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September 2020

Nucleic acid approaches to antibody-based therapeutics for COVID-19: A perspective

Elizabeth Parzych, PhD, and David B. Weiner, PhD

Dissecting the mechanism of action of intravenous immunoglobulin in human autoimmune disease: Lessons from therapeutic modalities targeting Fcg receptors

Anthony Shock, PhD; David Humphreys, PhD; and Falk Nimmerjahn, PhD


Since the first description of the administration of high doses of pooled serum IgG, also referred to as intravenous IgG (IVIg) therapy, as being able to ameliorate various autoimmune diseases, researchers have been investigating which molecular and cellular pathways underlie IVIg activity. Apart from trying to understand the obvious conundrum that IgG can trigger both autoimmune pathology and resolution of inflammation, the rapidly expanding use of IVIg has led to a lack of availability of this primary blood product, providing a strong rationale for developing recombinant alternatives. During the last decade, a tremendous number of novel insights into IVIg activity brought the goal of replacing IVIg within reach, at least in select indications, and has led to the initiation of several clinical trials. At the forefront of this effort is the modulation of autoantibody half-life and blocking access of autoantibodies to fragment cystallizable g receptors (Fcg receptors). In this rostrum article, we will briefly discuss current models of IVIg activity, followed by a more specific focus on novel therapeutic avenues that are entering the clinic and may replace IVIg in the future. (J Allergy Clin Immunol 2020;146:492-500.)

Frequency of food allergy in school-aged children in eight European countries—The EuroPrevall-iFAAM birth cohort

Linus Grabenhenrich; Valérie Trendelenburg; Johanna Bellach; Songül Yürek; Andreas Reich; Ana Fiandor; Daniela Rivero; Sigurveig Sigurdardottir; Michael Clausen; Nikolaos G. Papadopoulos; Paraskevi Xepapadaki; Aline B. Sprikkelman; Bianca Dontje; Graham Roberts; Kate Grimshaw; Marek L. Kowalski; Marcin Kurowski; Ruta Dubakiene; Odilija Rudzeviciene; Montserrat Fernández-Rivas; Philip Couch; Serge A. Versteeg; Ronald van Ree; Clare Mills; Thomas Keil; Kirsten Beyer


Background: The prevalence of food allergy (FA) among European school children is poorly defined. Estimates have commonly been based on parent-reported symptoms. We aimed to estimate the frequency of FA and sensitization against food allergens in primary school children in eight European countries.

Methods: A follow-up assessment at age 6-10 years of a multicentre European birth cohort based was undertaken using an online parental questionnaire, clinical visits including structured interviews and skin prick tests (SPT). Children with suspected FA were scheduled for double-blind, placebo-controlled oral food challenges (DBPCFC).

Results: A total of 6105 children participated in this school-age follow-up (57.8% of 10 563 recruited at birth). For 982 of 6069 children (16.2%), parents reported adverse reactions after food consumption in the online questionnaire. Of 2288 children with parental face-to-face interviews and/or skin prick testing, 238 (10.4%) were eligible for a DBPCFC. Sixty-three foods were challenge-tested in 46 children. Twenty food challenges were positive in 17 children, including seven to hazelnut and three to peanut. Another seventy-one children were estimated to suffer FA among those who were eligible but refused DBPCFC. This yielded prevalence estimates for FA in school age between 1.4% (88 related to all 6105 participants of this follow-up) and 3.8% (88 related to 2289 with completed eligibility assessment).

Interpretation: In primary school children in eight European countries, the prevalence of FA was lower than expected even though parents of this cohort have become especially aware of allergic reactions to food. There was moderate variation between centres hampering valid regional comparisons.

Neonatal Fc receptor in human immunity: Function and role in therapeutic intervention

Dhavalkumar D. Patel, MD, PhD and James B. Bussel, MD


The humoral immune response provides specific, long-lived protection against invading pathogens, via immunoglobulin production and other memory functions. IgG, the most abundant immunoglobulin isotype, has the longest half-life and protects against bacterial and viral infections. The neonatal Fc receptor (FcRn) transports IgG across barriers, for example, the placenta, enhancing fetal humoral immunity to levels similar to their mothers’. Importantly, FcRn, by protecting IgG from intracellular degradation, results in an approximately 21-day circulating IgG half-life and high plasma levels; similarly, FcRn recycles albumin and is the portal of entry for enteric cytopathic human orphan (echo) virus infection. Dysregulated immune responses may lead to antibodies against self-antigens (autoantibodies), resulting in organ-specific or systemic autoimmune diseases. Autoantibody-mediated diseases have been treated by nonspecific immunoglobulin-lowering/ modulating therapies, including immunoadsorption, plasma exchange, and high-dose intravenous immunoglobulin. However, targeting FcRn with specific inhibitors results in reduction in only IgG levels. The effectiveness of FcRn inhibitors in autoimmune diseases, including myasthenia gravis and immune thrombocytopenia, provides further evidence that IgG is a primary driver in these autoantibody-mediated diseases. We describe the role of FcRn in human biology, including insights that clinical testing of FcRn inhibitors have provided into FcRn biology and autoimmune disease mechanisms, allowing fact-based speculation on their therapeutic potential. (J Allergy Clin Immunol 2020;146:467-78.)

The effects of climate change on respiratory allergy and asthma induced by pollen and mold allergens

Gennaro D’Amato; Herberto Jose Chong-Neto; Olga Patricia Monge Ortega; Carolina Vitale; Ignacio Ansotegui; Nelson Rosario; Tari Haahtela; Carmen Galan; Ruby Pawankar; Margarita Murrieta-Aguttes; Lorenzo Cecchi; Christian Bergmann; Erminia Ridolo; German Ramon; Sandra Gonzalez Diaz; Maria D’Amato; Isabella Annesi-Maesano


The impact of climate change on the environment, biosphere, and biodiversity has become more evident in the recent years. Human activities have increased atmospheric concentrations of carbon dioxide (CO2) and other greenhouse gases. Change in climate and the correlated global warming affects the quantity, intensity, and frequency of precipitation type as well as the frequency of extreme events such as heat waves, droughts, thunderstorms, floods, and hurricanes. Respiratory health can be particularly affected by climate change, which contributes to the development of allergic respiratory diseases and asthma. Pollen and mold allergens are able to trigger the release of pro-inflammatory and immunomodulatory mediators that accelerate the onset the IgE-mediated sensitization and of allergy. Allergy to pollen and pollen season at its beginning, in duration and intensity are altered by climate change. Studies showed that plants exhibit enhanced photosynthesis and reproductive effects and produce more pollen as a response to high atmospheric levels of carbon dioxide (CO2). Mold proliferation is increased by floods and rainy storms are responsible for severe asthma. Pollen and mold allergy is generally used to evaluate the interrelation between air pollution and allergic respiratory diseases, such as rhinitis and asthma. Thunderstorms during pollen seasons can cause exacerbation of respiratory allergy and asthma in patients with hay fever. A similar phenomenon is observed for molds. Measures to reduce greenhouse gas emissions can have positive health benefits.

The Immunology of Multisystem Inflammatory Syndrome in Children with COVID-19

Camila Rosat Consiglio; Nicola Cotugno; Fabian Sardh; Christian Pou; Donato Amodio; Lucie Rodriguez; Ziyang Tan; Sonia Zicari; Alessandra Ruggiero; Giuseppe Rubens Pascucci; Veronica Santilli; Tessa Campbell; Yenan Bryceson; Daniel Eriksson; Jun Wang; Alessandra Marchesi; Tadepally Lakshmikanth; Andrea Campana; Alberto Villani; Paolo Rossi; the CACTUS Study Team, Nils Landegren; Paolo Palma; and Petter Brodin


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is typically very mild and often asymptomatic in children. A complication is the rare multisystem inflammatory syndrome in children (MISC) associated with COVID-19, presenting 4–6 weeks after infection as high fever, organ dysfunction, and strongly elevated markers of inflammation. The pathogenesis is unclear but has overlapping features with Kawasaki disease suggestive of vasculitis and a likely autoimmune etiology. Weapply systems-level analyses of blood immune cells, cytokines, and autoantibodies in healthy children, children with Kawasaki disease enrolled prior to COVID-19, children infected with SARS-CoV-2, and children presenting with MIS-C. We find that the inflammatory response in MIS-C differs from the cytokine storm of severe acute COVID-19, shares several features with Kawasaki disease, but also differs from this condition with respect to T cell subsets, interleukin (IL)-17A, and biomarkers associated with arterial damage. Finally, autoantibody profiling suggests multiple autoantibodies that could be involved in the pathogenesis of MIS-C.

The need for clean air: The way air pollution and climate change affect allergic rhinitis and asthma

Ibon Eguiluz-Gracia; Alexander G. Mathioudakis; Sabine Bartel; Susanne J. H. Vijverberg; Elaine Fuertes; Pasquale Comberiati; Yutong Samuel Cai; Peter Valentin Tomazic; Zuzana Diamant; Jørgen Vestbo; Carmen Galan; Barbara Hoffmann


Air pollution and climate change have a significant impact on human health and wellbeing and contribute to the onset and aggravation of allergic rhinitis and asthma among other chronic respiratory diseases. In Westernized countries, households have experienced a process of increasing insulation and individuals tend to spend most of their time indoors. These sequelae implicate a high exposure to indoor allergens (house dust mites, pets, molds, etc), tobacco smoke, and other pollutants, which have an impact on respiratory health. Outdoor air pollution derived from traffic and other human activities not only has a direct negative effect on human health but also enhances the allergenicity of some plants and contributes to global warming. Climate change modifies the availability and distribution of plant- and fungal-derived allergens and increases the frequency of extreme climate events. This review summarizes the effects of indoor air pollution, outdoor air pollution, and subsequent climate change on asthma and allergic rhinitis in children and adults and addresses the policy adjustments and lifestyle changes required to mitigate their deleterious effects.

The pseudoallergen receptor MRGPRX2 on peripheral blood basophils and eosinophils: Expression and function

Bettina Wedi; Manuela Gehring; Alexander Kapp


Background: Mas-related G protein-coupled receptor X2 (MRGPRX2) is regarded as a mast cell-specific receptor mediating non–IgE-dependent activation. We aimed to investigate whether human basophils and eosinophils express functional MRGPRX2.

Methods: Flow cytometry, immunocytochemistry, immunofluorescence, Western blot, and RT-PCR were performed in highly purified peripheral blood basophils and eosinophils of atopic and nonatopic donors. To assess functional activity, fluorescent avidinbased degranulation assay, calcium mobilization, cytokine production in supernatants, assessment of viability/apoptosis, and tricolor granulocyte activation test were used.

Results: MRGPRX2 was significantly expressed by basophils and eosinophils but not neutrophils. Functional capacity was shown by anti-MRGPRX2 mAb-induced calcium influx and concentration-dependent induction of degranulation. Sequential stimulation in the calcium mobilization assay gave no evidence for desensitization or receptor internalization. Anti-MRGPRX2 mAb significantly promoted survival. Inhibition of apoptosis could be due to released IL-3, IL-5, and GM-CSF found in supernatants. Shortterm incubation with IL-3 dose-dependently upregulated MRGPRX2 expression in both, stimulation for 24 hours with anti-IgE, C5a, fMLP, and IL-3 in basophils and by IL-3, IL-5, and IL-33 in eosinophils. Among known mast cell MRGPRX2 agonists ciprofloxacin but not PMX-53 was functional on basophils and eosinophils. In basophils of allergic subjects, tricolor granulocyte activation test using grass pollen demonstrated MRGPRX2 upregulation associated with degranulation and CD63 expression.

Conclusion: Unraveling the regulation and signaling mechanisms of MRGPRX2 on basophils and eosinophils might enable the development of new therapeutic strategies to prevent or inhibit allergic and nonallergic hypersensitivity. Moreover, addressing MRGPRX2 might have potential for diagnostic purposes in (drug) hypersensitivity.

The role of IL-6 and other mediators in the cytokine storm associated with SARS-CoV-2 infection

Ana Copaescu, MD, FRCPC; Olivia Smibert, MBBS, FRACP; Andrew Gibson, PhD; Elizabeth J. Phillips, MD, FRCPC, FRACP; and Jason A. Trubiano, MBBS, BBiomedSci, PhD, FRACP


The coronavirus disease 2019 pandemic caused by severe acute respiratory syndrome coronavirus 2 presents with a spectrum of clinical manifestations from asymptomatic or mild, self-limited constitutional symptoms to a hyperinflammatory state (‘‘cytokine storm’’) followed by acute respiratory distress syndrome and death. The objective of this study was to provide an evidence-based review of the associated pathways and potential treatment of the hyperinflammatory state associated with severe acute respiratory syndrome coronavirus 2 infection. Dysregulated immune responses have been reported to occur in a smaller subset of those infected with severe acute respiratory syndrome coronavirus 2, leading to clinical deterioration 7 to 10 days after initial presentation. A hyperinflammatory state referred to as cytokine storm in its severest form has been marked by elevation of IL-6, IL-10, TNF-a, and other cytokines and severeCD41 andCD81 T-cell lymphopenia and coagulopathy. Recognition of at-risk patients could permit early institution of aggressive intensive care and antiviral and immune treatment to reduce the complications related to this proinflammatory state. Several reports and ongoing clinical trials provide hope that available immunomodulatory therapies could have therapeutic potential in these severe cases. This review highlights our current state of knowledge of immune mechanisms and targeted immunomodulatory treatment options for the current coronavirus disease 2019 pandemic. (J Allergy Clin Immunol 2020;146:518-34.)

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