tuning of immune defenses for optimal host protection and minimal host damage. Beyond infections, IFNλs are also emerging as important players in immunity against cancer and autoimmunity, with several studies now demonstrating up-regulation of these molecules at disease sites, and functional involvement in experimental animal models. Here, we critically assess recent advances in our understanding of the IFNλ biology, with emphasis to their emerging roles in cancer and autoimmune diseases, and discuss their potential therapeutic implications.
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http://dx.doi.org/10.1016/j.jaut.2019.102319DOI Listing
November 2019

The many facets of macrophages in rheumatoid arthritis.

Biochem Pharmacol 2019 07 22;165:152-169. Epub 2019 Mar 22.

Laboratory of Immunobiology, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece; Airway Disease Infection Section, National Heart and Lung Institute, Medical Research Council and Asthma UK Centre in Allergic Mechanisms of Asthma, Imperial College London, London W2 1NY, United Kingdom. Electronic address:

Macrophages are central to the pathophysiology of rheumatoid arthritis (RA). They constitute the main source of pro-inflammatory cytokines and chemokines such as TNF and IL-1β, they activate a wide range of immune and non-immune cells, and they secrete diverse tissue degrading enzymes driving chronic pro-inflammatory, tissue destructive and pain responses in RA. However, they can also produce anti-inflammatory cytokines such as IL-10, secrete inhibitors of tissue degrading enzymes and promote immunoregulatory and protective responses, suggesting the existence of macrophages with distinct and diverse functional activities. Although the underlying basis of this phenomenon has remained obscure for years, emerging evidence has now provided insight into the mechanisms and molecular processes involved. Here, we review current knowledge on the biology of macrophages in RA, and highlight recent literature on the heterogeneity, origins and ontogeny of macrophages as part of the mononuclear phagocyte system. We also discuss their plasticity in the context of the M1/M2 paradigm, and the emerging theme of metabolic rewiring as a major mechanism for programming macrophage functions and pro-inflammatory activities. This sheds light into the many facets of macrophages in RA, their molecular regulation and their translational potential for developing novel protective and therapeutic strategies in the clinic.
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http://dx.doi.org/10.1016/j.bcp.2019.03.029DOI Listing
July 2019

Author Correction: Iron restriction inside macrophages regulates pulmonary host defense against Rhizopus species.

Nat Commun 2018 11 22;9(1):5015. Epub 2018 Nov 22.

Department of Medicine, University of Crete, Foundation for Research and Technology, 71300, Heraklion, Crete, Greece.

The original version of this Article contained an error in the spelling of the author Emilien Etienne, which was incorrectly given as Emilien Ettiene. These errors have now been corrected in both the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41467-018-07301-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6250689PMC
November 2018

Lambda interferons come to light: dual function cytokines mediating antiviral immunity and damage control.

Curr Opin Immunol 2019 02 3;56:67-75. Epub 2018 Nov 3.

Laboratory of Immunobiology, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece.

Lambda interferons (IFNλs, type III IFNs or interleukins-28/29) were described fifteen years ago as novel cytokines sharing structural and functional homology with IL-10 and type I IFNs, respectively. IFNλs engage a unique receptor complex comprising IFNLR1 and IL10R2, nevertheless they share signaling cascade and many functions with type I IFNs, questioning their possible non-redundant roles and overall biological importance. Here, we review the latest evidence establishing the primacy of IFNλs in front line protection at anatomical barriers, mediating antiviral immunity before type I IFNs. We also discuss their emerging role in regulating inflammation and limiting host damage, a major difference to type I IFNs. IFNλs come thus to light as dual function cytokines mediating antiviral immunity and damage control.
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http://dx.doi.org/10.1016/j.coi.2018.10.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6541392PMC
February 2019

Rhinovirus Species-Specific Antibodies Differentially Reflect Clinical Outcomes in Health and Asthma.

Am J Respir Crit Care Med 2018 12;198(12):1490-1499

Division of Infection, Immunity and Respiratory Medicine and.

Rhinoviruses (RVs) are major triggers of common cold and acute asthma exacerbations. RV species A, B, and C may have distinct clinical impact; however, little is known regarding RV species-specific antibody responses in health and asthma. To describe and compare total and RV species-specific antibody levels in healthy children and children with asthma, away from an acute event. Serum samples from 163 preschool children with mild to moderate asthma and 72 healthy control subjects from the multinational Predicta cohort were analyzed using the recently developed PreDicta RV antibody chip. RV antibody levels varied, with RV-C and RV-A being higher than RV-B in both groups. Compared with control subjects, asthma was characterized by significantly higher levels of antibodies to RV-A and RV-C, but not RV-B. RV antibody levels positively correlated with the number of common colds over the previous year in healthy children, and wheeze episodes in children with asthma. Antibody levels also positively correlated with asthma severity but not with current asthma control. The variable humoral response to RV species in both groups suggests a differential infectivity pattern between RV species. In healthy preschoolers, RV antibodies accumulate with colds. In asthma, RV-A and RV-C antibodies are much higher and further increase with disease severity and wheeze episodes. Higher antibody levels in asthma may be caused by a compromised innate immune response, leading to increased exposure of the adaptive immune response to the virus. Importantly, there is no apparent protection with increasing levels of antibodies.
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http://dx.doi.org/10.1164/rccm.201803-0575OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212800PMC
December 2018

Iron restriction inside macrophages regulates pulmonary host defense against Rhizopus species.

Nat Commun 2018 08 20;9(1):3333. Epub 2018 Aug 20.

Department of Medicine, University of Crete, Foundation for Research and Technology, 71300, Heraklion, Crete, Greece.

Mucormycosis is a life-threatening respiratory fungal infection predominantly caused by Rhizopus species. Mucormycosis has incompletely understood pathogenesis, particularly how abnormalities in iron metabolism compromise immune responses. Here we show how, as opposed to other filamentous fungi, Rhizopus spp. establish intracellular persistence inside alveolar macrophages (AMs). Mechanistically, lack of intracellular swelling of Rhizopus conidia results in surface retention of melanin, which induces phagosome maturation arrest through inhibition of LC3-associated phagocytosis. Intracellular inhibition of Rhizopus is an important effector mechanism, as infection of immunocompetent mice with swollen conidia, which evade phagocytosis, results in acute lethality. Concordantly, AM depletion markedly increases susceptibility to mucormycosis. Host and pathogen transcriptomics, iron supplementation studies, and genetic manipulation of iron assimilation of fungal pathways demonstrate that iron restriction inside macrophages regulates immunity against Rhizopus. Our findings shed light on the pathogenetic mechanisms of mucormycosis and reveal the role of macrophage-mediated nutritional immunity against filamentous fungi.
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http://dx.doi.org/10.1038/s41467-018-05820-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6102248PMC
August 2018

Dexamethasone induces ω3-derived immunoresolvents driving resolution of allergic airway inflammation.

J Allergy Clin Immunol 2018 08 24;142(2):691-695.e4. Epub 2018 Apr 24.

Laboratory of Immunobiology, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2018.04.004DOI Listing
August 2018

CD8+ T cells in beige adipogenesis and energy homeostasis.

JCI Insight 2018 03 8;3(5). Epub 2018 Mar 8.

Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation Academy of Athens, Athens, Greece.

Although accumulation of lymphocytes in the white adipose tissue (WAT) in obesity is linked to insulin resistance, it remains unclear whether lymphocytes also participate in the regulation of energy homeostasis in the WAT. Here, we demonstrate enhanced energy dissipation in Rag1-/- mice, increased catecholaminergic input to subcutaneous WAT, and significant beige adipogenesis. Adoptive transfer experiments demonstrated that CD8+ T cell deficiency accounts for the enhanced beige adipogenesis in Rag1-/- mice. Consistently, we identified that CD8-/- mice also presented with enhanced beige adipogenesis. The inhibitory effect of CD8+ T cells on beige adipogenesis was reversed by blockade of IFN-γ. All together, our findings identify an effect of CD8+ T cells in regulating energy dissipation in lean WAT, mediated by IFN-γ modulation of the abundance of resident immune cells and of local catecholaminergic activity. Our results provide a plausible explanation for the clinical signs of metabolic dysfunction in diseases characterized by altered CD8+ T cell abundance and suggest targeting of CD8+ T cells as a promising therapeutic approach for obesity and other diseases with altered energy homeostasis.
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http://dx.doi.org/10.1172/jci.insight.95456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5922290PMC
March 2018

Plasmacytoid dendritic cells drive acute asthma exacerbations.

J Allergy Clin Immunol 2018 08 17;142(2):542-556.e12. Epub 2017 Oct 17.

Department of Immunology, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece. Electronic address:

Background: Although acute exacerbations, mostly triggered by viruses, account for the majority of hospitalizations in asthmatic patients, there is still very little known about the pathophysiologic mechanisms involved. Plasmacytoid dendritic cells (pDCs), prominent cells of antiviral immunity, exhibit proinflammatory or tolerogenic functions depending on the context, yet their involvement in asthma exacerbations remains unexplored.

Objectives: We sought to investigate the role of pDCs in allergic airway inflammation and acute asthma exacerbations.

Methods: Animal models of allergic airway disease (AAD) and virus-induced AAD exacerbations were used to dissect pDC function in vivo and unwind the potential mechanisms involved. Sputum from asthmatic patients with stable disease or acute exacerbations was further studied to determine the presence of pDCs and correlation with inflammation.

Results: pDCs were key mediators of the immunoinflammatory cascade that drives asthma exacerbations. In animal models of AAD and rhinovirus-induced AAD exacerbations, pDCs were recruited to the lung during inflammation and migrated to the draining lymph nodes to boost T2-mediated effector responses. Accordingly, pDC depletion after allergen challenge or during rhinovirus infection abrogated exacerbation of inflammation and disease. Central to this process was IL-25, which was induced by allergen challenge or rhinovirus infection and conditioned pDCs for proinflammatory function. Consistently, in asthmatic patients pDC numbers were markedly increased during exacerbations and correlated with the severity of inflammation and the risk for asthma attacks.

Conclusions: Our studies uncover a previously unsuspected role of pDCs in asthma exacerbations with potential diagnostic and prognostic implications. They also propose the therapeutic targeting of pDCs and IL-25 for the treatment of acute asthma.
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http://dx.doi.org/10.1016/j.jaci.2017.08.032DOI Listing
August 2018

Interferon-λs: Front-Line Guardians of Immunity and Homeostasis in the Respiratory Tract.

Front Immunol 2017 29;8:1232. Epub 2017 Sep 29.

Laboratory of Immunobiology, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.

Type III interferons (IFNs), also termed lambda IFNs (IFNλs) or interleukins-28/29, constitute a new addition to the IFN family. They are induced upon infection and are particularly abundant at barrier surfaces, such as the respiratory and gastrointestinal tracts. Although they signal through a unique heterodimeric receptor complex comprising IFNLR1 and IL10RB, they activate a downstream signaling pathway remarkably similar to that of type I IFNs and share many functions with them. Yet, they also have important differences which are only now starting to unfold. Here, we review the current literature implicating type III IFNs in the regulation of immunity and homeostasis in the respiratory tract. We survey the common and unique characteristics of type III IFNs in terms of expression patterns, cellular targets, and biological activities and discuss their emerging role in first line defenses against respiratory viral infections. We further explore their immune modulatory functions and their involvement in the regulation of inflammatory responses during chronic respiratory diseases, such as asthma and chronic obstructive pulmonary disease. Type III IFNs are, therefore, arising as front-line guardians of immune defenses in the respiratory tract, fine tuning inflammation, and as potential novel therapeutics for the treatment of diverse respiratory diseases, including influenza virus infection and asthma.
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http://dx.doi.org/10.3389/fimmu.2017.01232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5626824PMC
September 2017

Interferon lambda1/IL-29 and inorganic polyphosphate are novel regulators of neutrophil-driven thromboinflammation.

J Pathol 2017 09 7;243(1):111-122. Epub 2017 Aug 7.

Laboratory of Molecular Hematology, Democritus University of Thrace, Alexandroupolis, Greece.

Neutrophils and neutrophil-released meshwork structures termed neutrophil extracellular traps (NETs) are major mediators of thromboinflammation and emerging targets for therapy, yet the mechanisms and pathways that control the role of neutrophils in thromboinflammation remain poorly understood. Here, we explored the role of IFN-λ1/IL-29, a major antiviral cytokine recently shown to suppress the neutrophil migratory capacity, in prothrombotic and proNETotic functions of neutrophils. In an ex vivo human experimental setting of acute ST-segment elevation myocardial infarction (STEMI), we show that IFN-λ1/IL-29 hinders NET release and diminishes the amount of cytoplasmic TF in neutrophils. Since platelet-neutrophil interaction plays a major role in NET-induced thromboinflammation, we further studied how IFN-λ1/IL-29 may interrupt this interaction. In this context, we identified inorganic polyphosphate (polyP) as a platelet-derived NET inducer in STEMI. In arterial STEMI thrombi, polyP was present in platelets and in close proximity to NET remnants. PolyP release from activated platelets was dependent on thrombin present in infarcted artery plasma, resulting in NET formation by promoting mTOR inhibition and autophagy induction. The effect of polyP on mTOR inhibition was counteracted by IFN-λ1/IL-29 treatment, leading to inhibition of NET formation. Consistently, we show in an in vivo model of FeCl -induced arterial thrombosis that IFN-λ2/IL-28A exerts strong antithrombotic potential. Taken together, these findings reveal a novel function of IFN-λ1/IL-29 in the suppression of thromboinflammation. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.4935DOI Listing
September 2017

Interferon-λ Mediates Non-redundant Front-Line Antiviral Protection against Influenza Virus Infection without Compromising Host Fitness.

Immunity 2017 05;46(5):875-890.e6

Laboratory of Immunobiology, Center for Clinical, Experimental Surgery, and Translational Research, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece. Electronic address:

Lambda interferons (IFNλs) or type III IFNs share homology, expression patterns, signaling cascades, and antiviral functions with type I IFNs. This has complicated the unwinding of their unique non-redundant roles. Through the systematic study of influenza virus infection in mice, we herein show that IFNλs are the first IFNs produced that act at the epithelial barrier to suppress initial viral spread without activating inflammation. If infection progresses, type I IFNs come into play to enhance viral resistance and induce pro-inflammatory responses essential for confronting infection but causing immunopathology. Central to this are neutrophils which respond to both cytokines to upregulate antimicrobial functions but exhibit pro-inflammatory activation only to type I IFNs. Accordingly, Ifnlr1 mice display enhanced type I IFN production, neutrophilia, lung injury, and lethality, while therapeutic administration of PEG-IFNλ potently suppresses these effects. IFNλs therefore constitute the front line of antiviral defense in the lung without compromising host fitness.
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http://dx.doi.org/10.1016/j.immuni.2017.04.025DOI Listing
May 2017

Addressing unmet needs in understanding asthma mechanisms: From the European Asthma Research and Innovation Partnership (EARIP) Work Package (WP)2 collaborators.

Eur Respir J 2017 05 1;49(5). Epub 2017 May 1.

Imperial College London, London, UK

Asthma is a heterogeneous, complex disease with clinical phenotypes that incorporate persistent symptoms and acute exacerbations. It affects many millions of Europeans throughout their education and working lives and puts a heavy cost on European productivity. There is a wide spectrum of disease severity and control. Therapeutic advances have been slow despite greater understanding of basic mechanisms and the lack of satisfactory preventative and disease modifying management for asthma constitutes a significant unmet clinical need. Preventing, treating and ultimately curing asthma requires co-ordinated research and innovation across Europe. The European Asthma Research and Innovation Partnership (EARIP) is an FP7-funded programme which has taken a co-ordinated and integrated approach to analysing the future of asthma research and development. This report aims to identify the mechanistic areas in which investment is required to bring about significant improvements in asthma outcomes.
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http://dx.doi.org/10.1183/13993003.02448-2016DOI Listing
May 2017

Type III interferons (IFNs): Emerging Master Regulators of Immunity.

Adv Exp Med Biol 2015 ;850:1-15

Department of Immunology, Center for Translational and Clinical Research, Biomedical Research Foundation, Academy of Athens, 11527, Athens, Greece.

Lambda interferons (IFN-λs), type III interferons or interleukins 28 and 29 are the latest addition to the class II cytokine family. They share low homology with the interferon (IFN) and IL-10 cytokine families, yet they exhibit common and unique activities, the full spectrum of which still remains incompletely understood. Although initially described for their antiviral functions, it is now appreciated that IFN-λs also mediate diverse antitumor and immune-modulatory effects, and are key determinants of innate immunity at mucosal sites such as the gastrointestinal and respiratory tracks. Here, we are reviewing the biological functions of IFN-λs, the mechanisms controlling their expression, their downstream effects and their role in the maintenance of homeostasis and disease. We are also exploring the potential application of IFN-λs as novel therapeutics.
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http://dx.doi.org/10.1007/978-3-319-15774-0_1DOI Listing
December 2015

Immunization of mice with a peptide derived from the HTLV-1 TAX1BP1 protein induces cross-reactive antibodies against aquaporin 4.

Autoimmunity 2015 14;48(7):453-9. Epub 2015 Aug 14.

a Department of Pathophysiology, Faculty of Medicine , National and Kapodistrian University of Athens , Athens , Greece and.

Antibodies against aquaporin-4 (AQP4) are specific and pathogenetic for Neuromyelitis Optica (NMO). In a previous study, three linear intracellular AQP4 B-cell epitopes were uncovered in NMO patients. A particular epitope showed high-sequence similarity with a segment of the human TAX1BP1 protein, which is necessary for the replication of HTLV-1 virus. The aim of the present study was to investigate whether immunization of mice with the TAX1BP1 peptide could produce specific antibodies against AQP4 epitopes or induce symptoms. Eight C57Bl/6 mice were immunized with TAX1BP1pep in Complete Freund's Adjuvant and eight with adjuvant only. Animals received three subcutaneous injections and sera were obtained before each immunization and at sacrifice. All sera were evaluated by ELISA for antibodies against the TAX1BP1peptide, the homologous AQP4 peptide and all linear AQP4 epitopes. Homologous and cross-inhibition assays were performed to ensure binding specificity, and reactivity against conformational AQP4 epitopes was evaluated by a cell-based assay. Sera from immunized animals showed high reactivity against the immunization peptide, and the homologous AQP4 epitope. Inhibition assays confirmed binding specificity. No antibodies were produced against any other epitopes, either linear or conformational. No clinical or brain inflammatory signs were observed in the animals. The induction of antibodies to an AQP4 epitope in mice immunized with the TAX1BP1-derived peptide suggests that a latent HTLV-1 infection could lead to TAX1BP1 antigen presentation and the production of anti-AQP4 antibodies, probably through T cell-mediated mechanisms. Further studies are needed for exploring triggering factors for NMO especially in HTLV-1-endemic regions.
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http://dx.doi.org/10.3109/08916934.2015.1070836DOI Listing
August 2016

Neutrophils in viral infections: Current concepts and caveats.

J Leukoc Biol 2015 Oct 9;98(4):557-64. Epub 2015 Jul 9.

Laboratory of Immunobiology, Center for Clinical and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece

Neutrophils are the first immune cell population recruited to sites of infection, including viral infections, and exhibit both protective and pathologic functions. In antibacterial and antifungal immunity, the role of neutrophils is well defined. However, in antiviral immunity, much less is known. Conventional wisdom suggests that neutrophils enhance antiviral defenses, yet evidence for that is limited. Interaction with other immune cell populations, virus internalization and killing, the release of cytokines, chemokines, and antimicrobial components are all mechanisms by which neutrophils can contribute to pathogen clearance. NET formation, extensively studied during bacterial infection, can further mediate antiviral defense by trapping and inactivating virus. In the present review, we discuss the current understanding of the complex role of neutrophil immunity in viral infections and disease pathogenesis and the potential mechanisms identified to date. We pinpoint the importance of a finely tuned neutrophilic response for achieving effective immune protection while avoiding detrimental tissue damage that can form the basis for the development of novel therapeutics.
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http://dx.doi.org/10.1189/jlb.4VMR1114-555RDOI Listing
October 2015

Rationale for the application of RANKL inhibition in the treatment of Langerhans cell histiocytosis.

J Clin Endocrinol Metab 2015 Feb 6;100(2):E282-6. Epub 2014 Nov 6.

Departments of Endocrinology and Diabetes (P.M.) and Pathology (K.R.), 251 Hellenic Air Force and VA General Hospital, Athens, Greece; Center for Immunology and Transplantations (M.S., E.A.), Biomedical Research Foundation, Academy of Athens, Greece; Department of Endocrinology (A.D.A.), 424 Military Hospital, Thessaloniki, Greece; and Department of Pathophysiology (M.S., M.T., G.K.), National University of Athens, Athens, Greece.

Context: Langerhans Cell Histiocytosis (LCH) is a rare disease exhibiting both neoplastic and inflammatory features including abundant cytokine secretion both at the lesional and systemic level.

Objective: Evaluation of RANKL expression within LCH lesions in various tissues.

Design: Cross-sectional study involving paraffin blocks from the diagnostic biopsies of adults with LCH.

Setting: The study was conducted among patients followed in an adult outpatient clinic.

Subjects: Eleven patients with active LCH, who were 41.27 ± 3.44 years old, and five patients who were 46.8 ± 7.19 years old with non-LCH diagnosis serving as controls.

Interventions: RANKL, p65 and CD1a immunostaining of deparaffinized sections from LCH lesions and control tissues.

Main Outcome Measure: Comparison of RANKL and p65 expression between LCH lesions, as indicated from concomitant CD1a immunostaining, and control tissue counterparts.

Results: A focal positive granular cytoplasmic RANKL staining was found at all lesional sites in a number of cells of the pathological infiltrate, mostly with morphologic features of pathological Langerhans cells (LCs). Compared to control tissues, RANKL positivity in LCH cases showed an excess of staining, both in intensity of staining and the number of stained cells, especially in areas of pathologic infiltration. RANKL staining also coincided with strong p65 NFκB nuclear positivity, especially in lesional infiltrates.

Conclusions: RANKL is highly expressed in active LCH at the lesional level, concomitant to p65 NFκB activation. The use of RANKL inhibition as a rational therapeutic approach of the disease now needs further clinical evaluation.
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http://dx.doi.org/10.1210/jc.2014-2654DOI Listing
February 2015

IL-25: the missing link between allergy, viral infection, and asthma?

Sci Transl Med 2014 Oct;6(256):256fs38

Center for Pediatrics and Child Health, Institute of Human Development, Royal Manchester Children's Hospital, University of Manchester, Manchester M13 9WL, UK. Allergy Department, 2nd Pediatric Clinic, Athens General Children's Hospital "P&A Kyriakou," University of Athens, Athens 11527, Greece.

Interleukin 25 boosts proinflammatory and proasthmatic responses in the allergic lung and emerges as a key determinant of virally induced asthma exacerbations and as a therapeutic target for asthma (Beale et al., this issue).
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http://dx.doi.org/10.1126/scitranslmed.3010273DOI Listing
October 2014

Therapeutic human monoclonal antibodies in inflammatory diseases.

Methods Mol Biol 2014 ;1060:37-59

Laboratory of Immunogenetics, Center of Immunology and Transplantation, Immunobiology Division, Biomedical Research Foundation of the Academy of Athens, Athens, Hellas, Greece.

Monoclonal antibodies (mAbs) are antibodies of a single antigen specificity produced by identical immune cells, i.e., clones of a common germ cell. They offer unprecedented opportunities to drug development because of their ability to target almost any cell surface or secreted molecule with remarkable efficacy and safety. In this chapter, the application of human mAbs in the treatment of inflammatory diseases is reviewed. We discuss in detail several mAb-based drugs such as anti-tumor necrosis factor (anti-TNF), anti-interleukin-1 (anti-IL-1) receptor, anti-IL-6 receptor, anti-α4 integrin subunit, and anti-CD20 agents, all of which have been documented by clinical trials to be efficacious and have been approved for the therapy of several inflammatory and immune diseases, including rheumatoid arthritis, Crohn's disease, ulcerative colitis, spondyloarthropathies, juvenile arthritis, psoriasis, psoriatic arthritis, and others. These novel drugs can be used either as a monotherapy or in combination with other conventional therapeutic modalities, particularly if the disease under treatment is refractory to therapy using solely conventional techniques. As a large variety of mAb-based agents targeting a plethora of cytokines, chemokines, adhesion and co-stimulatory molecules, receptors, as well as diverse cell types, are presently under investigation, the therapeutic armamentarium of the clinician is expected to greatly broaden in the near future, providing improved patient care for a wide range of devastating diseases of our times.
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http://dx.doi.org/10.1007/978-1-62703-586-6_3DOI Listing
March 2014
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