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Derived from the myeloid lineage, granulocytes, including basophils, eosinophils, and neutrophils, along with mast cells, play important, often disparate, roles across the allergic disease spectrum. While these cells and their mediators are commonly associated with allergic inflammation, they also exhibit several functions either promoting or restricting tumor growth. In this Position Paper we discuss common granulocyte and mast cell features relating to immunomodulatory functions in allergy and in cancer. We highlight key mechanisms which may inform cancer treatment and propose pertinent areas for future research. We suggest areas where understanding the communication between granulocytes, mast cells, and the tumor microenvironment, will be crucial for identifying immune mechanisms that may be harnessed to counteract tumor development. For example, a comprehensive understanding of allergic and immune factors driving distinct neutrophil states and those mechanisms that link mast cells with immunotherapy resistance, might enable targeted manipulation of specific subpopulations, leading to precision immunotherapy in cancer. We recommend specific areas of investigation in AllergoOncology and knowledge exchange across disease contexts to uncover pertinent reciprocal functions in allergy and cancer and allow therapeutic manipulation of these powerful cell populations. These will help address the unmet needs in stratifying and managing patients with allergic diseases and cancer., (© 2024 The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: We investigated the biological function of the mould allergen Alt a 1 as a carrier of micronutrients, such as the vitamin A metabolite retinoic acid (RA) and the influence of RA binding on its allergenicity in vitro and in vivo., Methods: Alt a 1-RA complex formation was analyzed in silico and in vitro. PBMCs from Alternaria-allergic donors were stimulated with Alt a 1 complexed with RA (holo-Alt a 1) or empty apo-Alt a 1 and analyzed for cytokine production and CD marker expression. Serum IgE-binding and crosslinking assays to apo- and holo-protein were correlated to B-cell epitope analysis. Female BALB/c mice already sensitized to Alt a 1 were intranasally treated with apo-Alt a 1, holo-Alt a 1 or RA alone before measuring anaphylactic response, serum antibody levels, splenic cytokines and CD marker expression., Results: In silico docking calculations and in vitro assays showed that the extent of RA binding depended on the higher quaternary state of Alt a 1. Holo-Alt a 1 loaded with RA reduced IL-13 released from PBMCs and CD3+CD4+CRTh2 cells. Complexing Alt a 1 to RA masked its IgE B-cell epitopes and reduced its IgE-binding capacity. In a therapeutic mouse model of Alternaria allergy nasal application of holo-Alt a 1, but not of apo-Alt a 1, significantly impeded the anaphylactic response, impaired splenic antigen-presenting cells and induced IL-10 production., Conclusion: Holo-Alt a 1 binding to RA was able to alleviate Th2 immunity in vitro, modulate an ongoing Th2 response and prevent anaphylactic symptoms in vivo, presenting a novel option for improving allergen-specific immunotherapy in Alternaria allergy., (© 2024 The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Epidemiological studies have explored the relationship between allergic diseases and cancer risk or prognosis in AllergoOncology. Some studies suggest an inverse association, but uncertainties remain, including in IgE-mediated diseases and glioma. Allergic disease stems from a Th2-biased immune response to allergens in predisposed atopic individuals. Allergic disorders vary in phenotype, genotype and endotype, affecting their pathophysiology. Beyond clinical manifestation and commonly used clinical markers, there is ongoing research to identify novel biomarkers for allergy diagnosis, monitoring, severity assessment and treatment. Gliomas, the most common and diverse brain tumours, have in parallel undergone changes in classification over time, with specific molecular biomarkers defining glioma subtypes. Gliomas exhibit a complex tumour-immune interphase and distinct immune microenvironment features. Immunotherapy and targeted therapy hold promise for primary brain tumour treatment, but require more specific and effective approaches. Animal studies indicate allergic airway inflammation may delay glioma progression. This collaborative European Academy of Allergy and Clinical Immunology (EAACI) and European Association of Neuro-Oncology (EANO) Position Paper summarizes recent advances and emerging biomarkers for refined allergy and adult-type diffuse glioma classification to inform future epidemiological and clinical studies. Future research is needed to enhance our understanding of immune-glioma interactions to ultimately improve patient prognosis and survival., (© 2024 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

The accumulation of senescent cells drives inflammaging and increases morbidity of chronic inflammatory lung diseases. Immune responses are built upon dynamic changes in cell metabolism that supply energy and substrates for cell proliferation, differentiation, and activation. Metabolic changes imposed by environmental stress and inflammation on immune cells and tissue microenvironment are thus chiefly involved in the pathophysiology of allergic and other immune-driven diseases. Altered cell metabolism is also a hallmark of cell senescence, a condition characterized by loss of proliferative activity in cells that remain metabolically active. Accelerated senescence can be triggered by acute or chronic stress and inflammatory responses. In contrast, replicative senescence occurs as part of the physiological aging process and has protective roles in cancer surveillance and wound healing. Importantly, cell senescence can also change or hamper response to diverse therapeutic treatments. Understanding the metabolic pathways of senescence in immune and structural cells is therefore critical to detect, prevent, or revert detrimental aspects of senescence-related immunopathology, by developing specific diagnostics and targeted therapies. In this paper, we review the main changes and metabolic alterations occurring in senescent immune cells (macrophages, B cells, T cells). Subsequently, we present the metabolic footprints described in translational studies in patients with chronic asthma and chronic obstructive pulmonary disease (COPD), and review the ongoing preclinical studies and clinical trials of therapeutic approaches aiming at targeting metabolic pathways to antagonize pathological senescence. Because this is a recently emerging field in allergy and clinical immunology, a better understanding of the metabolic profile of the complex landscape of cell senescence is needed. The progress achieved so far is already providing opportunities for new therapies, as well as for strategies aimed at disease prevention and supporting healthy aging., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

The rise of graph representation learning as the primary solution for many different network science tasks led to a surge of interest in the fairness of this family of methods. Link prediction, in particular, has a substantial social impact. However, link prediction algorithms tend to increase the segregation in social networks by disfavouring the links between individuals in specific demographic groups. This paper proposes a novel way to enforce fairness on graph neural networks with a fine-tuning strategy. We Drop the unfair Edges and, simultaneously, we Adapt the model's parameters to those modifications, DEA in short. We introduce two covariance-based constraints designed explicitly for the link prediction task. We use these constraints to guide the optimization process responsible for learning the new 'fair' adjacency matrix. One novelty of DEA is that we can use a discrete yet learnable adjacency matrix in our fine-tuning. We demonstrate the effectiveness of our approach on five real-world datasets and show that we can improve both the accuracy and the fairness of the link prediction tasks. In addition, we present an in-depth ablation study demonstrating that our training algorithm for the adjacency matrix can be used to improve link prediction performances during training. Finally, we compute the relevance of each component of our framework to show that the combination of both the constraints and the training of the adjacency matrix leads to optimal performances., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Naturalized dyes (NDs) are innovative and eco-friendly synthetic compounds in which a chromophore is covalently linked to a natural sugar (e.g., lactose). The sugar moiety confers water-solubility and biocompatibility to the dye molecule as a whole. NDs have demonstrated potential application in dyeing textiles and leather. The purpose of this work was to demonstrate that selected NDs can be also applied to dye wood. To that aim, two NDs were tested to color beech and poplar wood. The NDs were applied as a simple aqueous solution or mixed with a waterborne, biogenic staining agent (commercially available Gemma U50). Moreover, the effect of the application of a biogenic waterborne top coat (commercially available Resina Plus U49) was also studied. Different methods were tested to investigate the potential application of these NDs to wood. The dyeing behavior was analyzed in terms of penetration into the substrate, covering capacity and color homogeneity through macro- and microscopic observations and colorimetric measurements. The color fastness to water washout and the color stability to light, in particular by exposing the wooden samples to artificial aging (UV radiations in a Solar Box), were also investigated. The NDs, when used as water solutions, were able to afford a homogeneous coating and a pleasant appearance on the wood surface, as well as a good color fastness to washout with water. Dissolving the dyes in the stain or applying the top coat generally resulted in even better color fastness to washout. However, all the application methods tested showed limited resistance to fading in the Solar Box, which therefore remains a drawback for this type of product.

Alternaria alternata is a common fungus strongly related with severe allergic asthma, with 80% of affected individuals being sensitized solely to its major allergen Alt a 1. Here, we assessed the function of Alt a 1 as an innate defense protein binding to micronutrients, such as iron-quercetin complexes (FeQ2), and its impact on antigen presentation in vitro. Binding of Alt a 1 to FeQ2 was determined in docking calculations. Recombinant Alt a 1 was generated, and binding ability, as well as secondary and quaternary structure, assessed by UV-VIS, CD, and DLS spectroscopy. Proteolytic functions were determined by casein and gelatine zymography. Uptake of empty apo- or ligand-filled holoAlt a 1 were assessed in human monocytic THP1 cells under the presence of dynamin and clathrin-inhibitors, activation of the Arylhydrocarbon receptor (AhR) using the human reporter cellline AZ-AHR. Human PBMCs were stimulated and assessed for phenotypic changes in monocytes by flow cytometry. Alt a 1 bound strongly to FeQ2 as a tetramer with calculated K d values reaching pico-molar levels and surpassing affinities to quercetin alone by a factor of 5000 for the tetramer. apoAlt a 1 but not holoAlta 1 showed low enzymatic activity against casein as a hexamer and gelatin as a trimer. Uptake of apo- and holo-Alt a 1 occurred partly clathrin-dependent, with apoAlt a 1 decreasing labile iron in THP1 cells and holoAlt a 1 facilitating quercetin-dependent AhR activation. In human PBMCs uptake of holoAlt a 1 but not apoAlt a 1 significantly decreased the surface expression of the costimulatory CD86, but also of HLADR, thereby reducing effective antigen presentation. We show here for the first time that the presence of nutritional iron complexes, such as FeQ2, significantly alters the function of Alt a 1 and dampens the human immune response, thereby supporting the notion that Alt a 1 only becomes immunogenic under nutritional deprivation., Competing Interests: F.R.-W. and E.J.-J. declare inventorship of EP2894478 (Roth-Walter F et al. Method and means for diagnosing and treating allergy) (applicant Biomedical International R + D GmbH, Vienna, Austria). E.J.-J. declares shareholdership in Biomedical Int. R + D GmbH, Vienna, Austria. F.R.-W. received research funding from Biomedical International R + D GmbH, Vienna, Austria, Bencard Allergie GmbH, Munich, Germany and Vienna, Austria, and Allergy Therapeutics, Worthing, UK. Moreover, she received lecture honoraria by Bencard Allergie GmbH, Munich, Germany and Vienna, Austria, and Allergy Therapeutics, Worthing, UK. The other authors declare no relevant conflict of interest in relation to this publication.

The immune system interacts with many nominal 'danger' signals, endogenous danger-associated (DAMP), exogenous pathogen (PAMP) and allergen (AAMP)-associated molecular patterns. The immune context under which these are received can promote or prevent immune activating or inflammatory mechanisms and may orchestrate diverse immune responses in allergy and cancer. Each can act either by favouring a respective pathology or by supporting the immune response to confer protective effects, depending on acuity or chronicity. In this Position Paper under the collective term danger signals or DAMPs, PAMPs and AAMPs, we consider their diverse roles in allergy and cancer and the connection between these in AllergoOncology. We focus on their interactions with different immune cells of the innate and adaptive immune system and how these promote immune responses with juxtaposing clinical outcomes in allergy and cancer. While danger signals present potential targets to overcome inflammatory responses in allergy, these may be reconsidered in relation to a history of allergy, chronic inflammation and autoimmunity linked to the risk of developing cancer, and with regard to clinical responses to anti-cancer immune and targeted therapies. Cross-disciplinary insights in AllergoOncology derived from dissecting clinical phenotypes of common danger signal pathways may improve allergy and cancer clinical outcomes., (© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Functional iron deficiency facilitates allergy development and amplifies the symptom burden in people experiencing allergies. Previously we selectively delivered micronutrients to immune cells with β-lactoglobulin as carrier (holoBLG), resulting in immune resilience and allergy prevention., Objective: The clinical efficacy of a food for special medical purposes-lozenge containing β-lactoglobulin with iron, polyphenols, retinoic acid, and zinc (holoBLG lozenge) was assessed in allergic women., Methods: In a randomized, double-blind, placebo-controlled pilot study, grass- and/or birch pollen-allergic women (n = 51) were given holoBLG or placebo lozenges over 6 months. Before and after dietary supplementation, participants were nasally challenged and the blood was analyzed for immune and iron parameters. Daily symptoms, medications, pollen concentrations, and well-being were recorded by an electronic health application., Results: Total nasal symptom score after nasal provocations improved by 42% in the holoBLG group versus 13% in the placebo group. The combined symptom medication score during the birch peak and entire season as well as the entire grass pollen season improved in allergic subjects supplemented with the holoBLG lozenge by 45%, 31%, and 40%, respectively, compared with the placebo arm. Participants ingesting the holoBLG lozenge had improved iron status with increased hematocrit values, decreased red cell distribution width, and higher iron levels in circulating CD14 + cells compared with the placebo group., Conclusions: Targeted micronutrition with the holoBLG lozenge seemed to be effective in elevating the labile iron levels in immune cells and reducing the symptom burden in allergic women in this pilot study. The underlying allergen-independent mechanism provides evidence that dietary nutritional supplementation of the immune system is one of the ways to combat atopy., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Previously, the protective farm effect was imitated using the whey protein beta-lactoglobulin (BLG) that is spiked with iron-flavonoid complexes. Here, we formulated for clinical translation a lozenge as food for special medical purposes (FSMP) using catechin-iron complexes as ligands for BLG. The lozenge was tested in vitro and in a therapeutical BALB/c mice model., Methods: Binding of iron-catechin into BLG was confirmed by spectroscopy and docking calculations. Serum IgE binding of children allergic or tolerating milk was assessed to loaded (holo-) versus empty (apo-) BLG and for human mast cell degranulation. BLG and Bet v 1 double-sensitized mice were orally treated with the holoBLG or placebo lozenge, and immunologically analysed after systemic allergen challenge. Human PBMCs of pollen allergic subjects were flow cytometrically assessed after stimulation with apoBLG or holoBLG using catechin-iron complexes as ligands., Results: One major IgE and T cell epitope were masked by catechin-iron complexes, which impaired IgE binding of milk-allergic children and degranulation of mast cells. In mice, only supplementation with the holoBLG lozenge reduced clinical reactivity to BLG and Bet v 1, promoted Tregs, and suppressed antigen presentation. In allergic subjects, stimulation of PBMCs with holoBLG led to a significant increase of intracellular iron in circulating CD14+ cells with significantly lower expression of HLADR and CD86 compared to their stimulation with apoBLG., Conclusion: The FSMP lozenge targeted antigen presenting cells and dampened immune activation in human immune cells and allergic mice in an antigen-non-specific manner, thereby conferring immune resilience against allergic symptoms., (© 2021 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)

Background: Growing up on a cattle farm and consuming raw cow's milk protects against asthma and allergies. We expect a cattle-specific protein as active component in this farm effect., Methods: Dust was collected from cattle and poultry stables and from mattresses of households. Urine was obtained from cattle, and ambient aerosols were sampled. Samples were analysed for BLG by SDS PAGE/immunoblot and mass spectrometry, and for association with metals by SEC-ICP-MS. PBMC of healthy donors were incubated with BLG +/- zinc, and proliferation and cytokines determined. BALB/c mice were pre-treated intranasally with stable dust extract containing BLG or depleted of BLG, and subsequent allergy response after sensitization was evaluated on antibody and symptom level., Results: A major protein in dust from cattle farms and ambient air was identified as BLG. Urine from female and male cattle is a major source of BLG. In dust samples, BLG was associated with zinc. In vitro , zinc-BLG provoked significantly lower proliferation of CD4 + and CD8 + cells while inducing significantly higher levels of IFN-γ and IL-6 than the apo-BLG devoid of zinc. In vivo , pre-treatment of mice with dust extract containing BLG resulted in lower allergy symptom scores to BLG and unrelated Bet v 1 than pre-treatment with extract depleted of BLG. These in vitro and in vivo effects were independent of endotoxin., Conclusion: The lipocalin BLG is found in large amounts in cattle urine, accumulates in bovine dust samples and is aerosolized around farms. Its association with zinc favorably shapes the human cellular immune response towards Th1-cytokines in vitro . BLG together with zinc in stable dust protects mice from allergic sensitization. BLG with its associated ligands may in an innate manner contribute to the allergy-protective farm effect., Competing Interests: IPS and EJJ report personal fees from Bencard Allergie GmbH, Germany, outside the submitted work. EJJ, LFP and FRW are inventors of EP2894478; “LCN2 as a tool for allergy diagnostic and therapy”, EP 14150965.3, Year: 01/2014; US 14/204,570, owned by Biomedical International R+D GmbH, Vienna, Austria, the basis for the dietary lozenge immunoBON®. EJJ is shareholder in this company. Dr. von Mutius reports grants from German Centre for Lung Research (DZL), personal fees from Elsevier GmbH, personal fees from Georg Thieme Verlag, personal fees from Springer‐Verlag GmbH, personal fees from Elsevier Ltd., personal fees from Chinese University of Hongkong, personal fees from European Commission, personal fees from HIPP GmbH & Co. KG, personal fees from AstraZeneca, personal fees from Massachusetts Medical Society, personal fees from Böhringer Ingelheim International GmbH, from European Respiratory Society (ERS), personal fees from Universiteit Utrecht, Faculteit Diergeneeskunde, personal fees from Universität Salzburg, personal fees from Springer Medizin Verlag GmbH, personal fees from Japanese Society of Pediatric Allergy and Clinical Immunology (JSPACI), personal fees from Klinikum Rechts der Isar, Munich, personal fees from University of Colorado, personal fees from Paul‐Martini‐Stiftung, Berlin, personal fees from Imperial College London, personal fees from Verein zur Förderung der Pneumologie am Krankenhaus Großhansdorf e.V., personal fees from Pneumologie Development, personal fees from Mondial Congress & Events GmbH & Co. KG, personal fees from American Academy of Allergy, Asthma and Immunology , personal fees from Margaux Orange, personal fees from Volkswagen Stiftung, personal fees from Österreichische Gesellschaft für Allergologie und Immunologie, personal fees from OM Pharma S.A., personal fees from Hanson Wade Ltd., personal fees from iKOMM GmbH, personal fees from DSI Dansk Borneastma Cemter, personal fees from American Thoracic Society, personal fees from Universiteit Utrecht, Faculteit Betawetenschappen, outside the submitted work; In addition, Dr. von Mutius has a patent Patent LU101064 pending, a patent Patent EP2361632 with royalties paid to ProtectImmun, a patent Patent EP1411977 with royalties paid to ProtectImmun, a patent Patent EP1637147 with royalties paid to ProtectImmun, and a patent Patent EP1964570 licensed to ProtectImmun and Erika von Mutius is: Member of the EXPANSE (funded by European Commission) Scientific Advisory Board, Member of the BEAMS External Scientific Advisory Board (ESAB), Member of the Editorial Board of “The Journal of Allergy and Clinical Immunology: In Practice”, Member of the Scientific Advisory Board of the Children’s Respiratory and Environmental Workgroup (CREW), Member of the International Scientific & Societal Advisory Board (ISSAB) of Utrecht Life Sciences (ULS), University of Utrecht, Member of External Review Panel of the Faculty of Veterinary Science, University of Utrecht, Member of the Selection Committee for the Gottfried Wilhelm Leibniz Programme (DFG), Member of the International Advisory Board of Asthma UK Centre for Applied Research (AUKCAR), Member of the International Advisory Board of “The Lancet Respiratory Medicine”, Member of the Scientific Advisory Board of the CHILD (Canadian Healthy Infant Longitudinal Development) study, McMaster University, Hamilton, Canada. The other authors declare no relevant conflict of interest in relation to this publication., (© 2022 The Authors. Clinical and Translational Allergy published by John Wiley & Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology.)

Cuscutamantiqueirana Costea, S.S. Silva & Sim.-Bianch. a new species from montane cloud forests of the Serra da Mantiqueira, Brazil, is described and illustrated. The morphological and phylogenetic analyses revealed that the new species belongs to sect. Subulataeofsubg.Grammica. The new species is related to C.odoratavar.botryoides, C.rotundiflora and C.globiflora from which it differs in narrower calyx lobes and the presence of four stomatiferous lobes or projections at the distal part of the ovary. A detailed morphological comparison with C.odoratavar.botryoides, morphologically the most similar taxon, is provided along with the geographical distribution, ecology and host range of the species. The morphological and phylogenetic relationships of the new species, as well as the diversity of stomatiferous projections, are discussed in the broader context of sect. Subulatae and subg. Grammica. Cuscutabolivianavar.paranensis is considered a synonym of C.odoratavar.botryoides., (Mihai Costea, Simone Soares da Silva, Rosangela Simao-Bianchini, Ana Rita G. Simoes, Sasa Stefanovic.)

The purpose of this study was to report our institutional experience with patients with COVID-19 who developed acute limb ischemia during hospitalization and to determine the characteristics and clinical outcomes. Between March 2020 and January 2021, we treated 3 patients who were COVID-19-positive and developed acute limb ischemia after they received thromboprophylaxis. We performed an embolectomy by exposing the popliteal artery below the knee to treat an occlusion of the popliteal and tibial arteries. An infusion of unfractionated heparin was initiated immediately after surgery, maintaining a partial thromboplastin time ratio > 2.5 times the normal value and transferred the patients to the intensive care unit. However, after these patients developed recurrent acute limb ischemia in the same leg, we decided to perform an embolectomy of popliteal and tibial arteries at the ankle and created an arteriovenous fistula (AVF) with tibial veins using polypropylene 7-0. The first patient died from pneumonia after 3 weeks in the intensive care unit; at that time, the foot was viable with triphasic flow in the distal posterior tibial artery and the AVF was patent. The second and third patients are doing well, they can walk without any problems, and the tibial arteries and AFV were patent on duplex ultrasound after 6 months. The AVF allowed part of the flow of tibial arteries to divert into the small veins of the foot that have a low resistance to maintain patency of tibial vessels, despite a hypercoagulable state and extensive thrombotic microangiopathy in patients with COVID-19., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare in relation to the this work., (Copyright © 2021. Published by Elsevier Inc.)

IgG4 subclass antibodies are expressed in alternative Th2 environments featuring high IL-10 expression, including several solid tumors such as melanoma. To induce tolerance, allergen immunotherapy mediates antibody class switching from pro-inflammatory IgE to anti-inflammatory IgG4. We previously reported that IgG4 drives allergic M2 macrophages toward tolerogenic states. Here we assessed the roles of IgG4 and macrophage activation in colorectal cancer (CRC). In this observer-blinded, case-control study, we analyzed total circulating serum IgE, IgG1 and IgG4 levels in CRC (n = 38) patients with (n = 13, TxNxM1) or without (n = 25, TxNxM0) metastasis, and in healthy donors (n = 21). Primary cultures of circulating monocyte-derived macrophages from healthy controls and CRC patients were further evaluated in their responses to stimulation with IgG1 or IgG4. We found higher absolute serum levels of IgG4 in patients with CRC. IgG4 enabled polarization of macrophages derived from CRC patients and healthy controls into alternatively-activated tolerogenic M2b phenotypes. IgG4-stimulated M2 macrophages were characterized by lower surface CD206, CD163, CD14, and CD11b expression and higher CCL-1, IL-10, and IL-6 production. IgG4 was less potent that IgG1 in triggering antibody-dependent cell-mediated phagocytosis (ADCP) of cancer cells. Further, higher z-normalized IgG4/-IgE sera level ratios correlated with the presence of metastasis ( p = .0247 and p = .0009, respectively) in CRC patients. High IgG4 in CRC synergizes with macrophages in shaping an immunosuppressive microenvironment and impairs anti-cancer effector cell functions. The shift of serum IgG4/IgE ratios toward enhanced tolerance induction in metastatic disease indicates a role for high IgG4 in disease progression and poor prognostic outcome., Competing Interests: The authors declare no potential conflicts of interest., (© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Therapeutic advances using targeted biologicals and small-molecule drugs have achieved significant success in the treatment of chronic allergic, autoimmune, and inflammatory diseases particularly for some patients with severe, treatment-resistant forms. This has been aided by improved identification of disease phenotypes. Despite these achievements, not all severe forms of chronic inflammatory and autoimmune diseases are successfully targeted, and current treatment options, besides allergen immunotherapy for selected allergic diseases, fail to change the disease course. T cell-based therapies aim to cure diseases through the selective induction of appropriate immune responses following the delivery of engineered, specific cytotoxic, or regulatory T cells (Tregs). Adoptive cell therapies (ACT) with genetically engineered T cells have revolutionized the oncology field, bringing curative treatment for leukemia and lymphoma, while therapies exploiting the suppressive functions of Tregs have been developed in nononcological settings, such as in transplantation and autoimmune diseases. ACT with Tregs are also being considered in nononcological settings such as cardiovascular disease, obesity, and chronic inflammatory disorders. After describing the general features of T cell-based approaches and current applications in autoimmune diseases, this position paper reviews the experimental models testing or supporting T cell-based approaches, especially Treg-based approaches, in severe IgE-mediated responses and chronic respiratory airway diseases, such as severe asthma and COPD. Along with an assessment of challenges and unmet needs facing the application of ACT in these settings, this article underscores the potential of ACT to offer curative options for patients with severe or treatment-resistant forms of these immune-driven disorders., (© 2020 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Birch pollen allergy is among the most prevalent pollen allergies in Northern and Central Europe. This IgE-mediated disease can be treated with allergen immunotherapy (AIT), which typically gives rise to IgG antibodies inducing tolerance. Although the main mechanisms of allergen immunotherapy (AIT) are known, questions regarding possible Fc-mediated effects of IgG antibodies remain unanswered. This can mainly be attributed to the unavailability of appropriate tools, i.e., well-characterised recombinant antibodies (rAbs). We hereby aimed at providing human rAbs of several classes for mechanistic studies and as possible candidates for passive immunotherapy. We engineered IgE, IgG 1 , and IgG 4 sharing the same variable region against the major birch pollen allergen Bet v 1 using Polymerase Incomplete Primer Extension (PIPE) cloning. We tested IgE functionality and IgG blocking capabilities using appropriate model cell lines. In vitro studies showed IgE engagement with FcεRI and CD23 and Bet v 1-dependent degranulation. Overall, we hereby present fully functional, human IgE, IgG 1 , and IgG 4 sharing the same variable region against Bet v 1 and showcase possible applications in first mechanistic studies. Furthermore, our IgG antibodies might be useful candidates for passive immunotherapy of birch pollen allergy.

Among the four immunoglobulin G (IgG) subclasses, IgG4 is the least represented in serum of a healthy human and it is considered an "odd" antibody. The IgG4 antibody has unique structural features that affect its biological function. These include the ability to undergo antigen-binding fragment (Fab)-arm exchange, to create fragment crystallizable (Fc) - Fc binding with other IgG4 and other IgG subclass antibodies, have a unique affinity profile for Fc gamma receptors (FcγRs) and no binding to complement component C1q. Altogether, these characteristics support anti-inflammatory roles of IgG4 leading to immune tolerance. Under conditions of chronic antigenic stimulation and Th2-type inflammation, both tissue and serum IgG4 levels are increased. This review seeks to highlight how in allergen immunotherapy IgG4 can confer a protective role as a "blocking" antibody and safeguard from subsequent allergen exposure, while IgG4 can confer immunomodulatory functions to support malignancy. While Th2 conditions drive polarization of macrophages to the M2a subtype, chronic antigen stimulation drives B cell class switching to IgG4 to further support phenotypical macrophage changes towards an M2b-like state. M2b-like macrophages can secrete chemokine (C-C motif) ligand 1 (CCL1) and interleukin-10 (IL-10) to support regulatory cell recruitment and to further shape a tolerogenic microenvironment. Thereby, IgG4 have a Janus-faced role, favorable in allergy but detrimental in cancer.

Background: Hydration and moisturization both impact skin quality, directly reflecting its appearance. Signs and onset of dehydration-related skin aging are region-specific and require tailored treatment to be effective., Aims: To test the hydrating effects of formulas containing a novel 3-dimensional 3-polymer interpenetrating network (3D3P-IPN) to deliver humectants and actives to specific body sites., Methods: Two clinical studies were conducted focused on the skin under eyes and body (arms/legs). Healthy women ages 25-65 (eyes) or 35-65 (body) with mild to moderate dry and aged skin were enrolled. Study product containing the 3D3P-IPN and tailored actives was applied twice daily for 8 weeks on the periorbital area and for 4 weeks on the body. Changes in skin attributes were measured by biophysical instrumentation for hydration, dark circles, skin color, elasticity and transepidermal water loss, and by clinical grading and subject self-assessment., Results: Significant improvements in hydration and skin smoothing were demonstrated in both studies. In the periorbital region, actives and humectants delivered by the 3D3P-IPN also led to significant improvements in dark circles, fine lines/crow's feet, puffiness, restoring radiance, and overall younger-looking appearance. On the arms and legs, there were significant reductions in crepiness and dullness. The arms and legs also had improvements in tactile and visual skin texture, radiance, and general healthy look. Improvements were immediate and persisted through the end of both studies., Conclusion: The 3D3P-IPN provides immediate and long-lasting improvements in skin hydration and overall healthy appearance regardless of the targeted application site., (© 2019 Rodan+Fields. Journal of Cosmetic Dermatology published by Wiley Periodicals, Inc.)

The microbiota can play important roles in the development of human immunity and the establishment of immune homeostasis. Lifestyle factors including diet, hygiene, and exposure to viruses or bacteria, and medical interventions with antibiotics or anti-ulcer medications, regulate phylogenetic variability and the quality of cross talk between innate and adaptive immune cells via mucosal and skin epithelia. More recently, microbiota and their composition have been linked to protective effects for health. Imbalance, however, has been linked to immune-related diseases such as allergy and cancer, characterized by impaired, or exaggerated immune tolerance, respectively. In this AllergoOncology position paper, we focus on the increasing evidence defining the microbiota composition as a key determinant of immunity and immune tolerance, linked to the risk for the development of allergic and malignant diseases. We discuss novel insights into the role of microbiota in disease and patient responses to treatments in cancer and in allergy. These may highlight opportunities to improve patient outcomes with medical interventions supported through a restored microbiome., (© 2019 The Authors. Allergy Published by John Wiley & Sons Ltd.)

The regulatory peptide galanin is broadly distributed in the central- and peripheral nervous systems as well as in non-neuronal tissues, where it exerts its diverse physiological functions via three G-protein-coupled receptors (GAL 1-3 -R). Regulatory peptides are important mediators of the cross-communication between the nervous- and immune systems and have emerged as a focus of new therapeutics for a variety of inflammatory diseases. Studies on inflammatory animal models and immune cells revealed both pro- and anti-inflammatory functions of galanin. Here, we probed specific immune-related functions of the galanin system and found galanin and GAL 1 -R and GAL 2 -R mRNA to be expressed in a range of human immune cells. In particular, macrophages displayed differentiation- and polarization-dependent expression of galanin and its receptors. Exposure to exogenous galanin affected the cytokine/chemokine expression profile of macrophages differently, depending on their differentiation and polarization, and mainly modulated the expression of chemokines (CCL2, CCL3, CCL5 and CXCL8) and anti-inflammatory cytokines (TGF-β, IL-10 and IL-1Ra), especially in type-1 macrophages. Cytokine/chemokine expression levels in interferon-gamma- and lipopolysaccharide-polarized macrophages were upregulated whereas in unpolarized macrophages they were downregulated upon galanin treatment for 20 hours. This study illuminates the regulation of important cytokines/chemokines in macrophages by galanin, depending on specific cell activation.

Background: Antibody Fc-driven engagement of macrophages is critical for evoking cellular activation and effector functions and influencing tumour-associated macrophage (TAM) recruitment. We previously reported that IgE class antibodies promote restriction of cancer growth in rodent models associated with significant TAM infiltration. However, the human macrophage-associated IgE-Fc Receptor (FcεR) axis remains unexplored. We investigated the effects of anti-tumour IgE stimulation on human macrophage activation., Methods: Human blood monocyte-differentiated quiescent (M0), classically-(M1) and alternatively-(M2) activated macrophages were crosslinked with IgE and polyclonal antibodies to mimic immune complex formation. We examined surface marker expression, cytokine secretion, protein kinase phosphorylation and gene expression in IgE-stimulated macrophages and IgE antibody-dependent macrophage-mediated cytotoxicity (ADCC) against tumour cells., Findings: A proportion (40%) of M2 and (<20%) M0 and M1 macrophages expressed the high-affinity IgE receptor FcεRI. IgE crosslinking triggered upregulation of co-stimulatory CD80, increased TNFα, IFNγ, IL-1β, IL-12, IL-10, IL-13, CXCL9, CXCL11 and RANTES secretion by M0 and M2 and additionally enhanced MCP-1 by M2 macrophages. IgE-stimulated M1 macrophages retained secretion of pro-inflammatory cytokines. IgE crosslinking enhanced the FcεRI-dependent signalling pathway, including phosphorylation of the Lyn kinase, ERK1/2 and p38 in M2 macrophages and upregulated Lyn gene expression by M1 and M2 macrophages. Anti-tumour IgE engendered ADCC of cancer cells by all macrophage subsets., Interpretation: IgE can engage and re-educate alternatively-activated macrophages towards pro-inflammatory phenotypes and prime all subsets to mediate anti-tumour functions. This points to IgE-mediated cascades with potential to activate immune stroma and may be significant in the clinical development of strategies targeting tumour-resident macrophages., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Macrophages can be converted in vitro into immunoregulatory M2b macrophages in the presence of immune complexes (ICs), but the role of the specific subclasses IgG1 or IgG4 in this phenotypic and functional change is not known., Objective: We aimed to refine the original method by applying precisely defined ICs of the subclasses IgG4 or IgG1 constructed by two independent methods., Methods: Monocyte-derived macrophages (MDMs) were treated with M-CSF, followed by IL-4/IL-13 to induce the M2a allergic phenotype. To mimic unspecific or allergen-specific ICs, plates were coated with myeloma IgG1 or IgG4, or with grass pollen allergen Phl p 5 followed by recombinant human Phl p 5-specific IgG1 or IgG4. M2a polarized macrophages were then added, cultured, and examined for cellular markers and cytokines by flow cytometry, ELISA, and rtPCR. Alternatively, immune complexes with IgG1 or IgG4 were formed using protein L., Results: IgG4 ICs down regulated CD163 and CD206 on M2a cells, and significantly increased IL-10, IL-6, TNFα, and CCL1 secretion, indicating a shift to an M2b-like phenotype. Treatment with IgG4 ICs resulted in expression of FcγRII and down modulation of FcγRII compared with IgG1 treated cells (P = 0.0335) or untreated cells (P < 0.00001)., Conclusion: Immune complexes with subclasses IgG1 and IgG4 can in vitro be generated by plate absorption, and in fluid form by protein L. Cross-linking of FcγRIIb by the IgG4 subclass redirects pro-allergic M2a macrophages to an M2b-like immunosuppressive phenotype. This suggests an interplay of macrophages with IgG4 in immune tolerance, likely relevant in allergen immunotherapy., (© 2018 The Authors. Allergy Published by John Wiley & Sons Ltd.)

Chronic airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), together with their comorbidities, bear a significant burden on public health. Increased appreciation of molecular networks underlying inflammatory airway disease needs to be translated into new therapies for distinct phenotypes not controlled by current treatment regimens. On the other hand, development of new safe and effective therapies for such respiratory diseases is an arduous and expensive process. Antibody-based (biological) therapies are successful in treating certain respiratory conditions not controlled by standard therapies such as severe allergic and refractory eosinophilic severe asthma, while in other inflammatory respiratory diseases, such as COPD, biologicals are having a more limited impact. Small molecule drug (SMD)-based therapies represent an active field in pharmaceutical research and development. SMDs expand biologicals' therapeutic targets by reaching the intracellular compartment by delivery as either an oral or topically based formulation, offering both convenience and lower costs. Aim of this review was to compare and contrast the distinct pharmacological properties and clinical applications of SMDs- and antibody-based treatment strategies, their limitations and challenges, in order to highlight how they should be integrated for their optimal utilization and to fill the critical gaps in current treatment for these chronic inflammatory respiratory diseases., (© 2018 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

The M2a subtype of macrophages plays an important role in human immunoglobulin E (IgE-mediated allergies) and other Th2 type immune reactions. In contrast, very little is known about these cells in the dog. Here we describe an in vitro method to activate canine histiocytic DH82 cells and primary canine monocyte-derived macrophages (MDMs) toward the M2a macrophages using human cytokines. For a side-by-side comparison, we compared the canine cells to human MDMs, and the human monocytic cell line U937 activated towards M1 and M2a cells on the cellular and molecular level. In analogy to activated human M2a cells, canine M2a, differentiated from both DH82 and MDMs, showed an increase in CD206 surface receptor expression compared to M1. Interestingly, canine M2a, but not M1 derived from MDM, upregulated the high-affinity IgE receptor (FcεRI). Transcription levels of M2a-associated genes (IL10, CCL22, TGFβ, CD163) showed a diverse pattern between the human and dog species, whereas M1 genes (IDO1, CXCL11, IL6, TNF-α) were similarly upregulated in canine and human M1 cells (cell lines and MDMs). We suggest that our novel in vitro method will be suitable in comparative allergology studies focussing on macrophages., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background/aim: Our aim was to investigate the crosstalk between tumor and immune cells (M2 macrophages) and its effects on cyclo-oxygenase-2 (COX2) regulation in canine mammary tumors (CMT)., Materials and Methods: Sh1b CMT cells and human BT474 mammary or HT29 colon cancer cells were co-cultured with canine peripheral blood mononuclear cells (PBMCs) or with macrophage-like differentiated THP1 monocytes (dTHP1). Intracellular COX2 expression by PBMCs, dTHP1 and cancer cells was evaluated by flow cytometry., Results: Co-culturing of Sh1b and canine PBMCs induced COX2 overexpression in CMT cells. In turn, COX2 expression by PBMCs, mostly CD68 + macrophages, was attenuated by co-culture with Sh1b (p=0.0001). In accordance, co-culture with dTHP1 prompted intracellular production of COX2 in both Sh1b CMT cells and HT29 human colon cancer cells and reduced production of COX2 in BT474 human mammary cancer cells. The intracellular COX2 expression from dTHP1 decreased when treated with conditioned medium from cultured Sh1b and HT29 cancer cells., Conclusion: Bidirectional COX2 regulation between cancer and monocytes/macrophages might shape a tolerogenic tumor microenvironment in CMT., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

While desired for the cure of allergy, regulatory immune cell subsets and nonclassical Th2-biased inflammatory mediators in the tumour microenvironment can contribute to immune suppression and escape of tumours from immunological detection and clearance. A key aim in the cancer field is therefore to design interventions that can break immunological tolerance and halt cancer progression, whereas on the contrary allergen immunotherapy exactly aims to induce tolerance. In this position paper, we review insights on immune tolerance derived from allergy and from cancer inflammation, focusing on what is known about the roles of key immune cells and mediators. We propose that research in the field of AllergoOncology that aims to delineate these immunological mechanisms with juxtaposed clinical consequences in allergy and cancer may point to novel avenues for therapeutic interventions that stand to benefit both disciplines., (© 2017 The Authors. Allergy Published by John Wiley & Sons Ltd.)

The major cow's milk allergen Bos d 5 belongs to the lipocalin protein family, with an intramolecular pocket for hydrophobic ligands. We investigated whether Bos d 5 when loaded with the active vitamin A metabolite retinoic acid (RA), would elicit differential immune responses compared to the unloaded state. By in silico docking an affinity energy of -7.8 kcal/mol was calculated for RA into Bos d 5. Loading of RA to Bos d 5 could be achieved in vitro, as demonstrated by ANS displacement assay, but had no effect on serum IgE binding in tolerant or challenge-positive milk allergic children. Bioinformatic analysis revealed that RA binds to the immunodominant T-cell epitope region of Bos d 5. In accordance, Bos d 5 significantly suppressed the CD3+ CD4+ cell numbers, proliferative response and IL-10, IL-13 and IFN-γ secretion from stimulated human PBMCs only when complexed with RA. This phenomenon was neither associated with apoptosis of T-cells nor with the activation of Foxp3+ T-cells, but correlated likely with enhanced stability to lysosomal digestion due to a predicted overlap of Cathepsin S cleavage sites with the RA binding site. Taken together, proper loading of Bos d 5 with RA may suppress its immunogenicity and prevent its allergenicity.

Atopic individuals tend to develop a Th2 dominant immune response, resulting in hyperresponsiveness to harmless antigens, termed allergens. In the last decade, epidemiological studies have emerged that connected allergy with a deficient iron-status. Immune activation under iron-deficient conditions results in the expansion of Th2-, but not Th1 cells, can induce class-switching in B-cells and hampers the proper activation of M2, but not M1 macrophages. Moreover, many allergens, in particular with the lipocalin and lipocalin-like folds, seem to be capable of binding iron indirectly via siderophores harboring catechol moieties. The resulting locally restricted iron-deficiency may then lead during immune activation to the generation of Th2-cells and thus prepare for allergic sensitization. Moreover, iron-chelators seem to also influence clinical reactivity: mast cells accumulate iron before degranulation and seem to respond differently depending on the type of the encountered siderophore. Whereas deferoxamine triggers degranulation of connective tissue-type mast cells, catechol-based siderophores reduce activation and degranulation and improve clinical symptoms. Considering the complex interplay of iron, siderophores and immune molecules, it remains to be determined whether iron-deficiencies are the cause or the result of allergy.

Natural killer (NK) cells are part of the innate immune system and combat pathogens and tumors by secreting pro-inflammatory cytokines like interferon gamma (IFN-γ) and by their cytotoxic action. Galanin is a neuropeptide also expressed in peripheral tissue where it impacts several physiological functions, including inflammation. The effects of galanin are mediated via three receptors, GAL 1-3 . Since other neuropeptides have been shown to regulate NK cell activity, we investigated the potential of galanin to modulate human NK cell function. NK cells were isolated from human peripheral blood mononuclear cells. mRNA expression was analyzed by qRT-PCR. The dynamic mass redistribution of NK cells upon regulatory peptide stimulation was determined by label-free biochip technology. IFN-γ producing NK cells were identified by flow cytometry analysis and IFN-γ secretion was measured by ELISA. NK cell cytotoxicity was analyzed by flow cytometry via CD107a mobilization. NK cells were found to express the receptor GAL 2 but not GAL 1 , GAL 3 or galanin. Galanin per se did not affect the dynamic mass redistribution of NK cells, but significantly enhanced the response of NK cells to IL-18. Galanin significantly modulated the IFN-γ production of the CD56 bright NK cell population upon IL-12 and IL-18 stimulation. Furthermore, galanin significantly modulated the IL-12 and IL-18 stimulated IFN-γ secretion. NK cell cytotoxicity was not modulated by galanin treatment. Galanin can be classified as an immunomodulatory peptide as it is able to sensitize NK cells toward specific cytokines., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Th2 immunity and allergic immune surveillance play critical roles in host responses to pathogens, parasites and allergens. Numerous studies have reported significant links between Th2 responses and cancer, including insights into the functions of IgE antibodies and associated effector cells in both antitumour immune surveillance and therapy. The interdisciplinary field of AllergoOncology was given Task Force status by the European Academy of Allergy and Clinical Immunology in 2014. Affiliated expert groups focus on the interface between allergic responses and cancer, applied to immune surveillance, immunomodulation and the functions of IgE-mediated immune responses against cancer, to derive novel insights into more effective treatments. Coincident with rapid expansion in clinical application of cancer immunotherapies, here we review the current state-of-the-art and future translational opportunities, as well as challenges in this relatively new field. Recent developments include improved understanding of Th2 antibodies, intratumoral innate allergy effector cells and mediators, IgE-mediated tumour antigen cross-presentation by dendritic cells, as well as immunotherapeutic strategies such as vaccines and recombinant antibodies, and finally, the management of allergy in daily clinical oncology. Shedding light on the crosstalk between allergic response and cancer is paving the way for new avenues of treatment., (© 2016 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.)

Abnormal redox homeostasis and oxidative stress have been proposed to play a role in the etiology of several neuropsychiatric spectrum disorders. Emerging interest has recently focused on markers of oxidative stress and neuroinflammation in schizophrenic spectrum disorders, at least in particular subgroups of patients. Altered expression of genes related to oxidative stress, oxidative damage to DNA, protein and lipids, as well as reduced glutathione levels in central and peripheral tissues could act synergistically, and contribute to the course of the disease.  Herein, we discuss cellular mechanisms that may be operative in neuroinflammation and contributory to schizophrenia. We address modulation of endogenous cellular defense mechanisms as a potentially innovative approach to therapeutics for schizophrenia, and other neuropsychiatric conditions that are associated with neuroinflammation. Specifically, we discuss the emerging role of heme oxygenase as prominent member of neuroprotective network in redox stress responsive mechanisms, as well as the importance of glutathione relevant in schizophrenia pathophysiology. Finally we introduce the hormetic dose response concept as relevant and important to neuroprotection, and review hormetic mechanisms as possible approaches to manipulation of neuroinflammatory targets that may be viable for treating schizophrenia spectrum disorders. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Objectives: To quantify residual coronary artery disease measured using the SYNTAX score (SS) and its relation to outcomes after coronary artery bypass grafting (CABG)., Methods: We conducted a retrospective analysis on a consecutive series of 1608 patients [mean age 68 years, standard deviation (SD): 7, F:M, 242:1366] undergoing first-time isolated CABG from 2004 to 2015. The baseline SS was retrospectively determined from preoperative angiograms, and the residual SS (rSS) was measured during assessment of the actual operative report for each patient after CABG. Patients were then stratified according to tercile cut points of low (rSS low 0-11, N  = 537), intermediate (rSS mid  >11-18.5, N  = 539) and high residual SS (rSS high  >18.5, N  = 532). The Cox regression model was used to investigate the impact of rSS on major adverse cardiac and cerebrovascular events (MACCE) at 1 year., Results: The mean preoperative SS was 26.6 (SD: 9.4) (range 10.1-53), and the residual SS after CABG was 15.3 (SD: 8.4) (range 0-34) ( P  <   0.001 versus preoperative). At 1 year, cumulative incidence of MACCE in the low rSS was 1.5% ( N  = 8/537), 4.5% ( N  = 24/539) in the intermediate and 8.8% ( N  = 47/532) in the high rSS group. Kaplan-Meier analysis showed a statistically significant difference of MACCE-free survival between the three groups (log-rank test, P  <   0.001). The estimated MACCE-free survival rate at 1 year was 98.1% [standard error (SE): 1.6] for the rSS low , 95.5% (SE: 1.9) for the rSS mid , and 90.5% (SE: 1.3) for the rSS high group, respectively. After multivariable adjustment, the rSS high group was independently associated with a higher incidence of MACCE at 1 year (hazard ratio 1.92, 95% confidence interval 1.21-3.23) compared to the rSS low group., Conclusions: These unanticipated findings suggest that a residual SS may be a useful tool for risk stratification of patients undergoing isolated first-time CABG. Our study may set the stage for further investigations addressing this important clinical question., (© The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Cytokines belonging to the TNF superfamily play a relevant role in neurodegenerative processes. Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL), released during neuronal injury, has proven to potently mediate and sustain neurotoxic processes leading to neuronal death. Similarly to TRAIL, the cytokine Glucocorticoid-induced TNF receptor ligand (GITRL) is able to transduce proapoptotic signals. In spite of the array of reports suggesting relationships between TRAIL and other cytokines, scanty data are, so far, available about a GITRL/TRAIL crosstalk., Methods: Here, we investigated possible interactions between TRAIL and the GITRL system in an in vitro model of neurodegeneration, using the human cortical neuronal cell line HCN-2. Cultured HCN-2 neurons were incubated at different times with GITRL and/or TRAIL, and thereafter nucleic acid and protein expression were measured. Real-time PCR analysis showed that the human cortical neuronal cell line HCN-2 does not express GITRL mRNA, but the latter is induced after treatment with TRAIL. In addition, HCN-2 cells did not express the GITRL receptor GITR mRNA, neither in control cultures, nor after treatment with TRAIL. All mRNA data were confirmed by western blot analysis of proteins. Cell viability assay showed that TRAIL, when associated to GITRL, was able to exert additive toxic effects. A counterproof was provided in experiments performed blocking GITRL, in which TRAIL-mediated toxicity appeared significantly reduced. Results suggest that GITRL/TRAIL redundancy during neurodegenerative processes implies extended potentiation of detrimental effects of both cytokines on neurons, eventually leading to larger cell damage and death., Conclusion: Finally, characterization of novel molecular targets within the TRAIL/GITRL interplay may represent a platform for innovative therapy of neurodegenerative disorders., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

In the United States, 1.1-1.5% of children have been diagnosed with autism spectrum disorders (ASD), corresponding to a 30% increase in incidence and prevalence. Social and communication impairments are the main signs and symptoms of ASD, and currently available medications have been ineffective in reducing these core deficits. Observational studies have indicated that children with ASD tend to show improved cognition and behavior after febrile illness, which is associated with alteration of metabolic pathways, leading to cellular stress responses and increased expression of heat shock proteins (Hsps). Sulforaphane and hydroxytyrosol, phytochemicals derived from cruciferous vegetables and extra virgin olive oil, respectively, can induce metabolic effects in cellular stress responses that are similar to those produced by fever. Thus, modulation of endogenous cellular defense mechanisms may be an innovative approach for therapeutic intervention in ASD and other disorders associated with neuroinflammation and neurodegeneration. This Review introduces the hormetic dose-response concept and presents possible mechanisms and applications for neuroprotection. We address the emerging role of Hsps in the neuroprotective network of redox stress-responsive mechanisms and propose the potential therapeutic utility of the nutritional antioxidants sulforaphane and hydroxytyrosol against particular signs and symptoms of ASD. We argue that such research findings must be approached with pragmatism and prudence. It is vital to capitalize on recent and ongoing investments in brain science research and to refine neuroscientific knowledge and capability for more accurate diagnosis and safe, effective, and ethically sound treatment of ASD and other neuropsychiatric spectrum disorders. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Galanin and its receptors (GAL1, GAL2, GAL3) modulate a range of neuronal, immune and vascular activities. In vivo administration of SNAP 37889 (1-phenyl-3-[[3-(trifluoromethyl)phenyl]imino]-1H-indol-2-one), a potent small non-peptidergic antagonist of GAL3, was reported to reduce anxiety- and depression-related behavior, ethanol consumption, and antagonizes the effect of galanin on plasma extravasation in rodent models. Accordingly, SNAP 37889 has been proposed as a potential therapeutic agent to treat anxiety and depression disorders. Therefore, we evaluated the toxicity of SNAP 37889 to different cell types. Our experiments revealed that SNAP 37889 (≥10μM) induced apoptosis in epithelial (HMCB) and microglial (BV-2) cell lines expressing endogenous GAL3, in peripheral blood mononuclear cells and promyelocytic leukemia cells (HL-60) expressing GAL2, and in a neuronal cell line (SH-SY5Y) lacking galanin receptor expression altogether. In conclusion, SNAP 37889 is toxic to a variety of cell types independent of GAL3 expression. We caution that the clinical use of SNAP 37889 at doses that might be used to treat anxiety- or depression- related diseases could have unexpected non-galanin receptor-mediated toxicity, especially on immune cells., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Owners and their domestic animals via skin shedding and secretions, mutually exchange microbiomes, potential pathogens and innate immune molecules. Among the latter especially lipocalins are multifaceted: they may have an immunomodulatory function and, furthermore, they represent one of the most important animal allergen families. The amino acid identities, as well as their structures by superposition modeling were compared among human lipocalins, hLCN1 and hLCN2, and most important animal lipocalin allergens, such as Can f 1, Can f 2 and Can f 4 from dog, Fel d 4 from cats, Bos d 5 from cow's milk, Equ c 1 from horses, and Mus m 1 from mice, all of them representing major allergens. The β-barrel fold with a central molecular pocket is similar among human and animal lipocalins. Thereby, lipocalins are able to transport a variety of biological ligands in their highly conserved calyx-like cavity, among them siderophores with the strongest known capability to complex iron (Fe(3+) ). Levels of human lipocalins are elevated in nonallergic inflammation and cancer, associated with innate immunoregulatory functions that critically depend on ligand load. Accordingly, deficient loading of lipocalin allergens establishes their capacity to induce Th2 hypersensitivity. Our similarity analysis of human and mammalian lipocalins highlights their function in innate immunity and allergy., (© 2015 The Authors. Allergy Published by John Wiley & Sons Ltd.)

Infiltrating cells of the immune system are widely accepted to be generic constituents of tumor microenvironment. It has been well established that the development of mammary cancer, both in humans and in dogs, is associated with alterations in numbers and functions of immune cells at the sites of tumor progression. These tumor infiltrating immune cells seem to exhibit exclusive phenotypic and functional characteristics and mammary cancer cells can take advantage of signaling molecules released by them. Cancer related inflammation has an important role in mammary carcinogenesis, contributing to the acquisition of core hallmark capabilities that allow cancer cells to survive, proliferate, and disseminate. Indeed, recent studies in human breast cancer and in canine mammary tumors have identified a growing list of signaling molecules released by inflammatory cells that serve as effectors of their tumor-promoting actions. These include the COX-2, the tumor EGF, the angiogenic VEGF, other proangiogenic factors, and a large variety of chemokines and cytokines that amplify the inflammatory state. This review describes the intertwined signaling pathways shared by T-lymphocytic/macrophage infiltrates and important tissue biomarkers in both human and dog mammary carcinogenesis., Competing Interests: The authors declare that they have no conflict of interests concerning the contents of this article.

Escherichia coli strain DH5α was successfully employed in the decolorization of commercial anthraquinone and azo dyes, belonging to the general classes of acid or basic dyes. The bacteria showed an aptitude to survive at different pH values on any dye solution tested, and a rapid decolorization was obtained under aerobic conditions for the whole collection of dyes. A deep investigation about the mode of action of E. coli was carried out to demonstrate that dye decolorization mainly occurred via three different pathways, specifically bacterial induced precipitation, cell wall adsorption, and metabolism, whose weight was correlated with the chemical nature of the dye. In the case of basic azo dyes, an unexpected fast decolorization was observed after just 2-h postinoculation under aerobic conditions, suggesting that metabolism was the main mechanism involved in basic azo dye degradation, as unequivocally demonstrated by mass spectrometric analysis. The reductive cleavage of the azo group by E. coli on basic azo dyes was also further demonstrated by the inhibition of decolorization occurring when glucose was added to the dye solution. Moreover, no residual toxicity was found in the E. coli-treated basic azo dye solutions by performing Daphnia magna acute toxicity assays. The results of the present study demonstrated that E. coli can be simply exploited for its natural metabolic pathways, without applying any recombinant technology. The high versatility and adaptability of this bacterium could encourage its involvement in industrial bioremediation of textile and leather dyeing wastewaters.

Aims: Polymorphonuclear neutrophils are key players in innate immunity. The innate immune system needs to be tightly controlled to ensure proper activation but also no overactivation. Galanin has been shown to regulate inflammatory reactions, and therefore, we aimed to elucidate the expression of galanin and its three receptors (GAL1 -GAL3 ) in polymorphonuclear neutrophils and to evaluate whether galanin exerts direct or indirect effects on human and murine polymorphonuclear neutrophils., Methods: Human peripheral polymorphonuclear neutrophils were isolated from fresh blood of healthy donors, and murine polymorphonuclear neutrophils were isolated from bone marrow of C57BL/6N mice. Gene expression was evaluated by qRT-PCR. As a marker for polymorphonuclear neutrophil activation, CD11b integrin surface expression was measured by FACS analysis. Furthermore, a label-free technology measuring ligand-induced dynamic mass redistribution was used to evaluate the response of polymorphonuclear neutrophils to galanin., Results: GAL2 receptor expression was found in both human and murine polymorphonuclear neutrophils, galanin and GAL3 receptor were exclusively expressed in murine bone marrow polymorphonuclear neutrophils, and GAL1 receptor was not detectable in polymorphonuclear neutrophils of either species. Galanin treatment was not able to induce CD11b integrin surface expression or dynamic mass redistribution in human polymorphonuclear neutrophils and murine bone marrow polymorphonuclear neutrophils. However, galanin treatment significantly enhanced the response of polymorphonuclear neutrophils of both species to interleukin-8., Conclusion: Galanin can be regarded as an immunomodulatory peptide as it can sensitize polymorphonuclear neutrophils towards pro-inflammatory cytokines in humans and mice., (© 2014 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

Group B Streptococcus (GBS) has evolved several strategies to avoid host defences. We have shown that interaction of macrophages with GBS causes macrophage calpain activation, cytoskeletal disruption and apoptosis, consequences of intracellular calcium increase induced by membrane permeability alterations provoked by GBS-β-haemolysin. Open question remains about what effect calcium influx has on other calcium-sensing proteins such as gelsolin, involved in cytoskeleton modulation and apoptosis. Therefore we analysed the effect of GBS-III-COH31:macrophage interaction on gelsolin expression. Here we demonstrate that an early macrophage response to GBS-III-COH31 is a very strong gelsolin increase, which occurs in a time- and infection-ratio-dependent manner. This is not due to transcriptional events, translation events, protein turnover alterations, or protein-kinase activation, but to calcium influx, calpain activation and caspase-3 degradation. In fact, EGTA and PD150606 (calpain inhibitor) prevented gelsolin increase while BAF (caspase inhibitor) enhanced it. Since gelsolin increase is induced by highly β-haemolytic GBS-III-NEM316 and GBS-V-10/84, but not by weakly β-haemolytic GBS, or GBS-III-COH31 in conditions suppressing β-haemolysin expression/activity and the presence of dipalmitoylphosphatidylcholine (β-haemolysin inhibitor), GBS-β-haemolysin is solely responsible for gelsolin increase causing, through membrane permeability defects, calcium influx and calpain activation. Early gelsolin increase could represent a macrophage response to antagonize apoptosis since gelsolin knockdown increases macrophage susceptibility to GBS-induced apoptosis. This response seems to be GBS specific because macrophage apoptosis by Staurosporine or Cycloeximide does not induce gelsolin., (© 2014 John Wiley & Sons Ltd.)

Objectives: The purpose of this work was to quantify textural properties of cosmetic and pharmaceutical raw materials., Methods: Textural parameters such as hardness, consistency, cohesiveness, index of viscosity, stickiness and resilience were evaluated. The measurements were performed using texture analyser - a tensile metre equipped with special probes (in the form of acrylic cylinder and stainless steel sphere), which can penetrate the measured sample of a product recording the force, distance and time. The instrument simulates the action of a human finger touching the surface and probing the properties of an object. The set-up has been previously shown to quantify the rheological/textural properties of cosmetic and pharmaceutical products such as creams, lotion and gels as well as rheological behaviour of human skin., Results and Conclusions: The results include the analysis of water, glycerine and mineral oil as well as aqueous solutions of thickeners such as Acrylates/C10-30 Alkyl Acrylate Crosspolymer (Ultrez-20 obtained from Noveon) and carbomer. Solutions of common surfactants and complex surfactant formulations such as shampoos have also been investigated. The results, in the form plots of force as a function of time or distance, resulting from slow bidirectional probe movement (submergence and desubmergence) in the analysed fluid, were interpreted by considering buoyancy, drag and viscous drag force given by Stokes equation. The data can be used to correlate with tactile evaluations of products by trained panel evaluations., (© 2014 Society of Cosmetic Scientists and the Société Française de Cosmétologie.)

Textile dye effluents are among the most problematic pollutants because of their toxicity on several organisms and ecosystems. Low cost and ecocompatible bioremediation processes offer a promising alternative to the conventional and aspecific physico-chemical procedures adopted so far. Here, microorganisms resident on three real textile dyeing effluent were isolated, characterized, and tested for their decolorizing performances. Although able to survive on these real textile-dyeing wastewaters, they always showed a very low decolorizing activity. On the contrary, several plant-associated fungi (Bjerkandera adusta, Funalia trogii, Irpex lacteus, Pleurotus ostreatus, Trametes hirsuta, Trichoderma viride, and Aspergillus nidulans) were also assayed and demonstrated to be able both to survive and to decolorize to various extents the three effluents, used as such in liquid cultures. The decolorizing potential of these fungi was demonstrated to be influenced by nutrient availability and pH. Best performances were constantly obtained using B. adusta and A. nidulans, relying on two strongly different mechanisms for their decolorizing activities: degradation for B. adusta and biosorption for A. nidulans. Acute toxicity tests using Daphnia magna showed a substantial reduction in toxicity of the three textile dyeing effluents when treated with B. adusta and A. nidulans, as suggested by mass spectrometric analysis as well., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The interaction of glucocorticoid-induced tumor necrosis factor receptor-family related (GITR) protein with its ligand (GITRL) modulates different functions, including immune/inflammatory response. These effects are consequent to intracellular signals activated by both GITR and GITRL. Previous results have suggested that lack of GITR expression in GITR(-/-) mice decreases the number of leukocytes within inflamed tissues. We performed experiments to analyze whether the GITRL/GITR system modulates leukocyte adhesion and extravasation. For that purpose, we first evaluated the capability of murine splenocytes to adhere to endothelial cells (EC). Our results indicated that adhesion of GITR(-/-) splenocytes to EC was reduced as compared with wild-type cells, suggesting that GITR plays a role in adhesion and that this effect may be due to GITRL-GITR interaction. Moreover, adhesion was increased when EC were pretreated with an agonist GITR-Fc fusion protein, thus indicating that triggering of GITRL plays a role in adhesion by EC regulation. In a human in vitro model, the adhesion to human EC of HL-60 cells differentiated toward the monocytic lineage was increased by EC pretreatment with agonist GITR-Fc. Conversely, antagonistic anti-GITR and anti-GITRL Ab decreased adhesion, thus further indicating that GITRL triggering increases the EC capability to support leukocyte adhesion. EC treatment with GITR-Fc favored extravasation, as demonstrated by a transmigration assay. Notably, GITRL triggering increased intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression and anti-ICAM-1 and anti-VCAM-1 Abs reversed GITR-Fc effects. Our study demonstrates that GITRL triggering in EC increases leukocyte adhesion and transmigration, suggesting new anti-inflammatory therapeutic approaches based on inhibition of GITRL-GITR interaction.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common diagnosis for children and adolescents, although the reported estimates for prevalence are extremely variable worldwide. In the present work we investigate the prevalence of ADHD in a sample of Italian students in a study divided in two phases. In Phase I, a total of 6183 schoolchildren (3178 males and 3005 females, aged range 5-15 years) were screened using the SDAI rating scale for teachers. In Phase II, the parents of children and adolescents who met high screen criteria according to SDAI (cut-off>14; n=471, 7.3%) were invited to complete a specific clinical-diagnostic assessment for ADHD with the help of an experienced clinician. Within the entire sample, 107 children dropped out and 12 had mental retardation, whereas 332 subjects (278 males and 54 females, age range 5-14 years) completed the Phase II of the study. One hundred ninety subjects (163 males and 27 females, male: female ratio 6:1, mean age 8 years) were diagnosed with ADHD, indicating a prevalence of 3%. ADHD subtypes included the following: combined (n=108; 56.8%), inattentive (n=48; 25.2%) and hyperactive/impulsive (n=33; 17.3%). Our findings are in line with other reports of ADHD prevalence in the European Countries, and may contribute to underline the impact of this phenomenon in the population, and the need of achieving an improvement in the quality of the public health mental service for the prevention and treatment of ADHD., (Copyright © 2013 Elsevier Ltd. All rights reserved.)