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• W4239487488 abstract "Binding of IgE to its high-affinity FcεRIα receptor subunit is often assumed to be consistent across IgEs. Thus many allergy studies that investigate the role of IgE in allergy were focused on Fab or Fc regions. Using the therapeutic antibodies pertuzumab and trastuzumab as models for studying the IgE molecule holistically, Lua et al (p 514) demonstrated the importance of whole-antibody investigations, as summarized in the figure below. Their study had the following key findings:•IgE V-regions can modulate the IgE Fc–FcεRIα interaction, but there was no notable effect on omalizumab binding to IgE Fc.•Interaction with protein A superantigen, which previously was reported to be caused by the VH3 framework, also was modulated by minor changes in V-region complementarity-determining regions. These results may explain the overrepresentation of specific IgE populations on sensitized effector cells in allergy pathogenesis. Therapeutic IgE antibodies in allergo-oncology can be engineered to avoid superantigen activation. Mutations in filaggrin (FLG) affect the risk of atopic dermatitis (AD), but filaggrin has not yet been targeted in therapy. Genome-wide studies have identified multiple loci associated with atopic disease, but translation of these results to the clinic remains challenging. In this issue, Elias et al (p 470) detail the following study approach and findings:•A region between genes on chromosome 11 is associated with atopic diseases. Thus, Elias et al assessed whether one adjacent candidate gene, EMSY, played a role in skin barrier formation using organotypic models and functional and molecular analyses.•EMSY knockdown led to improved barrier function and increased expression of skin barrier proteins, including filaggrin. Overexpression of EMSY in vitro had the opposite effect, and skin biopsy specimens of patients with AD showed increased EMSY expression. Previous work demonstrated a multiplicative effect of FLG and a variant on chromosome 11, increasing AD risk. These findings may provide a mechanism by which this synergistic risk occurs, and identify EMSY inhibition as a therapeutic strategy for skin barrier repair. The genetic basis of many cases of EBV-driven lymphoproliferation remains unknown. 4-1BB (CD137) is expressed on activated T cells and provides a costimulatory signal that enhances CD8+ T-cell survival, mitochondrial activity, and cytotoxicity, thereby promoting immunity against viruses and tumors. In this issue, Alosaimi et al (p 574) report 4-1BB deficiency as a novel cause of EBV-driven lymphoproliferation.•Two unrelated patients with EBV-driven lymphoproliferation shared a homozygous mutation in 4-1BB that abolished protein expression.•The patients' CD8+ T cells demonstrated reduced proliferation, impaired expression of IFN-γ and perforin, and diminished cytotoxicity to allogeneic and HLA-matched EBV-transformed B-cell lines.•4-1BB blockade abolished the cytotoxicity of normal CD8+ T cells to EBV-transformed B-cell lines, recapitulating the patients' defects. These findings demonstrate the clinical importance of 4-1BB in immune surveillance against EBV infection and EBV-driven lymphoproliferation. Milito et al (p 584) demonstrated that long-term prophylactic treatment with low-dose azithromycin (250 mg once daily, 3 consecutive days a week) decreased the frequency of annual episodes of respiratory exacerbation in primary immunodeficiency patients with frequent respiratory infections. The principal study features and findings were:•This is the first double-blind randomized trial demonstrating the efficacy and safety of long-term prophylactic treatment with azithromycin in patients with primary antibody deficiencies.•Long-term azithromycin prophylaxis reduced the need for additional antibiotic courses and risk of hospitalization and improved quality of life.•Low-dose azithromycin did not increase the rate of adverse events or the risk of macrolide-resistant organisms. Adding azithromycin prophylaxis to the treatment regimen of patients affected by primary antibody deficiencies with respiratory exacerbations should be considered. Loss of bronchoprotection (LOBP) with a regularly used long-acting β2-adrenergic receptor agonist (LABA) is well-documented. LOBP has been attributed to β2-adrenergic receptor (B2AR) downregulation, a process requiring farnesylation, which is inhibited by alendronate. In this issue, Cardet et al (p 416) sought to determine whether alendronate can reduce LABA-associated LOBP in inhaled corticosteroid–treated patients in a randomized, double-blind, placebo-controlled, parallel-design, proof-of-concept trial.•Seventy-eight participants with persistent asthma receiving 250 μg of fluticasone twice daily for 2 weeks were randomized to receive alendronate or placebo while initiating salmeterol for 8 weeks.•Thirty-eight percent of participants receiving alendronate and 33% receiving placebo developed LOBP (P = .81)•Changes in lung function and B2AR numbers and signaling were similar between those who did and did not experience LOBP. This study did not find evidence that alendronate reduced LABA-associated LOBP. LOBP appears to be less common than presumed in concomitant inhaled corticosteroid plus LABA–treated asthmatic patients. B2AR downregulation does not appear to be associated with the presence of LOBP. Severe allergic reactions and anaphylaxis to insect stings remain major clinical problems globally. Current immunotherapy approaches give multiple subcutaneous injections of escalating doses of bee venom to build up tolerance, which is costly and time-consuming. Heddle et al (p 504) report the following in patients with honeybee venom allergy:•Patients with bee venom allergy exhibited several distinct patterns of antibody response to immunotherapy, suggesting venom allergy may be a heterogeneous disorder with several different underlying mechanisms.•Formulating bee venom therapy with a plant-based polysaccharide adjuvant known as delta inulin or Advax both boosted and accelerated the appearance of bee venom–specific IgG4, a marker of successful allergy treatment, in the subjects being desensitized. This study offers hope that an adjuvant approach could enable faster and more effective allergy immunotherapy not only for bee sting allergy but also potentially for all allergies amenable to subcutaneous desensitization. Clinical trials are already underway to apply this same adjuvant approach to ant sting allergy immunotherapy." @default.
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• W4239487488 date "2019-08-01" @default.
• W4239487488 modified "2023-09-27" @default.
• W4239487488 title "The Editors’ Choice" @default.
• W4239487488 doi "https://doi.org/10.1016/j.jaci.2019.06.022" @default.
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