Background Approximately 70 % of individuals allergic to birch pollen (Bet v 1.01 [Bet]) develop a secondary food allergy (e.g. hazelnut: Cor a 1.04 [Cor]), due to allergen cross-reactivity. However, standard immunotherapy for type I allergies often does not improve the food allergy sufficiently. We analyzed the allergen-specific and cross-reactive suppressive capacity of primary human regulatory T cells (Treg) induced by autologous IL-10-modulated dendritic cells (IL-10 DC) in vitro and in vivo. Methods CD4 + T cells of patients with birch pollen and associated hazelnut allergies were differentiated into Bet-specific or non-specific induced Treg (iTreg). After Bet- or Cor- specific restimulation the phenotype, proliferation and suppressive capacity of iTreg subsets were analyzed. iTreg function was further investigated in humanized mouse models of airway and intestinal allergy, generated by engraftment of peripheral blood mononuclear cells from allergic donors into immunodeficient animals. Results After IL-10 DC priming and allergen-specific restimulation (Bet or Cor) non-specific control iTreg remained anergic, whereas Bet-specific iTreg proliferated extensively and exhibited a regulatory phenotype (enhanced expression of CTLA-4, PD-1, TNFR2, IL-10). Accordingly, activated Bet-specific iTreg displayed a high capacity to suppress Bet- and Cor-induced responder T H2 cell responses in vitro, indicating induction of both allergen-specific (birch) and cross-reactive tolerance (hazelnut). In vivo, the beneficial effect of Bet-specific iTreg was verified in humanized mouse models of allergic airway and intestinal inflammation, resulting in reduced allergen-induced clinical symptoms and immune responses. Conclusion Human IL-10 DC-induced iTreg facilitate allergen-specific and cross-reactive tolerance. Therefore, they are potential candidates for regulatory cell therapy in allergic and autoimmune diseases.
Artemisia annua sublingual immunotherapy in children with seasonal allergic rhinitis To the Editor,Artemisia pollen is the main aeroallergen of seasonal allergic rhinitis (SAR) in summer and autumn.1,2Artemisia annua Allergens Sublingual Immunotherapy (SLIT) Drops (Zhejiang Wolwo Bio-Pharmaceutical Co., Ltd., Zhejiang, China, National Drug Approval No.: S20210001) is the only standardized SLIT preparation approved in China for treatingArtemisia-induced allergic rhinitis with or without conjunctivitis (AC).3 In this study, we aimed to evaluate the safety and efficacy of A. annua- SLIT in children with SARs.Pediatric patients with at least a two-year clinical history ofArtemisia pollen-induced SAR with or without AC from Inner Mongolia were included in this randomized, double-blind, placebo-controlled, single-center clinical trial and randomized to receive A. annua -SLIT or placebo at a 2:1 ratio for approximately 28 weeks. The combined score of medication and rhinitis symptoms (CSMS; primary endpoint) and combined score of medication and rhinoconjunctivitis symptoms (CSMRS; secondary endpoint) were recorded to evaluate efficacy; adverse events (AEs) were reported to assess safety.Fifty-seven eligible patients aged 4–18 years were randomized into the SLIT (n=38) and placebo (n=19) groups (Figure 1). Finally, 54 patients (SLIT group: n=36; placebo group: n=18) completed the study with 3 patients withdrew by themselves. No significant differences were observed between the groups in terms of sex, age, atopic status, comorbidity of other allergic diseases, and CSMS and CSMRS scores in the previous pollen season (P >0.05, Table S1).The 2019 pollen season in Inner Mongolia was from 20th July to 7th September (50 days; Figure 2A). The temporal variation of daily CSMRS in both groups showed a similar trend of positive correlation with pollen concentration throughout the pollen season (SLIT group: r=0.66, 95% CI: 0.53–0.76; placebo group: r=0.68, 95% CI: 0.56–0.77). The SLIT group showed significant improvements in CSMS (1.55±0.81 vs. 1.97±0.73) and CSMRS (1.46±0.75 vs. 1.88±0.75) compared with the placebo group (P <0.05, Figure 2B–C). Fifty-three (98.1%) patients experienced AEs [35, SLIT group; 18, placebo group] (Table S2). All AEs were mild or moderate and resolved without any action or by adjusting the dose of the study drug. There were no significant differences in the incidence and severity of AEs between the groups (P >0.05). Epinephrine use was not reported, and no patients withdrew from the trial because of AEs. Furthermore, 94.4% and 100% of patients in the SLIT and placebo groups, respectively, experienced treatment-related AEs (TRAEs), which frequently occurred in the nose, eyes, throat, and tongue in both groups (P >0.05, Figure 2D). The common TRAEs in children with SLIT are shown in Figure 2E. Most TRAEs in the SLIT group were mild, similar to those in the placebo group.To our knowledge, this is the first study to report the efficacy and safety of A. annua -SLIT in a Chinese pediatric population. Our results showed a consistent trend of clinical efficacy improvements withA. annua -SLIT in children similar to those in adults.4 Recently, a cumulative AE incidence of 93.0% was reported with ragweed SLIT in children and adolescents, with no serious AEs.5 The incidence of AEs in our study were comparable to those in the previous study. Lou et al. found that the most common TRAEs in adults with A. annua -SLIT were mild or moderate.4,6 Our results showed a safety profile similar to that in adults. No new safety signals emerged, and no throat irritation was observed in adults.In conclusion, 28-week A. annua -SLIT treatment was effective and safe for children with SAR, with no major safety concerns. Investigating the benefits of A. annua -SLIT in children will not only expand its application for treatment but also provide the basis for intervention in the early phase of SAR.
Background: Various biomarkers are used to define peanut allergy (PA). We aimed to observe changes in PA resolution and persistence over time comparing biomarkers in PA and peanut sensitised but tolerant (PS) children in a population-based cohort. Methods: Participants were recruited from the EAT and EAT-On studies, conducted across England and Wales and were generally well exclusively breastfed babies recruited at 3 months old and followed up until 11 years old. Clinical characteristics, skin prick test (SPT), sIgE to peanut and peanut components and mast cell activation tests (MAT) were assessed at 12m, 36m and 7-11y. Results: The prevalence of PA was 2.1% with only 1 child having PA resolution at 7-11y. PA children had larger SPT size, higher peanut-sIgE, Ara h 2-sIgE and MAT (all p<0.001) compared to PS children at 36m and 7-11y. SPT, peanut-sIgE, Ara h 2-sIgE and MAT between children with persistent PA, new PA, outgrown PA and PS were statistically significant at both 36m and 7-11y (p<0.001). Those with persistent PA had SPT, peanut-sIgE and Ara h 2-sIgE that increased over time and MAT which was highest at 36m. New PA children had increased SPT and peanut-sIgE from 36m to 7-11y, but MAT remained low. PS children had low biomarkers across time. Conclusions: In this cohort, few children outgrow or develop new PA between 36m and 7-11y. Children with PA have significantly higher SPT, peanut-sIgE, Ara h 2-sIgE and MAT compared to PS children, evident from 12-36m of age.
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.
Transcriptomic Profiles of Well-Differentiated Airway Epithelial Cells in Response to Environmental Triggers of Asthma ExacerbationAntonella Marrocco1, Jennifer A. Mitchel1, Margaret Parker2, Maureen McGill1, Robert P. Chase2, Scott T. Weiss2, Diane R. Gold1,2, Peter J. Castaldi2, Jin-Ah Park1, Joanne Sordillo34Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA2Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.3Division of Chronic Disease Research Across the Lifecourse (CoRAL), Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA.Corresponding Author: Joanne E. SordilloEmail : [email protected]:Landmark Center West 401 Park Dr., 4th Floor Boston, MA 02115The authors have no conflicts of interest to disclose.Funding: R01HL148152, P30ES000002, T32HL007118, Francis Family FoundationKeywords: Bronchial epithelial cells, gene expression, RNAseq, asthma
The gut microbiome is indispensable for the host physiological functioning. Yet, the impact of non-nutritious dietary compounds on the human gut microbiota and the role of the gut microbes in their metabolism and potential adverse biological effects have been overlooked. Identifying potential hazards and benefits would contribute to protecting and harnessing the gut microbiome’s role in supporting human health. We discuss the evidence on the potential detrimental impact of certain food additives and microplastics on the gut microbiome and health endpoints, with a focus on underlying mechanisms and causality. We provide recommendations for the incorporation of gut microbiome science in food risk assessment and identify knowledge and tools needed to fulfill the gaps. The incorporation of gut microbiome endpoints to safety assessments, together with well-established toxicity and mutagenicity studies, might better inform the risk assessment of certain contaminants in food, and/or food additives.
Background: The use of allergy tests to guide dietary exclusions for disease control in children with atopic dermatitis (AD) is controversial. We undertook a consensus exercise on how to interpret skin prick test (SPT) results and dietary history for cow’s milk, hen’s egg, wheat and soya in children <2 years old with AD. Methods: Fourteen clinicians from general practice, paediatrics, paediatric dermatology, paediatric allergy and paediatric dietetics from UK and Ireland took part in an online modified Delphi study. Over three rounds, participants gave their anonymous opinions and received individualised and group feedback. The findings were discussed in an online workshop. Results: Of 14 symptoms, 12 were identified as relevant to immediate and 7 to delayed allergy. Regarding SPTs, there was consensus over which allergens to use for wheat and soya but not cow’s milk or hen’s egg; for all study foods, wheal size was determined as 0-1 mm negative, ≥5mm sensitised , but between 2-4 mm categorisation varied by food. During the final workshop, consensus was reached on dietary advice should be given according to SPT results and dietary history. Conclusion: We attained consensus on how SPTs combined with dietary history for four common food allergens should be interpreted in young children under two years of age with AD. These pragmatic recommendations may support clinician education, consistency of decision-making and future research.
The skin barrier is vital for protection against environmental threats including insults caused by skin-resident microbes. Dysregulation of this barrier is a hallmark of atopic dermatitis (AD) and ichthyosis, with variable consequences for host immune control of colonizing commensals and opportunistic pathogens. While Malassezia is the most abundant commensal fungus of the skin, little is known about the host control of this fungus in inflammatory skin diseases. Here we show that in barrier-impaired skin, Malassezia acquires enhanced fitness and overt growth properties. By using four distinct and complementary murine models of atopic dermatitis and ichthyosis we provide evidence that structural and metabolic changes in the dysfunctional epidermal barrier environment provide increased accessibility and an altered lipid profile, to which the lipid-dependent yeast adapts for enhanced nutrient assimilation. These findings reveal fundamental insights into the implication of the mycobiota in the pathogenesis of common skin barrier disorders.
Following the European Forum for Research and Education in Allergy and Airway Diseases (EUFOREA) treatment algorithm for chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP), patients suffering from severe uncontrolled CRSwNP are recommended to receive oral corticosteroids, (revision) sinus surgery, systemic biologicals, and/or aspirin treatment after desensitization (ATAD). Given the major differences in indications, outcomes, practical considerations, risks and costs of these key pillars of treatment, there is a growing need to define criteria for each treatment option and list the clinically relevant and major considerations for them. This EUFOREA document therefore provides an expert panel overview of the expected outcomes, specific considerations and (contra)indications of the five major treatment arms of severe uncontrolled CRSwNP: oral corticosteroids, primary and revision sinus surgery, biological treatment, and ATAD. This overview of treatment considerations is needed to allow physicians and patients to consider the different options in the context of providing optimal and personalized care for severe uncontrolled CRSwNP. In conclusion, the five major treatment options for severe uncontrolled CRSwNP have intrinsic advantages, specific indications, and considerations that are of importance to the patient, the physician, and the society. This EUFOREA statement supports the unmet need to define criteria for the indication of every treatment pillar of CRSwNP.
Sputum cytokines associated with raised FeNO after anti-IL5 biologic therapy in severe asthma.To the Editor,Biomarkers such as circulating absolute eosinophil count, % of eosinophils in sputum, and fraction of exhaled nitric oxide (FeNO) are predictors of response to anti-inflammatory therapy for asthma. Failure to normalize FeNO with high doses of corticosteroids are likely to be related to cytokines and chemokines such as IL-5, IL-4, IL-13, eotaxin and TARC derived from eosinophils and other Th2 cells, and alarmins such as TSLP and IL-33 from sources such as the airway epithelium(1). All Anti-IL5 biologics suppress eosinophils in sputum. However benralizumab (anti-IL5RMab) has greater effect in the severe prednisone-dependent patients than mepolizumab/reslizumab (anti-IL5 neutralizing Mab)(2,3). While raised eosinophil count is a predictor of clinical response to anti-IL5 biologics, raised FeNO is often not(4). However, they reduce FeNO to variable levels(4,5) suggesting that FeNO is partly regulated by cytokines derived from eosinophils in the airway(1). The cytokines in sputum associated with raised FeNO in prednisone-dependent severe asthmatics treated with effective anti-eosinophil drugs are not known.In this retrospective observational study, we measured cytokines in sputum using an automated ELISA reader (EllaTM, Protein Simple, R&D Systems, BioTechne, Minneapolis) at baseline and after 4 months of treatment with either benralizumab or mepolizumab/reslizumab and compared the levels of cytokines in those whose FeNO remained high after treatment. Raised FeNO was defined by FeNO >40ppb and an increase of at least 16ppb from pre-treatment value. The study was approved by Hamilton Integrated Research Ethics Board (#11227, 5037), and all patients gave written informed consent. The cytokines assayed were IL-5, IL-4 and IL-13 (Th2 inflammation) and IL-1β, IL-6, IL-10, IL-12p70, IL-15 IL-17A, IL-18, IL-33, IFNγ and TNFα (Th1/Th17 inflammation, Table e3). Details of baseline demographics, methods and statistics are shown in the online supplement.Paired measurements were made in 30 patients who received benralizumab, and 10 each who received mepolizumab/reslizumab. Overall, as previously reported(5), FeNO levels were not significantly reduced by anti-IL5 treatment (median FeNO pre-treatment 29 [5-156] vs FeNO post treatment 37 [6-280]; p=0.25; Figure e1). This change in FeNO did not correlate with a reduction of sputum eosinophils (r=-0.24; p=0.16).Among 15 patients, FeNO remained raised after treatment (Table 1). On average, IL-4 and IL-13 were the only cytokines significantly higher in the sputum of these patients compared to those in whom the FeNO values normalized (Figure 1, Figure e2). Within this group, there were patients with raised IL-4 (31%) and IL-13 (15%) and those with normal IL-4/IL-13. A small proportion of those with normal IL4/13 had raised levels of IL-18 or IL-1β (20%). Residual eosinophilic airway inflammation was significantly more present in patients with raised FeNO (30.8% vs 8.1%; P=0.04; Table e2). Patients with raised FeNO remained to have poor asthma control with an ACQ>1.5, however this did not significantly differ from those with a normalized FeNO (ACQ 1.7±0.9 vs 1.4±1.1; P=0.36; Table 1).This study, despite its limitation of retrospective design and small numbers, provide novel information on the cytokine profile in the airways of severe prednisone-dependent eosinophilic asthma patients whose FeNO remain high after anti-IL5 treatment. This is a common clinically encountered situation. Our observations suggest that IL-4/IL-13 are the cytokines most associated with this phenomenon. This may be due to the airway eosinophilia being uncontrolled or due to a non-eosinophilic source of these cytokines. However, there could be non-IL-4/IL-13 related increase in FeNO that may be due to inflammasome activation and through non-Th2 cytokine pathways that may raise the possibility of airway infections or autoimmune activation(6). This has important clinical implication. These patients may not show adequate response to switching to anti-IL4R Mab if their asthma remains uncontrolled. This needs to be evaluated prospectively.References:Couillard S, Shrimanker R, Chaudhuri R, et al. Fractional Exhaled Nitric Oxide Nonsuppression Identifies Corticosteroid-Resistant Type 2 Signaling in Severe Asthma. Am J Respir Crit Care Med 2021; 204: 731-734.Mukherjee M, Forero DF, Tran S, Boulay ME, et al. Suboptimal treatment response to anti-IL-5 monoclonal antibodies in severe eosinophilic asthmatics with airway autoimmune phenomena. Eur Respir J 2020 Oct 8;56(4):2000117. doi: 10.1183/13993003.00117-2020.Mukherjee M, Bhalla A, Venegas-Garrido C, et al. Benralizumab attenuates blood and airway eosinophilia in severe asthmatics with inadequate response to anti-IL-5 neutralizing antibodies [abstract]. Eur Respir J 2022; 60 (suppl 66): 3994; DOI: 10.1183/13993003.Hearn AP, Kavanagh J, d’Ancona G, et al. The relationship between Feno and effectiveness of mepolizumab and benralizumab in severe eosinophilic asthma. J Allergy Clin Immunol Pract 2021; 9: 2093-2096.e1.Nair P, Kjarsgaard M, Armstrong S, Efthimiadis A, O’Byrne PM, Hargreave FE. Nitric oxide in exhaled breath is poorly correlated to sputum eosinophils in patients with prednisone-dependent asthma. J Allergy Clin Immunol 2010; 126: 404-6.Donnelly LE, Barnes PJ. Expression and regulation of inducible nitric oxide synthase from human primary airway epithelial cells. Am J Respir Cell Mol Biol 2002; 26: 144-51.AuthorsPieter-Paul Hekking 1,2, Kayla Zhang1, Carmen Paz Venegas Garrido 1, Raquel Lopez-Rodriguez 1,3, Melanie Kjarsgaard1, Manali Mukherjee 1, Parameswaran Nair 11. Division of Respirology, Department of Medicine, St. Joseph’s Healthcare Hamilton, McMaster University, Hamilton, Ontario, Canada.2. Department of Respiratory Diseases, STZ Centre of Excellence for Asthma & COPD, Franciscus Gasthuis & Vlietland Hospital, Rotterdam, the Netherlands.3. Department of Allergy, Lucus Augusti Hospital, Lugo, SpainCorrespondenceDr Parameswaran NairFirestone Institute for Respiratory HealthSt Joseph’s Healthcare Hamilton50 Charlton Avenue EastHamilton, Ontario, L8N4A6, CanadaTel: 905-522-1155 x 35044Fax: 905-521-6183E-mail: [email protected]
Background: Increasing evidence are available about the presence of increased serum concentration of Immunoglobulin (Ig) Free Light Chains (FLCs) in both atopic and non-atopic inflammatory diseases, including severe asthma, providing a possible new biomarker of disease, disease severity and also an alternative approach to the treatment. Methods: We analyzed clinical and laboratory data, including FLCs, obtained from a cohort of 79 asthmatic subjects, clinically classified into different GINA steps. A control group of 40 age-matched healthy donors (HD) was considered. Particularly, HD have been selected according to the absence of monoclonal components (in order to exclude paraproteinemias), were tested for total IgE (that were in the normal ranges) and were negative for aeroallergens specific IgE. Moreover, no abnormality of common inflammatory markers (i.e. erythrocyte sedimentation rate, C-reactive protein) was detectable. Results: FLC-k levels were significantly increased in the asthmatic population, compared to the control group. Despite the absence of statistically significant differences in FLC-λ levels, the FLC-k/FLC-λ ratio displayed remarkable differences between the two groups. A positive correlation between FLC-κ and FLC-λ levels was found. FLC- λ level displayed a significant negative correlation with the FEV1 value. Moreover, the FLC-κ /FLC- λ ratio was negatively correlated with the SNOT-22 score and a positive correlation was observed between FLCs and Staphylococcus Aureus IgE enterotoxins sensitization. Conclusions: Our findings confirmed the role of FLCs in asthma as a potential biomarker in an inflammatory disease characterized by different endotypes and phenotypes. In particular, FLC-κ and FLC-k/FLC-λ ratio could be a qualitative indicator for asthma, while FLC-λ levels could be a quantitative indicator for disease severity.
Background: IgE-mediated cow’s milk allergy (IgE-CMA) is one of the first allergies to arise in early childhood and may result from exposure to various milk allergens, of which β-lactoglobulin (BLG) and casein are the most important. Understanding the underlying mechanisms behind IgE-CMA is imperative for the discovery of novel biomarkers and the design of innovative treatment and prevention strategies. Methods: We report a longitudinal in vivo murine model, in which 2 mice strains (BALB/c and C57Bl/6) were sensitized to BLG using either cholera toxin or an oil emulsion (n=6 per group). After sensitization, mice were challenged orally, their clinical signs monitored, antibody (IgE and IgG1) and cytokine levels (IL-4 and IFN-γ) measured, and fecal samples subjected to metabolomics. The results of the murine models were further supported by fecal microbiome-metabolome data from our population of IgE-CMA (n=24) and healthy (n=23) children (Trial: NCT04249973), on which polar metabolomics, lipidomics and 16S rRNA metasequencing were performed. In vitro gastrointestinal digestions and multi-omics corroborated the microbial origin of proposed metabolic changes. Results: During sensitization, we observed multiple microbially derived metabolic alterations, most importantly bile acid, energy and tryptophan metabolites, that preceded allergic inflammation. The latter was reflected in a disturbed sphingolipid metabolism. We confirmed microbial dysbiosis, and its causal effect on metabolic alterations in our patient cohort, which was accompanied by metabolic signatures of low-grade inflammation. Conclusion: Our results indicate that gut dysbiosis precedes allergic inflammation and nurtures a chronic low-grade inflammation in children on elimination diets, opening important new opportunities for future prevention and treatment strategies.
Background Thymic stromal lymphopoietin (TSLP), a pleiotropic cytokine mainly expressed by epithelial cells, plays a key role in asthma pathobiology. In humans, TSLP exists in two variants: the long form TSLP (lfTSLP) and a shorter TSLP isoform (sfTSLP), overlapping the lfTSLP C-terminus. Macrophages (HLMs) and mast cells (HLMCs) are in close proximity in the human lung and play central roles in different asthma phenotypes. Methods Immunofluorescence and Western blot were employed to localize intracellular TSLP. Limited proteolysis and mass spectrometry allowed the identification of cleavage sites of TSLP caused by tryptase and chymase. ELISA assays were employed to measure TSLP and VEGF-A. Results TSLP was detected in highly purified (≥ 99%) macrophages isolated from human lung and subcellularly localized in the cytoplasm by confocal microscopy and Western blot. IL-4 and lipopolysaccharide induced the release of TSLP from HLMs. HLMCs contain and release tryptase and chymase that specifically cleaved TSLP. Mass spectrometric analyses of TSLP treated with tryptase showed the production of 1-97 and 98-132 fragments. Chymase treatment of TSLP generated two peptides 1-36 and 37-132. HLM activation by lfTSLP induced VEGF-A, the most potent angiogenic factor, release. The four TSLP fragments generated by tryptase and chymase failed to activate HLMs. sfTSLP neither activated HLMs nor interfered with activating property of lfTSLP on HLMs. Conclusions Given the close proximity between mast cells and macrophages in the human lung, our results illuminate a new circuit between HLMs and mast cells. These findings have potential relevance in understanding novel aspects of asthma pathobiology.
Background Activation of mast cells through IgE results in secretion and shedding of mast cell proteins and in vivo models suggest that these processes are governed by IgE antibody affinity. Methods We passively sensitized cultured primary human mast cells with recombinant human IgE clones with either high or low affinity for Der p 2, with a 200-fold affinity difference, and activated them with recombinant allergen. Activation was assessed by CD63 upregulation and PGD 2 secretion. Supernatants collected from mast cells activated for 0, 3, 6 and 24 hours were assessed for PGD 2 and inflammatory mediators on the OLINK platform at repeated time points. Results CD63 upregulation and PGD 2 synthesis scaled with affinity, as did secretion of cytokines like IL-8 and IL-13. Secretion of chemokines like CCL3 and CCL4 appeared to depend less on affinity, whereas shedding of surface markers CD40, SLAMF4 and CD5, and secretion of intracellular markers SIRT2 and CASP-8, were elevated by stimulation through low affinity IgE compared with high affinity IgE, illustrating differential responses dependent on the affinity of IgE. Conclusion Cytokine secretion and shedding of surface receptors of sensitized, cultured primary human mast cells is differentially regulated depending on the affinity of IgE for the Der p 2 allergen and may shape the chronic response to repeated allergic activation.
Background Respiratory syncytial virus (RSV) infection in infants is a major cause of viral bronchiolitis and hospitalisation. We have previously shown in a murine model that ongoing infection with the gut helminth Heligmosomoides polygyrus ( H. polygyrus) protects against RSV infection through type I interferon (IFN-I) dependent reduction of viral load. Yet, the cellular basis for this protection has remained elusive. Given that recruitment of mononuclear phagocytes to the lung is critical for early RSV infection control, we assessed their role in this coinfection model. Methods Mice were infected by oral gavage with H. polygyrus. Myeloid immune cell populations were assessed by flow cytometry in lung, blood and bone marrow throughout infection and after secondary infection with RSV. Monocyte numbers were depleted by anti-CCR2 antibody or increased by intravenous transfer of enriched monocytes. Results H. polygyrus infection induces bone marrow monopoiesis, increasing circulatory monocytes and lung mononuclear phagocytes in a IFN-I signalling dependent manner. This expansion causes enhanced lung mononuclear phagocyte counts early in RSV infection that may contribute to the reduction of RSV load. Depletion or supplementation of circulatory monocytes prior to RSV infection confirms that these are both necessary and sufficient for helminth induced antiviral protection. Conclusions H. polygyrus infection induces systemic monocytosis contributing to elevated mononuclear phagocyte numbers in the lung. These cells are central to an anti-viral effect that reduces the peak viral load in RSV infection. Treatments to promote or modulate these cells may provide novel paths to control RSV infection in high risk individuals.
Background: The German Therapy Allergen Ordinance (TAO) triggered an ongoing upheaval in the market for house dust mite (HDM) allergen immunotherapy (AIT) products. Three HDM subcutaneous AIT (SCIT) products hold approval in Germany and therefore will be available after the scheduled completion of the TAO procedure in 2026. In general, data from clinical trials on the long-term effectiveness of HDM AIT are rare. We evaluated real-world data (RWD) in a retrospective, observational cohort study based on a longitudinal claims database including 60% of all German statutory healthcare prescriptions to show the long-term effectiveness of one of these products in daily life. Methods: Subjects between 5 to 70 years receiving their first (index) prescription of SCIT with a native HDM product (SCIT group) between 2009 and 2013 were included. The exactly 3:1 matched control group received prescriptions for only symptomatic AR medication (non-AIT group); the evaluation period for up to 6 years of follow-up ended in February 2017. Study endpoints were the progression of allergic rhinitis (AR) and asthma, asthma occurrence and time to the onset of asthma after at least 2 treatment years. Results: 892 subjects (608 adults, 284 children/adolescents) were included in the SCIT group and 2676 subjects (1824 adults, 852 children/adolescents) in the non-AIT group. During the follow-up period after at least two years of SCIT, the number of prescriptions in the SCIT group was reduced by 62.8% (p<0.0001) for AR medication and by 42.4% for asthma medication (p=0.0003). New‐onset asthma risk was significantly reduced in the SCIT vs non‐AIT group by 27.0% (p=0.0212). The asthma preventive effect of SCIT occurred 15 months after start of the treatment. In the SCIT group, the time to onset of asthma was reduced compared to the non-AIT group (p=0.0010). Conclusion: In this RWD analysis patients aged between 5 to 70 years benefited from SCIT with a native HDM product in terms of the reduced progression of AR and asthma after at least 2 years of treatment in the long term. The effects lasted for up to six years after treatment termination. A significantly reduced risk of asthma onset was observed, starting after 15 months of treatment.
Early expansion of allergen-responsive LAP+ B regulatory cells in allergic rhinitis but not in allergic asthma subjects during allergen immunotherapyAstrid L. Voskamp1, Nicolette W. de Jong2, Simon P. Jochems1, Arifa Ozir-Fazalalikhan1, Luciën E.P.M. van der Vlugt1, Koen A. Stam1, Gert-Jan Braunstahl3,4, Gertrude M. Möller5, Roy Gerth van Wijk2, Hermelijn H. Smits11Department of Parasitology, Leiden University Center for Infectious Diseases (LU-CID), Leiden University Medical Center; Leiden, The Netherlands.2Dept of Internal Medicine, Section Allergology and Clinical Immunology, Erasmus University Medical Center; Rotterdam, The Netherlands.3Department of Pulmonology, Franciscus Gasthuis and Vlietland, Rotterdam, 3045 PM, the Netherlands.4Department of Pulmonology, Erasmus Medical Center, Rotterdam, 3015 GD, the Netherlands.5Netherlands Center of Clinical Occupational Medicine, The Netherlands.