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ObjectivesA European League Against Rheumatism taskforce was convened to review the literature and develop recommendations on lifestyle behaviours for rheumatic and musculoskeletal diseases (RMDs).MethodsSix lifestyle exposures (exercise, diet, weight, alcohol, smoking, work participation) and seven RMDs (osteoarthritis, rheumatoid arthritis, axial spondyloarthritis, psoriatic arthritis, systemic lupus erythematosus, systemic sclerosis, gout) were considered. The taskforce included health professionals in rheumatology, geriatricians, epidemiologists, public health experts, people with RMDs and exposure domain experts. Systematic reviews were conducted to gather available evidence, from which recommendations were developed.ResultsFive overarching principles and 18 specific recommendations were defined based on available evidence. The overarching principles define the importance of a healthy lifestyle, how lifestyle modifications should be implemented, and their role in relation to medical treatments. Exercise recommendations highlight the safety and benefits of exercise on pain and disability, particularly among people with osteoarthritis and axial spondyloarthritis. The diet recommendations emphasise the importance of a healthy, balanced diet for people with RMDs. People with RMDs and health professionals should work together to achieve and maintain a healthy weight. Small amounts of alcohol are unlikely to negatively affect the outcomes of people with RMDs, although people with rheumatoid arthritis and gout may be at risk of flares after moderate alcohol consumption. Smokers should be supported to quit. Work participation may have benefits on RMD outcomes and should be discussed in consultations.ConclusionsThese recommendations cover a range of lifestyle behaviours and can guide shared decision making between people with RMDs and health professionals when developing and monitoring treatment plans.

Immune modulation is a key therapeutic approach for allergic diseases, asthma and autoimmunity. It can be achieved in an antigen-specific manner via allergen immunotherapy (AIT) or in an endotype-driven approach using biologicals that target the major pathways of the type 2 (T2) immune response: immunoglobulin (Ig)E, interleukin (IL)-5 and IL-4/IL-13 or non-type 2 response: anti-cytokine antibodies and B-cell depletion via anti-CD20. Coronavirus disease 2019 (COVID-19) vaccination provides an excellent opportunity to tackle the global pandemics and is currently being applied in an accelerated rhythm worldwide. The vaccine exerts its effects through immune modulation, induces and amplifies the response against the severe acute respiratory syndrome coronavirus (SARS-CoV-2). Thus, as there may be a discernible interference between these treatment modalities, recommendations on how they should be applied in sequence are expected. The European Academy of Allergy and Clinical Immunology (EAACI) assembled an expert panel under its Research and Outreach Committee (ROC). This expert panel evaluated the evidence and have formulated recommendations on the administration of COVID-19 vaccine in patients with allergic diseases and asthma receiving AIT or biologicals. The panel also formulated recommendations for COVID-19 vaccine in association with biologicals targeting the type 1 or type 3 immune response. In formulating recommendations, the panel evaluated the mechanisms of COVID-19 infection, of COVID-19 vaccine, of AIT and of biologicals and considered the data published for other anti-infectious vaccines administered concurrently with AIT or biologicals.

Mesenchymal stromal cells (MSCs) are well known for their immunoregulatory roles on allergic inflammation particularly by acting on T cells, B cells, and dendritic cells (DCs). MSC-derived small extracellular vesicles (MSC-sEV) are increasingly considered as one of the main factors for the effects of MSCs on immune responses. However, the effects of MSC-sEV on DCs in allergic diseases remain unclear. MSC-sEV were prepared from the induced pluripotent stem cells (iPSC)-MSCs by anion-exchange chromatography, and were characterized with the size, morphology, and specific markers. Human monocyte-derived DCs were generated and cultured in the presence of MSC-sEV to differentiate the so-called sEV-immature DCs (sEV-iDCs) and sEV-mature DCs (sEV-mDCs), respectively. The phenotypes and the phagocytic ability of sEV-iDCs were analyzed by flow cytometry. sEV-mDCs were co-cultured with isolated CD4

Universitat Zurich

OBJECTIVE Physicians are increasingly confronted with patients presenting with symptoms of esophageal dysfunction resembling eosinophilic esophagitis (EoE), but absence of significant esophageal eosinophilia. The purpose of this study was to characterize and classify this group of EoE variants. DESIGN Patients from six EoE-centers with symptoms of esophageal dysfunction, but peak eosinophil counts of

© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.Environmental exposure plays a major role in the development of allergic diseases. The exposome can be classified into internal (e.g., aging, hormones, and metabolic processes), specific external (e.g., chemical pollutants or lifestyle factors), and general external (e.g., broader socioeconomic and psychological contexts) domains, all of which are interrelated. All the factors we are exposed to, from the moment of conception to death, are part of the external exposome. Several hundreds of thousands of new chemicals have been introduced in modern life without our having a full understanding of their toxic health effects and ways to mitigate these effects. Climate change, air pollution, microplastics, tobacco smoke, changes and loss of biodiversity, alterations in dietary habits, and the microbiome due to modernization, urbanization, and globalization constitute our surrounding environment and external exposome. Some of these factors disrupt the epithelial barriers of the skin and mucosal surfaces, and these disruptions have been linked in the last few decades to the increasing prevalence and severity of allergic and inflammatory diseases such as atopic dermatitis, food allergy, allergic rhinitis, chronic rhinosinusitis, eosinophilic esophagitis, and asthma. The epithelial barrier hypothesis provides a mechanistic explanation of how these factors can explain the rapid increase in allergic and autoimmune diseases. In this review, we discuss factors affecting the planet’s health in the context of the ‘epithelial barrier hypothesis,’ including climate change, pollution, changes and loss of biodiversity, and emphasize the changes in the external exposome in the last few decades and their effects on allergic diseases. In addition, the roles of increased dietary fatty acid consumption and environmental substances (detergents, airborne pollen, ozone, microplastics, nanoparticles, and tobacco) affecting epithelial barriers are discussed. Considering the emerging data from recent studies, we suggest stringent governmental regulations, global policy adjustments, patient education, and the establishment of individualized control measures to mitigate environmental threats and decrease allergic disease.

Objective: Persistence of the viral reservoir is the main barrier to curing HIV. Initiation of ART during acute HIV infection can limit the size and diversity of the reservoir. In depth characterization of the reservoir in individuals who initiate ART during acute infection will be critical for clinical trial design and cure strategies. Methods: Four cohortswith participantswhoinitiatedARTduring acute infection or during chronic infectionwere enrolled in a cross-sectional, noninterventional study.Viral reservoir was evaluated by the Intact Proviral DNA Assay (IPDA), the Total HIVDNA Assay (THDA) and the Quantitative Viral Outgrowth Assay (QVOA). Viral diversity and susceptibility to V3-glycan bNAbs were determined by genotyping of the viral envelope gene. Results: Participants who initiated ART during the acute Fiebig I-IV stages had lower level of total HIV DNA than participants who initiated ART during chronic infection whereas no difference was observed in intact HIV DNA or outgrowth virus. Participants who initiated ART during Fiebig I-IV also had lower viral diversity and appeared to have higher susceptibility to bNAbs than participants initiating ART during chronic infection. Conclusion: Individuals initiating ART during Fiebig I-IV had small viral reservoirs, low viral diversity, and high susceptibility to bNAbs, and would be an optimal target population for proof-of-concept HIV cure trials.

Human skin is a preferred vaccination site as it harbors multiple dendritic cell (DC) subsets, which display distinct C-type lectin receptors (CLR) that recognize pathogens. Antigens can be delivered to CLR by antibodies or ligands to boost antigen-specific immune responses. This concept has been established in mouse models but detailed insights into the functional consequences of antigen delivery to human skin DC in situ are sparse. In this study, we cloned and produced an anti-human Langerin antibody conjugated to the EBV nuclear antigen 1 (EBNA1). We confirmed specific binding of anti-Langerin-EBNA1 to Langerhans cells (LC). This novel LC-based vaccine was then compared to an existing anti-DEC-205-EBNA1 fusion protein by loading LC in epidermal cell suspensions before coculturing them with autologous T cells. After restimulation with EBNA1-peptides, we detected elevated levels of IFN-γ- and TNF-α-positive CD4

The generation of functional regulatory T cells (Tregs) is essential to keep tissue homeostasis and restore healthy immune responses in many biological and inflammatory contexts. Cannabinoids have been pointed out as potential therapeutic tools for several diseases. Dendritic cells (DCs) express the endocannabinoid system, including the cannabinoid receptors CB1 and CB2. However, how cannabinoids might regulate functional properties of DCs is not completely understood. We uncover that the triggering of cannabinoid receptors promote human tolerogenic DCs that are able to prime functional FOXP3+ Tregs in the context of different inflammatory diseases. Mechanistically, cannabinoids imprint tolerogenicity in human DCs by inhibiting NF-κB, MAPK and mTOR signalling pathways while inducing AMPK and functional autophagy flux via CB1- and PPARα-mediated activation, which drives metabolic rewiring towards increased mitochondrial activity and oxidative phosphorylation. Cannabinoids exhibit in vivo protective and anti-inflammatory effects in LPS-induced sepsis and also promote the generation of FOXP3+ Tregs. In addition, immediate anaphylactic reactions are decreased in peanut allergic mice and the generation of allergen-specific FOXP3+ Tregs are promoted, demonstrating that these immunomodulatory effects take place in both type 1- and type 2-mediated inflammatory diseases. Our findings might open new avenues for novel cannabinoid-based interventions in different inflammatory and immune-mediated diseases.

Background: Although avian coronavirus infectious bronchitis virus (IBV) and SARS-CoV-2 belong to different genera of the Coronaviridae family, exposure to IBV may result in the development of cross-reactive antibodies to SARS-CoV-2 due to homologous epitopes. We aimed to investigate whether antibody responses to IBV cross-react with SARS-CoV-2 in poultry farm personnel who are occupationally exposed to aerosolized IBV vaccines. Methods: We analyzed sera from poultry farm personnel, COVID-19 patients, and pre-pandemic controls. IgG levels against the SARS-CoV-2 antigens S1, RBD, S2, and N and peptides corresponding to the SARS-CoV-2 ORF3a, N, and S proteins as well as whole virus antigens of the four major S1-genotypes 4/91, IS/1494/06, M41, and D274 of IBV were investigated by in-house ELISAs. Moreover, live-virus neutralization test (VNT) was performed. Results: A subgroup of poultry farm personnel showed elevated levels of specific IgG for all tested SARS-CoV-2 antigens compared to pre-pandemic controls. Moreover, poultry farm personnel, COVID-19 patients, and pre-pandemic controls showed specific IgG antibodies against IBV strains. These antibody titers were higher in long-term vaccine implementers. We observed a strong correlation between IBV-specific IgG and SARS-CoV-2 S1-, RBD-, S2-, and N-specific IgG in poultry farm personnel compared to pre-pandemic controls and COVID-19 patients. However, no neutralization was observed for these cross-reactive antibodies from poultry farm personnel using the VNT. Conclusion: We report here for the first time the detection of cross-reactive IgG antibodies against SARS-CoV-2 antigens in humans exposed to IBV vaccines. These findings have implications for future vaccination strategies and possibly cross-reactive T cell immunity.

Bone and joint infection (BJI) epidemiology and outcomes in solid organ transplant recipients (SOTr) remain largely unknown. We aim to describe BJI in a multi-center cohort of SOTr (Swiss Transplant Cohort Study). All consecutive SOTr with BJI (01.05.2008-31.12.2019) were included. A nested case-control study to identify risk factors for BJI was performed. Among 4482 patients, 61 SOTr with 82 BJI were included, at an incidence of 1.4% (95% CI 1.1-1.7), higher in heart and kidney-pancreas SOTr (Gray's test p .01). Although BJI were predominately late events (median of 18.5 months post-SOT), most infections occurred during the first year post-transplant in thoracic SOTr. Diabetic foot osteomyelitis was the most frequent infection (38/82, 46.3%), followed by non-vertebral osteomyelitis (26/82, 31.7%). Pathogens included Gram-positive cocci (70/131, 53.4%), Gram-negative bacilli (34/131, 26.0%), and fungi (9/131, 6.9%). BJI predictors included male gender (OR 2.94, 95% CI 1.26-6.89) and diabetes (OR 2.97, 95% CI 1.34-6.56). Treatment failure was observed in 25.9% (21/81) patients and 1-year mortality post-BJI diagnosis was 14.8% (9/61). BJI remain a rare event in SOTr, associated with subtle clinical presentations, high morbidity and relapses, requiring additional studies in the future.

Neutrophil granulocytes, or neutrophils, are the most abundant circulating leukocytes in humans and indispensable for antimicrobial immunity, as exemplified in patients with inborn and acquired defects of neutrophils. Neutrophils were long regarded as the foot soldiers of the immune system, solely destined to execute a set of effector functions against invading pathogens before undergoing apoptosis, the latter of which was ascribed to their short life span. This simplistic understanding of neutrophils has now been revised on the basis of insights gained from the use of mouse models and single-cell high-throughput techniques, revealing tissue- and context-specific roles of neutrophils in guiding immune responses. These studies also demonstrated that neutrophil responses were controlled by sophisticated feedback mechanisms, including directed chemotaxis of neutrophils to tissue-draining lymph nodes resulting in modulation of antimicrobial immunity and inflammation. Moreover, findings in mice and humans showed that neutrophil responses adapted to different deterministic cytokine signals, which controlled their migration and effector function as well as, notably, their biologic clock by affecting the kinetics of their aging. These mechanistic insights have important implications for health and disease in humans, particularly, in allergic diseases, such as atopic dermatitis and allergic asthma bronchiale, as well as in autoinflammatory and autoimmune diseases. Hence, our improved understanding of neutrophils sheds light on novel therapeutic avenues, focusing on molecularly defined biologic agents.

Microbiota composition and associated metabolic activities are essential for the education and development of a healthy immune system. Microbial dysbiosis, caused by risk factors such as diet, birth mode, or early infant antimicrobial therapy, is associated with the inception of allergic diseases. In turn, allergic diseases increase the risk for irrational use of antimicrobial therapy. Microbial therapies, such as probiotics, have been studied in the prevention and treatment of allergic diseases, but evidence remains limited due to studies with high heterogeneity, strain-dependent effectiveness, and variable outcome measures. In this review, we sketch the relation of microbiota with allergic diseases, the overuse and rationale for the use of antimicrobial agents in allergic diseases, and current knowledge concerning the use of bacterial products in allergic diseases. We urgently recommend 1) limiting antibiotic therapy in pregnancy and early childhood as a method contributing to the reduction of the allergy epidemic in children and 2) restricting antibiotic therapy in exacerbations and chronic treatment of allergic diseases, mainly concerning asthma and atopic dermatitis. Future research should be aimed at antibiotic stewardship implementation strategies and biomarker-guided therapy, discerning those patients that might benefit from antibiotic therapy.

BACKGROUND: Inborn errors of immunity (IEI) are rare diseases, which makes diagnosis a challenge. A better description of the initial presenting manifestations should improve awareness and avoid diagnostic delay. Although increased infection susceptibility is a well-known initial IEI manifestation, less is known about the frequency of other presenting manifestations.OBJECTIVE: We sought to analyze age-related initial presenting manifestations of IEI including different IEI disease cohorts.METHODS: We analyzed data on 16,486 patients of the European Society for Immunodeficiencies Registry. Patients with autoinflammatory diseases were excluded because of the limited number registered.RESULTS: Overall, 68% of patients initially presented with infections only, 9% with immune dysregulation only, and 9% with a combination of both. Syndromic features were the presenting feature in 12%, 4% had laboratory abnormalities only, 1.5% were diagnosed because of family history only, and 0.8% presented with malignancy. Two-third of patients with IEI presented before the age of 6 years, but a quarter of patients developed initial symptoms only as adults. Immune dysregulation was most frequently recognized as an initial IEI manifestation between age 6 and 25 years, with male predominance until age 10 years, shifting to female predominance after age 40 years. Infections were most prevalent as a first manifestation in patients presenting after age 30 years.CONCLUSIONS: An exclusive focus on infection-centered warning signs would have missed around 25% of patients with IEI who initially present with other manifestations.

Earlier studies have suggested that the leukocyte redistribution can be considered as an immunological marker of the clinical response to corticosteroids (CS), representing an easy measurable potential biomarker in severe asthma.The aim of this study was to determinate the utility of the leukocyte redistribution as a biomarker of disease heterogeneity in patients with severe asthma and as a bioindicator of potential CS resistance.We developed an unbiased clustering approach based on the clinical data and the flow cytometry results of peripheral blood leukocyte phenotypes of 142 patients with severe asthma before and after systemic CS administration.Based on the differences in the blood count eosinophils, neutrophils and lymphocytes, together with the flow cytometry measurements of basic T cell, B cell and NK cell subpopulations before and after systemic CS administration, we identified two severe asthma clusters, which differed in the cell frequencies, response to CS and atopy status. Patients in cluster 1 had higher frequency of blood eosinophils at baseline, were sensitized to less allergens and had better steroid responsiveness, measured as the pronounced leukocyte redistribution after the administration of systemic CS. Patients in cluster 2 were determined by the higher frequency of B-cells and stronger IgE sensitization status to the multiple allergens. They also displayed higher steroid resistance, as the clinical correlate for the lower leukocyte redistribution after administration of systemic CS.The flow cytometry-based profiling of the basic populations of immune cells in the blood and its analysis before and after systemic corticosteroid administration could improve personalized treatment approaches in patients with severe asthma.

Background and aimsThe role of inflammatory immune responses in colorectal cancer (CRC) development and response to therapy is a matter of intense debate. While inflammation is a known driver of CRC, inflammatory immune infiltrates are a positive prognostic factor in CRC and predispose to response to immune checkpoint blockade (ICB) therapy. Unfortunately, over 85% of CRC cases are primarily unresponsive to ICB due to the absence of an immune infiltrate, and even the cases that show an initial immune infiltration can become refractory to ICB. The identification of therapy supportive immune responses in the field has been partially hindered by the sparsity of suitable mouse models to recapitulate the human disease. In this study, we aimed to understand how the dysregulation of the complement anaphylatoxin C3a receptor (C3aR), observed in subsets of patients with CRC, affects the immune responses, the development of CRC, and response to ICB therapy.MethodsWe use a comprehensive approach encompassing analysis of publicly available human CRC datasets, inflammation-driven and newly generated spontaneous mouse models of CRC, and multiplatform high-dimensional analysis of immune responses using microbiota sequencing, RNA sequencing, and mass cytometry.ResultsWe found that patients’ regulation of the complement C3aR is associated with epigenetic modifications. Specifically, downregulation of C3ar1 in human CRC promotes a tumor microenvironment characterized by the accumulation of innate and adaptive immune cells that support antitumor immunity. In addition, in vivo studies in our newly generated mouse model revealed that the lack of C3a in the colon activates a microbiota-mediated proinflammatory program which promotes the development of tumors with an immune signature that renders them responsive to the ICB therapy.ConclusionsOur findings reveal that C3aR may act as a previously unrecognized checkpoint to enhance antitumor immunity in CRC. C3aR can thus be exploited to overcome ICB resistance in a larger group of patients with CRC.

Background Activation of melanocortin 1 receptor (MC1R) is known to exert broad anti-inflammatory and anti-fibrotic effects. The purpose of this study is to investigate the potential of dersimelagon, a novel oral MC1R agonist, as a therapeutic agent for systemic sclerosis (SSc). Methods The effects of dersimelagon phosphoric acid (MT-7117) on skin fibrosis and lung inflammation were evaluated in bleomycin (BLM)-induced SSc murine models that were optimized for prophylactic and therapeutic evaluation. Microarray-based gene expression analysis and serum protein profiling were performed in the BLM-induced SSc models. The effect of MT-7117 on transforming growth factor-β (TGF-β)-induced activation of human dermal fibroblasts was evaluated in vitro. Immunohistochemical analyses of MC1R expression in the skin of SSc patients were performed. Results Prophylactic treatment with MT-7117 (≥ 0.3 mg/kg/day p.o.) significantly inhibited skin fibrosis and lung inflammation, and therapeutic treatment with MT-7117 (≥ 3 mg/kg/day p.o.) significantly suppressed the development of skin fibrosis in the BLM-induced SSc models. Gene array analysis demonstrated that MT-7117 exerts an anti-inflammatory effect via suppression of the activation of inflammatory cells and inflammation-related signals; additionally, vascular dysfunction was extracted as the pathology targeted by MT-7117. Serum protein profiling revealed that multiple SSc-related biomarkers including P-selectin, osteoprotegerin, cystatin C, growth and differentiation factor-15, and S100A9 were suppressed by MT-7117. MT-7117 inhibited the activation of human dermal fibroblasts by suppressing TGF-β-induced ACTA2 (encoding α-smooth muscle actin) mRNA elevation. MC1R was expressed by monocytes/macrophages, neutrophils, blood vessels (endothelial cells), fibroblasts, and epidermis (keratinocytes) in the skin of SSc patients, suggesting that these MC1R-positive cells could be targets for MT-7117. Conclusions MT-7117 demonstrates disease-modifying effects in preclinical models of SSc. Investigations of its mechanism of action and target expression analyses indicate that MT-7117 exerts its positive effect by affecting inflammation, vascular dysfunction, and fibrosis, which are all key pathologies of SSc. The results of the present study suggest that MT-7117 is a potential therapeutic agent for SSc. A phase 2 clinical trial investigating the efficacy and tolerability of MT-7117 in patients with early, progressive diffuse cutaneous SSc is currently in progress.

Last year brought a significant advance in asthma management, unyielding to the pressure of the pandemics. Novel key findings in asthma pathogenesis focus on the resident cell compartment, epigenetics and the innate immune system. The precision immunology unbiased approach was supplemented with novel tools and greatly facilitated by the use of artificial intelligence. Several randomised clinical trials and good quality real-world evidence shed new light on asthma treatment and supported the revision of several asthma guidelines (GINA, Expert Panel Report 3, ERS/ATS guidelines on severe asthma) and the conception of new ones (EAACI Guidelines for the use of biologicals in severe asthma). Integrating asthma management within the broader context of Planetary Health has been put forward. In this review, recently published articles and clinical trials are summarised and discussed with the goal to provide clinicians and researchers with a concise update on asthma research from a translational perspective.

Background The question how to treat the clinically negative neck in sinonasal malignancies is controversial. Objectives To investigate patterns of treatment failure and to assess outcome measures in patients with primary sinonasal malignancies. Methods Retrospective cohort study of patients treated for primary malignant sinonasal malignancies. Results Lymph node (LN) metastases at initial presentation were present in 8 of 152 patients (5.3%). Ipsi- and contralateral LN levels 1 and 2 were identified as nodal basins at risk. We found a 5-year overall survival (OS) of 75.2% and disease free survival of 61.1%. Among patients with cN0 neck, nodal recurrence free survival was not different between patients with and without elective neck treatment ( P = .23). On logistic regression analysis, we found initial T classification as an independent factor for achievement of complete remission (CR) and OS. Conclusions LN metastases at initial presentation are rare and initial T classification was identified as the most important prognostic factor for OS and CR, emphasizing the need for a thorough initial staging of the primary tumor.

Background Coronavirus disease-2019 (COVID-19) has been associated with cutaneous findings, some being the result of drug hypersensitivity reactions such as maculopapular drug rashes (MDR). The aim of this study was to investigate whether COVID-19 may impact the development of the MDR. Methods Blood and skin samples from COVID-19 patients (based on a positive nasopharyngeal PCR) suffering from MDR (COVID-MDR), healthy controls, non-COVID-19—related patients with drug rash with eosinophilia and systemic symptoms (DRESS), and MDR were analyzed. We utilized imaging mass cytometry (IMC) to characterize the cellular infiltrate in skin biopsies. Furthermore, RNA sequencing transcriptome of skin biopsy samples and high-throughput multiplexed proteomic profiling of serum were performed. Results IMC revealed by clustering analyses a more prominent, phenotypically shifted cytotoxic CD8+ T cell population and highly activated monocyte/macrophage (Mo/Mac) clusters in COVID-MDR. The RNA sequencing transcriptome demonstrated a more robust cytotoxic response in COVID-MDR skin. However, severe acute respiratory syndrome coronavirus 2 was not detected in skin biopsies at the time point of MDR diagnosis. Serum proteomic profiling of COVID-MDR patients revealed upregulation of various inflammatory mediators (IL-4, IL-5, IL-6, TNF, and IFN-γ), eosinophil and Mo/Mac -attracting chemokines (MCP-2, MCP-3, MCP-4 and CCL11). Proteomics analyses demonstrated a massive systemic cytokine storm in COVID-MDR compared with the relatively milder cytokine storm observed in DRESS, while MDR did not exhibit such features. Conclusion A systemic cytokine storm may promote activation of Mo/Mac and cytotoxic CD8+ T cells in severe COVID-19 patients, which in turn may impact the development of MDR., Allergy, 77 (2), ISSN:0105-4538, ISSN:1398-9995

The latest outbreak of a coronavirus disease in 2019 (COVID‐19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), evolved into a worldwide pandemic with massive effects on health, quality of life, and economy. Given the short period of time since the outbreak, there are several knowledge gaps on the comparative and zoonotic aspects of this new virus. Within the One Health concept, the current EAACI position paper dwells into the current knowledge on SARS‐CoV‐2’s receptors, symptoms, transmission routes for human and animals living in close vicinity to each other, usefulness of animal models to study this disease and management options to avoid intra‐ and interspecies transmission. Similar pandemics might appear unexpectedly and more frequently in the near future due to climate change, consumption of exotic foods and drinks, globe‐trotter travel possibilities, the growing world population, the decreasing production space, declining room for wildlife and free‐ranging animals, and the changed lifestyle including living very close to animals. Therefore, both the society and the health authorities need to be aware and well prepared for similar future situations, and research needs to focus on prevention and fast development of treatment options (medications, vaccines).

Background Coronavirus disease 2019 (COVID-19) is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and shows a broad clinical presentation ranging from asymptomatic infection to fatal disease. A very prominent feature associated with severe COVID-19 is T cell lymphopenia. However, homeostatic and functional properties of T cells are ill-defined in COVID-19. Methods We prospectively enrolled individuals with mild and severe COVID-19 into our multicenter cohort and performed a cross-sectional analysis of phenotypic and functional characteristics of T cells using 40-parameter mass cytometry, flow cytometry, targeted proteomics, and functional assays. Results Compared with mild disease, we observed strong perturbations of peripheral T cell homeostasis and function in severe COVID-19. Individuals with severe COVID-19 showed T cell lymphopenia and redistribution of T cell populations, including loss of naïve T cells, skewing toward CD4+T follicular helper cells and cytotoxic CD4+ T cells, and expansion of activated and exhausted T cells. Extensive T cell apoptosis was particularly evident with severe disease and T cell lymphopenia, which in turn was accompanied by impaired T cell responses to several common viral antigens. Patients with severe disease showed elevated interleukin-7 and increased T cell proliferation. Furthermore, patients sampled at late time points after symptom onset had higher T cell counts and improved antiviral T cell responses. Conclusion Our study suggests that severe COVID-19 is characterized by extensive T cell dysfunction and T cell apoptosis, which is associated with signs of homeostatic T cell proliferation and T cell recovery., Allergy, 76 (9), ISSN:0105-4538, ISSN:1398-9995

Following the emergency use authorization of the vaccine mRNA-1273 on 18th December 2020 in the US and the vaccine BNT162b2 one week earlier, two mRNA vaccines are in currently used for the prevention of coronavirus disease 2019 (COVID-19). Phase 3 pivotal trials on both vaccines excluded individuals with a history of allergy to vaccine components. Immediately after the initiation of vaccination in the United Kingdom, Canada, and in the US, anaphylactic reactions have been reported. While the culprit trigger requires investigation, initial reports suggested the excipient polyethylene glycol 2000 (PEG-2000), which is contained in both vaccines as PEG-micellar carrier system as the potential culprit. Surface PEG chains form a hydrate shell to increase stability and prevent opsonization. Allergic reactions to such PEG-ylated lipids are rarely IgE-mediated, but may result from complement activation-related pseudoallergy (CARPA) that has been described to similar liposomes. In addition, mRNA-1273 also contains tromethamine (trometamol), which has been reported to cause anaphylaxis to e.g. gadolinium-based or iodinated contrast media. Skin prick-, intradermal-, epicutaneous- tests, in vitro sIgE assessment, evaluation of sIgG/IgM, as well as basophil activation test are in use to demonstrate allergic reactions to various components of the vaccines.

The kinetics of immunoglobulin G (IgG) avidity maturation during severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection obtained from 217 participants of the Ischgl cohort, Austria, was studied 0.5–1.5 months (baseline) and 7–8 months (follow-up) after infection. The IgG avidity assay, using a modified IgG enzyme-linked immunosorbent assay (ELISA) and 5.5 M urea, revealed that old age does not diminish the increase in avidity, detected in all participants positive at both time points, from 18% to 42%. High avidity was associated with a marked residual neutralization capacity in 97.2.% of participants (211/217), which was even higher in the older age group, revealing an important role of avidity assays as easy and cheap surrogate tests for assessing the maturation of the immune system conveying potential protection against further SARS-CoV-2 infections without necessitating expensive and laborious neutralization assays.

Background aims Cultured patient-specific keratinocyte sheets have been used clinically since the 1970s for the treatment of large severe burns. However, despite significant developments in recent years, successful and sustainable treatment is still a challenge. Reliable, high-quality grafts with faster availability and a flexible time window for transplantation are required to improve clinical outcomes. Methods Keratinocytes are usually grown in vitro at 37°C. Given the large temperature differences in native skin tissue, the aim of the authors’ study was to investigate thermal conditioning of keratinocyte sheet production. Therefore, the influence of 31°C, 33°C and 37°C on cell expansion and differentiation in terms of proliferation and sheet formation efficacy was investigated. In addition, the thermal effect on the biological status and thus the quality of the graft was assessed on the basis of the release of wound healing-related biofactors in various stages of graft development. Results The authors demonstrated that temperature is a decisive factor in the production of human keratinocyte sheets. By using specific temperature ranges, the authors have succeeded in optimizing the individual manufacturing steps. During the cell expansion phase, cultivation at 37°C was most effective. After 6 days of culture at 37°C, three times and six times higher numbers of viable cells were obtained compared with 33°C and 31°C. During the cell differentiation and sheet formation phase, however, the cells benefited from a mildly hypothermic temperature of 33°C. Keratinocytes showed increased differentiation potential and formed better epidermal structures, which led to faster biomechanical sheet stability at day 18. In addition, a cultivation temperature of 33°C resulted in a longer lasting and higher secretion of the investigated immunomodulatory, anti-inflammatory, angiogenic and pro-inflammatory biofactors. Conclusions These results show that by using specific temperature ranges, it is possible to accelerate the large-scale production of cultivated keratinocyte sheets while at the same time improving quality. Cultivated keratinocyte sheets are available as early as 18 days post-biopsy and at any time for 7 days thereafter, which increases the flexibility of the process for surgeons and patients alike. These findings will help to provide better clinical outcomes, with an increased take rate in severe burn patients.

Coronavirus disease 2019 (COVID-19) vaccine BNT162b2 received approval and within the first few days of public vaccination several severe anaphylaxis cases occurred. An investigation is taking place to understand the cases and their triggers. The vaccine will be administered to a large number of individuals worldwide and concerns raised for severe adverse events might occur. With the current information, the European Academy of Allergy and Clinical Immunology (EAACI) states its position for the following preliminary recommendations that are to be revised as soon as more data emerges. To minimize the risk of severe allergic reactions in vaccinated individuals, it is urgently required to understand the specific nature of the reported severe allergic reactions, including the background medical history of the individuals affected and the mechanisms involved. To achieve this goal all clinical and laboratory information should be collected and reported. Mild and moderate allergic patients should not be excluded from the vaccine as the exclusion of all these patients from vaccination may have a significant impact on reaching the goal of population immunity. Health care practitioners vaccinating against COVID-19 are required to be sufficiently prepared to recognise and treat anaphylaxis properly with the ability to administer adrenaline. A mandatory observation period after vaccine administration of at least 15 minutes for all individuals should be followed. The current data has not shown any higher risk for patients suffering from allergic rhinitis or asthma and this message should be clearly stated by physicians to give our patients trust. The benefit of the vaccination clearly outweighs the risk of severe COVID-19 development including the more than 30% of the population suffering from allergic diseases.

Air pollution is a leading cause of death globally and has resulted in the loss of millions of healthy years of life. Moreover, the health burden has fallen disproportionately upon people in many low- and middle-income countries, where air quality continues to deteriorate. To assist authorities and civil society in improving air quality, World Health Organization has published the first global update to its 2005 air quality guidelines based on a significantly improved body of evidence. To facilitate the implementation of the World Health Organization Global Air Quality Guideline recommendations, this article summarizes the purpose and rationale of the quantitative air quality guidelines and interim target levels for six key pollutants: particulate matter 2.5, particulate matter 10, sulfur dioxide, nitrogen dioxide, ozone, and carbon monoxide. In addition, good practice statements are established for the management of pollutants of concern that lack sufficient evidence to substantiate numerical targets.

Various lung insults can result in replacement of resident alveolar macrophages (AM) by bone marrow monocyte–derived (BMo)–AM. However, the dynamics of this process and its long-term consequences for respiratory viral infections remain unclear. Using several mouse models and a marker to unambiguously track fetal monocyte–derived (FeMo)–AM and BMo-AM, we established the kinetics and extent of replenishment and their function to recurrent influenza A virus (IAV) infection. A massive loss of FeMo-AM resulted in rapid replenishment by self-renewal of survivors, followed by the generation of BMo-AM. BMo-AM progressively outcompeted FeMo-AM over several months, and this was due to their increased glycolytic and proliferative capacity. The presence of both naïve and experienced BMo-AM conferred severe pathology to IAV infection, which was associated with a proinflammatory phenotype. Furthermore, upon aging of naïve mice, FeMo-AM were gradually replaced by BMo-AM, which contributed to IAV disease severity in a cell-autonomous manner. Together, our results suggest that the origin rather than training of AM determines long-term function to respiratory viral infection and provide an explanation for the increased severity of infection seen in the elderly.

BackgroundA EULAR taskforce was convened to develop recommendations for lifestyle behaviours in rheumatic and musculoskeletal diseases (RMDs). In this paper, the literature on the effect of diet on the progression of RMDs is reviewed.MethodsSystematic reviews and meta-analyses were performed of studies related to diet and disease outcomes in seven RMDs: osteoarthritis (OA), rheumatoid arthritis (RA), systemic lupus erythematosus, axial spondyloarthritis, psoriatic arthritis, systemic sclerosis and gout. In the first phase, existing relevant systematic reviews and meta-analyses, published from 2013 to 2018, were identified. In the second phase, the review was expanded to include published original studies on diet in RMDs, with no restriction on publication date. Systematic reviews or original studies were included if they assessed a dietary exposure in one of the above RMDs, and reported results regarding progression of disease (eg, pain, function, joint damage).ResultsIn total, 24 systematic reviews and 150 original articles were included. Many dietary exposures have been studied (n=83), although the majority of studies addressed people with OA and RA. Most dietary exposures were assessed by relatively few studies. Exposures that have been assessed by multiple, well conducted studies (eg, OA: vitamin D, chondroitin, glucosamine; RA: omega-3) were classified as moderate evidence of small effects on disease progression.ConclusionThe current literature suggests that there is moderate evidence for a small benefit for certain dietary components. High-level evidence of clinically meaningful effect sizes from individual dietary exposures on outcomes in RMDs is missing.

Eosinophils are traditionally considered as end-stage effector cells involved in the pathogenesis of Th2 immune-mediated disorders as well as in the protection against parasite infection. However, this restricted view has recently been challenged by a series of studies revealing the highly plastic nature of these cells and implication in various homeostatic processes. Large numbers of eosinophils reside in the lamina propria of the gastrointestinal tract, at the front line of host defence, where they contribute to maintain the intestinal epithelial barrier function in the face of inflammation-associated epithelial cell damage. Eosinophils confer active protection against bacterial pathogens capable of penetrating the mucosal barrier through the release of cytotoxic compounds and the generation of extracellular DNA traps. Eosinophils also integrate tissue-specific cytokine signals such as IFN-γ, which synergise with bacterial recognition pathways to enforce different context-dependent functional responses, thereby ensuring a rapid adaptation to the ever-changing intestinal environment. The ability of eosinophils to regulate local immune responses and respond to microbial stimuli further supports the pivotal role of these cells in the maintenance of tissue homeostasis at the intestinal interface.

Antibodies play an important role in host defense against microorganisms. Besides direct microbicidal activities, antibodies can also provide indirect protection via crosstalk to constituents of the adaptive immune system. Similar to many human chronic viral infections, persistence of Lymphocytic choriomeningitis virus (LCMV) is associated with compromised T- and B-cell responses. The administration of virus-specific non-neutralizing antibodies (nnAbs) prior to LCMV infection protects against the establishment of chronic infection. Here, we show that LCMV-specific nnAbs bind preferentially Ly6Chi inflammatory monocytes (IMs), promote their infection in an Fc-receptor independent way, and support acquisition of APC properties. By constituting additional T-cell priming opportunities, IMs promote early activation of virus-specific CD8 T cells, eventually tipping the balance between T-cell exhaustion and effector cell differentiation, preventing establishment of viral persistence without causing lethal immunopathology. These results document a beneficial role of IMs in avoiding T-cell exhaustion and an Fc-receptor independent protective mechanism provided by LCMV-specific nnAbs against the establishment of chronic infection., European Journal of Immunology, 51 (6), ISSN:0014-2980, ISSN:1521-4141

Introduction: Few studies assess biologicals such as, omalizumab, mepolizumab, benralizumab, and dupilumab in patients suffering from chronic rhinosinusitis with nasal polyposis (CRSwNP). The reported success rate in these studies differ, and it remains uncertain if there are any biomarkers to predict successful therapy. Our aim was to analyze the therapeutic outcome in a real life setting and to identify predictive biomarkers for successful treatment. Methods: Data from patients with CRSwNP treated with a monoclonal antibody between November 2014 and January 2020 were analyzed retrospectively. Improvement in the polyp score and clinical symptoms like nasal obstruction, sense of smell, nasal discharge, and facial pain were evaluated. Other characteristics, including use of nasal or systemic steroids, comorbidities, previous history of sinus surgery, eosinophilia tissue, blood values (eosinophils, total immunoglobulin E, eosinophilic cationic protein, and interleukin 5), and allergic sensitization in serum were also investigated to identify possible predictive biomarkers. Results: Forty-eight treatments in 29 patients (m/f = 15/14) aged 27–70 years were reviewed. Treatments with mepolizumab showed the best success rates (78.9%), followed by omalizumab (50%) and benralizumab treatments (50%). However, a correlation between biomarkers and treatment success could not be found. Discussion/Conclusion: Treatment of CRSwNP with biologicals is a promising option for severe cases not responding to conventional therapy, including difficult-to-treat patients. Predictive biomarkers for a successful treatment could not be identified, but the reduction of eosinophilic cationic protein was linked with the response.

Biologicals have transformed the management of severe disease phenotypes in asthma, atopic dermatitis, and chronic spontaneous urticaria. As a result, the number of approved biologicals for the treatment of atopic diseases is continuously increasing. Although atopic diseases are among the most common diseases in the reproductive age, investigations, and information on half-life, pharmacokinetics defining the neonatal Fc receptors (FcRn) and most important safety of biologicals in pregnancy are lacking. Given the complex sequence of immunological events that regulate conception, fetal development, and the intrauterine and postnatal maturation of the immune system, this information is of utmost importance. We conducted a systematic review on biologicals in pregnancy for indications of atopic diseases. Evidence in this field is scare and mainly reserved to reports on the usage of omalizumab. This lack of evidence demands the establishment of a multidisciplinary approach for the management of pregnant women who receive biologicals and multicenter registries for long-term follow-up, drug trial designs suitable for women in the reproductive age, and better experimental models that represent the human situation. Due to the very long half-life of biologicals, pre-conception counseling, and health care provider education is crucial to offer the best care for mother and fetus. This position paper integrates available data on safety of biologicals during pregnancy in atopic diseases via a systematic review with a detailed review on immunological considerations how inhibition of different pathways may impact pregnancy.

Background Donor-specific antibodies are associated with high immunological risk and poor allograft outcome. Risk and clinical relevance of non-donor-specific HLA antibodies is less clear. Methods A retrospective single-center study was conducted in all patients receiving a first kidney transplant at the University hospital of Zurich between 01/2006 and 02/2015. Patients were stratified into 3 groups having either no HLA antibodies at all (NoAB), HLA antibodies with donor specificity (DSA) and HLA antibodies without donor specificity (NonDSA). Allograft outcome was assessed using the slope of the estimated glomerular filtration rate (eGFR slope) starting at 12 months after transplantation. Results During a median follow-up of 1808 days HLA antibodies were detected in 106 of 238 eligible patients (44%). Out of these, 73 patients (69%) had DSA and 33 patients (31%) had NonDSA only. Medium-term allograft function, as determined by eGFR slope over three years, improved in patients with NoAB (months 12–48: +0.7 ml/min/1.73 m2) but deteriorated significantly in patients with both DSA (months 12–48: −1.5 ml/min per1.73 m2/year, p = 0.015) and NonDSA (months 12–48: −1.8 ml/min per1.73 m2/year, p = 0.03) as compared to the group with NoAB. Conclusion Both, donor-specific and non-donor-specific HLA antibodies are associated with medium-term kidney allograft dysfunction as compared to patients with no HLA antibodies.

An increasing number of people suffer from IgE-mediated food allergies. The immunological mechanisms that cause IgE-mediated food allergy have been extensively studied. B cells play a key role in the development of IgE-mediated food allergies through the production of allergen-specific antibodies. While this particular function of B cells has been known for many years, we still do not fully understand the mechanisms that regulate the induction and maintenance of allergen-specific IgE production. It is still not fully understood where in the body IgE class switch recombination of food allergen-specific B cells occurs, and what processes are involved in the immunological memory of allergen-specific IgE responses. B cells can also contribute to the regulation of allergen-specific immune responses through other mechanisms such as antigen presentation and cytokine production. Recent technological advances have enabled highly detailed analysis of small subsets of B cells down to the single-cell level. In this review, we provide an overview of the current knowledge on the biology of B cells in relation to IgE-mediated food allergies.

Background We recently described increased NFATc1, IRF4, and NIP45 messenger RNA (mRNA) expression in peripheral blood mononuclear cells (PBMCs) of asthmatic children and adults with multiple allergies. Objective NFATc2 has been described to associate with IRF4 to induce interleukin‐4, and to be inhibited by T‐bet. Here, we analyzed the role of NFATc2 in asthmatic children and adults. Methods PBMCs were isolated from the blood of control of asthmatics subjects. Some PBMCs were analyzed untreated and some cultured with and without phytohemagglutinin. Then, RNA was extracted from the cells and cytokines were measured in the supernatants via enzyme‐linked immunosorbent assay or multiplex analysis. RNA was then reverse‐transcribed and NFATc1, NFATC2, IRF4, and T‐bet mRNA were analyzed by real‐time polymerase chain reaction. In addition, in peripheral blood cells, NFATc2 expression was analyzed, in a population of asthmatic children and adults from the Asthma BRIDGE study. Results In addition to NFATc1 and NIP45, also NFATc2 was found upregulated in PBMCs and peripheral blood cells from asthmatic children and adults with allergic asthma. Moreover, NFATc1 directly correlated with lymphocytes number whereas NFATc2 correlated with peripheral eosinophilia in asthma. Conclusions In addition to NFATc1 and NIP45, NFATc2 was found upregulated in asthma. Moreover, NFATc1 mRNA correlated with lymphocytes both in control and asthma, and NFATC1 and NFATc2 mRNA showed a direct correlation with eosinophils in controls but not in asthma, indicating that NFATc1 is associated with lymphocytes and not eosinophils in asthma. Clinical Significance Targeting NFATc2 in T lymphocytes might ameliorate the allergic phenotype in asthmatic subjects., In addition to NFATc1 and NIP45, NFATc2 was found upregulated in asthma. Moreover, NFATc1 messenger RNA (mRNA) correlated with lymphocytes both in control and asthma. NFATc2 mRNA showed a direct correlation with eosinophils both in controls and asthma, indicating that NFATc1 is associated with lymphocytes and not eosinophils in asthma.

Cutaneous melanoma is one of the most aggressive human malignancies and shows increasing incidence. Mast cells (MCs), long-lived tissue-resident cells that are particularly abundant in human skin where they regulate both innate and adaptive immunity, are associated with melanoma stroma (MAMCs). Thus, MAMCs could impact melanoma development, progression, and metastasis by secreting proteases, pro-angiogenic factors, and both pro-inflammatory and immuno-inhibitory mediators. To interrogate the as-yet poorly characterized role of human MAMCs, we have purified MCs from melanoma skin biopsies and performed RNA-seq analysis. Here, we demonstrate that MAMCs display a unique transcriptome signature defined by the downregulation of the FcεRI signaling pathway, a distinct expression pattern of proteases and pro-angiogenic factors, and a profound upregulation of complement component C3. Furthermore, in melanoma tissue, we observe a significantly increased number of C3+ MCs in stage IV melanoma. Moreover, in patients, C3 expression significantly correlates with the MC-specific marker TPSAB1, and the high expression of both markers is linked with poorer melanoma survival. In vitro, we show that melanoma cell supernatants and tumor microenvironment (TME) mediators such as TGF-β, IL-33, and IL-1β induce some of the changes found in MAMCs and significantly modulate C3 expression and activity in MCs. Taken together, these data suggest that melanoma-secreted cytokines such as TGF-β and IL-1β contribute to the melanoma microenvironment by upregulating C3 expression in MAMCs, thus inducing an MC phenotype switch that negatively impacts melanoma prognosis.

The high incidence and increased mortality of COVID-19 make Italy among the most impacted countries by SARS-CoV-2 outbreak. In the beginning of the pandemic, Northern regions accounted for 40% of cases and 45% of deaths from COVID-19 in Italy. Several factors have been suggested to explain the higher incidence and excess mortality from COVID-19 in these regions. It is noticed that Northern Italian regions, and particularly the cities in Po Valley, are the areas with the highest air pollution due to commercial vehicle traffic, industry and a stagnant meteorological condition, with one of the highest levels in Italy and Europe of fine particulate matter 2.5 micron or smaller in size (PM2.5). PM2.5, the major environmental pollutant deriving mainly by factory and automobile exhaust emissions and coal combustion, increases the expression of angiotensin-converting enzyme 2, the epithelial cell entry receptor for SARS-CoV-2, and thus increase the susceptibility to this virus. The epithelial barrier hypothesis proposes that many diverse diseases may rise from the disruption of epithelial barrier of skin, respiratory tract and gastrointestinal system, including allergic diseases, metabolic and autoimmune diseases, and chronic neuropsychiatric conditions. There is evidence of a close correlation between air pollution and airway epithelial barrier dysfunction. Air pollution, causing lung epithelial barrier dysfunction, may contribute to local chronic inflammation, microbiome dysbiosis and impaired antiviral immune response against SARS-CoV-2, all of which contribute to the high incidence and excess mortality from COVID-19. In addition, air pollution and epithelial barrier dysfunction contribute also to the higher prevalence of several comorbidities of COVID-19, such as diabetes, chronic obstructive pulmonary disease and obesity, which have been identified as risk factors for mortality of COVID-19. In this article, on the basis of epidemiological and environmental monitoring data in Northern Italy, it is suggested that epithelial barrier hypothesis may help to understand the excess burden and mortality from COVID-19.

It remains uncertain as to whether nutrient supplementation for the general population considered healthy could be useful in the prevention of RTIs, such as COVID-19. In this systematic review and meta-analysis, the evidence was evaluated for primary prevention of any viral respiratory tract infection (RTI) such as SARS-CoV-2, through supplementation of nutrients with a recognized role in immune function: multiple micronutrients, vitamin A, folic acid, vitamin B12, C, D, E, beta-carotene, zinc, iron and long-chain polyunsaturated fatty acids. The search produced 15,163 records of which 93 papers (based on 115 studies) met the inclusion criteria, resulting in 199,055 subjects (191,636 children and 7,419 adults) from 37 countries. Sixty-three studies were included in the meta-analyses, which was performed for children and adults separately. By stratifying the meta-analysis by world regions, only studies performed in Asia showed a significant but heterogeneous protective effect of zinc supplementation on RTIs (RR 0.86, 95% CI 0.7-0.96, I2 = 79.1%, p = .000). Vitamin D supplementation in adults significantly decreased the incidence of RTI (RR 0.89, 95% CI 0.79-0.99, p = .272), particularly in North America (RR 0.82 95% CI 0.68-0.97), but not in Europe or Oceania. Supplementation of nutrients in the general population has either no or at most a very limited effect on prevention of RTIs. Zinc supplementation appears protective for children in Asia, whilst vitamin D may protect adults in the USA and Canada. In 10/115 (8.7%) studies post-hoc analyses based on stratification for nutritional status was performed. In only one study zinc supplementation was found to be more effective in children with low zinc serum as compared to children with normal zinc serum levels.

Background Vaccines against SARS-CoV-2 have been rapidly approved. While pivotal studies were conducted in healthy volunteers, little information is available on safety and efficacy of mRNA vaccines in immunocompromised patients, including recipients of allogeneic hematopoietic cell transplantations (allo-HCT). Objectives Here, we used a novel assay to analyze patient- and transplant-related factors and their influence on immune responses over an extended period of time (up to 6 months) to the SARS-CoV-2 vaccination in a large and homogenous group of allo-HCT recipients at a single center in Switzerland. Study Design We examined longitudinal antibody responses to SARS-CoV-2 vaccination with BNT162b2 (BioNTech/Pfizer) or mRNA-1273 (Moderna) in 110 allo-HCT recipients and 86 healthy controls. Seroprofiling recording IgG, IgA, and IgM reactivities against SARS-CoV-2 antigens (receptor-binding domain (RBD), spike glycoprotein subunits S1 and S2, and nucleocapsid protein (N)) was performed prior to vaccination, prior to the 2nd dose, and 1, 3, and 6 months (m) after the 2nd dose. Patients were stratified to three groups (A) 3-6m post HCT; (B) 6-12m post HCT; and (C) >12m post HCT. Results Individuals early post allo-HCT (3-6 and 6-12m post HCT) developed significantly lower antibody titers after vaccination compared to patients >12m post allo-HCT and healthy controls (p65 years (p=0.030), those under immunosuppression for prevention or treatment of graft-vs-host disease (GVHD) (p=0.033), and/or with relapsed disease (p=0.014) displayed poor humoral immune response to the vaccine. In contrast, the intensity of the conditioning regimen, underlying disease (myeloid/lymphoid/other), and presence of chronic GVHD had no impact on antibody levels. Antibody titers achieved the highest levels 1m after the 2nd dose of the vaccine but substantially waned in all transplanted groups and healthy controls over time. Conclusions This analysis of long-term vaccine antibody response is of critical importance to allo-HCT recipients and transplant physicians to guide treatment decisions regarding re-vaccination and social behavior during the SARS-CoV-2 pandemic., Graphical Abstract Image, graphical abstract

The oncotherapeutic promise of IL-15, a potent immunostimulant, is limited by a short serum t1/2. The fusion protein N-803 is a chimeric IL-15 superagonist that has a >20-fold longer in vivo t1/2 versus IL-15. This phase 1 study characterized the pharmacokinetic (PK) profile and safety of N-803 after s.c. administration to healthy human volunteers. Volunteers received two doses of N-803, and after each dose, PK and safety were assessed for 9 d. The primary endpoint was the N-803 PK profile, the secondary endpoint was safety, and immune cell levels and immunogenicity were measures of interest. Serum N-803 concentrations peaked 4 h after administration and declined with a t1/2 of ∼20 h. N-803 did not cause treatment-emergent serious adverse events (AEs) or grade ≥3 AEs. Injection site reactions, chills, and pyrexia were the most common AEs. Administration of N-803 was well tolerated and accompanied by proliferation of NK cells and CD8+ T cells and sustained increases in the number of NK cells. Our results suggest that N-803 administration can potentiate antitumor immunity.

BackgroundSeveral autoimmune features occur during coronavirus disease 2019 (COVID-19), with possible implications for disease course, immunity, and autoimmune pathology. In this study, we longitudinally screened for clinically relevant systemic autoantibodies to assess their prevalence, temporal trajectory, and association with immunity, comorbidities, and severity of COVID-19.MethodsWe performed highly sensitive indirect immunofluorescence assays to detect anti-nuclear antibodies (ANA) and anti-neutrophil cytoplasmic antibodies (ANCA), along with serum proteomics and virome-wide serological profiling in a multicentric cohort of 175 COVID-19 patients followed-up to one year after infection, eleven vaccinated individuals, and 41 unexposed controls.ResultsCompared to healthy controls, similar prevalence and patterns of ANA were present in patients during acute COVID-19 and recovery. However, paired analysis revealed a subgroup of patients with transient presence of certain ANA patterns during acute COVID-19. Furthermore, patients with severe COVID-19 exhibited a high prevalence of ANCA during acute disease. These autoantibodies were quantitatively associated with higher SARS-CoV-2-specific antibody titers in COVID-19 patients and in vaccinated individuals, thus linking autoantibody production to increased antigen-specific humoral responses. Notably, the qualitative breadth of antibodies cross-reactive with other coronaviruses was comparable in ANA-positive and ANA- negative individuals during acute COVID-19. In autoantibody-positive patients, multiparametric characterization demonstrated an inflammatory signature during acute COVID-19 and alterations of the B cell compartment after recovery.ConclusionHighly sensitive indirect immunofluorescence assays revealed transient autoantibody production during acute SARS-CoV-2 infection, while the presence of autoantibodies in COVID-19 patients correlated with increased anti-viral humoral immune responses and inflammatory immune signatures.

This work was funded by the European League Against Rheumatism. SMMV and JMG are supported by Versus Arthritis (grant number 21755) and the NIHR Manchester Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health., Gwinnutt J.M., Wieczorek M., Cavalli G., Balanescu A., Bischoff-Ferrari H.A., Boonen A., De Souza S., De Thurah A., Dorner T.E., Moe R.H., Putrik P., Rodríguez-Carrio J., Silva-Fernández L., Stamm T., Walker-Bone K., Welling J., Zlatković-Švenda M.I., Guillemin F., Verstappen S.M.M.

IVIG preparations consisting of pooled IgG are increasingly used for the treatment of autoimmune diseases. IVIG is known to regulate the viability of immune cells, including neutrophils. We report that plasma-derived IgA efficiently triggers death of neutrophils primed by cytokines or TLR agonists. IgA-mediated programmed neutrophil death was PI3K-, p38 MAPK–, and JNK-dependent and evoked anti-inflammatory cytokines in macrophage cocultures. Neutrophils from patients with acute Crohn's disease, rheumatoid arthritis, or sepsis were susceptible to both IgA- and IVIG-mediated death. In contrast to IVIG, IgA did not promote cell death of quiescent neutrophils. Our findings suggest that plasma-derived IgA might provide a therapeutic option for the treatment of neutrophil-associated inflammatory disorders.

Bu çalışmada 22 yazar bulunmaktadır. Bu yazarlardan sadece Bursa Uludağ Üniversitesi mensuplarının girişleri yapılmıştır. In this review, we discuss recent publications on asthma and review the studies that have reported on the different aspects of the prevalence, risk factors and prevention, mechanisms, diagnosis, and treatment of asthma. Many risk and protective factors and molecular mechanisms are involved in the development of asthma. Emerging concepts and challenges in implementing the exposome paradigm and its application in allergic diseases and asthma are reviewed, including genetic and epigenetic factors, microbial dysbiosis, and environmental exposure, particularly to indoor and outdoor substances. The most relevant experimental studies further advancing the understanding of molecular and immune mechanisms with potential new targets for the development of therapeutics are discussed. A reliable diagnosis of asthma, disease endotyping, and monitoring its severity are of great importance in the management of asthma. Correct evaluation and management of asthma comorbidity/multimorbidity, including interaction with asthma phenotypes and its value for the precision medicine approach and validation of predictive biomarkers, are further detailed. Novel approaches and strategies in asthma treatment linked to mechanisms and endotypes of asthma, particularly biologicals, are critically appraised. Finally, due to the recent pandemics and its impact on patient management, we discuss the challenges, relationships, and molecular mechanisms between asthma, allergies, SARS-CoV-2, and COVID-19. Sanofi & Regeneron GlaxoSmithKline European Commission Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung Christine Kühne – Center for Allergy Research and Education

Background There is considerable variability across European patch test centres as to which allergens are included in local and national cosmetics series. Objectives To propose a standardised, evidence-based cosmetic series for Europe based on up-to-date analysis of relevant contact allergens. Methods We collated data from the European Surveillance System on Contact Allergies (ESSCA) from 2009-2018 to determine which cosmetic allergens produce a high yield of contact allergy. Contact allergens with a prevalence of >0.3% that were considered relevant were included. Rare contact allergens were excluded if deemed no longer relevant or added to a supplemental cosmetic series for further analysis. Results Sensitisation prevalence rates of 39 cosmetic contact allergens are tabulated. Thirty of these allergens yield >0.3% positive reactions and are therefore included in our proposed European Cosmetic Series. Six are considered no longer relevant and therefore excluded. Three are included in a supplementary European cosmetic series. An additional 9 allergens are included in either the core or supplemental European cosmetic series following literature review. Conclusion We have derived a potential European cosmetic series based upon the above methods. This will require ongoing investigation based upon the changing exposure profiles of cosmetic allergens as well as new and evolving substances. This article is protected by copyright. All rights reserved.