Background: Chronic rhinosinusitis with nasal polyposis (CRSwNP) is a type 2‐mediated inflammatory disease associated with significant clinical, social, and economic burdens and high unmet therapeutic need. Dupilumab, a fully human monoclonal antibody targeting the interleukin‐4 receptor α (IL‐4Rα) subunit, demonstrated efficacy and acceptable safety in CRSwNP and other type 2 diseases (eg, atopic dermatitis and asthma). We now report the local effects of dupilumab on type 2 inflammatory biomarkers in nasal secretions and nasal polyp tissues of patients with CRSwNP in a randomized, placebo‐controlled, phase 2 trial (NCT01920893).Methods: Cytokines, chemokines, and total immunoglobulin E (IgE) levels were measured using immunoassay techniques in nasal secretions and nasal polyp tissue homogenates of CRSwNP patients receiving dupilumab 300 mg or placebo weekly for 16 weeks.Results: With dupilumab, type 2 biomarker concentrations decreased in nasal secretions (least squares mean area under the curve from 0 to 16 weeks for the change from baseline) vs placebo for eotaxin‐3 (−30.06 vs −0.86 pg/mL; P = 0.0008) and total IgE (−7.90 vs −1.86 IU/mL; P = 0.022). Dupilumab treatment also decreased type 2 biomarker levels in nasal polyp tissues at Week 16 vs baseline for eosinophilic cationic protein (P = 0.008), eotaxin‐2 (P = 0.008), eotaxin‐3 (P = 0.031), pulmonary and activation‐regulated chemokine (P = 0.016), IgE (P = 0.023), and IL‐13 (P = 0.031).Conclusions: Dupilumab treatment reduced multiple biomarkers of type 2 inflammation in nasal secretions and polyp tissues of patients with CRSwNP, demonstrating that antagonism of IL‐4Rα signaling suppresses IL‐4‐/IL‐13‐dependent processes, such as mucosal IgE formation, as well as the expression of chemokines attracting inflammatory cells to the nasal mucosa.

In less than half a century, allergy, originally perceived as a rare disease, has become a major public health threat, today affecting the lives of more than 60 million people in Europe, and probably close to one billion worldwide, thereby heavily impacting the budgets of public health systems. More disturbingly, its prevalence and impact are on the rise, a development that has been associated with environmental and lifestyle changes accompanying the continuous process of urbanization and globalization. Therefore, there is an urgent need to prioritize and concert research efforts in the field of allergy, in order to achieve sustainable results on prevention, diagnosis and treatment of this most prevalent chronic disease of the 21^stcentury.The European Academy of Allergy and Clinical Immunology (EAACI) is the leading professional organization in the field of allergy, promoting excellence in clinical care, education, training and basic and translational research, all with the ultimate goal of improving the health of allergic patients. The European Federation of Allergy and Airways Diseases Patients’ Associations (EFA) is a non‐profit network of allergy, asthma and Chronic Obstructive Pulmonary Disorder (COPD) patients’ organizations. In support of their missions, the present EAACI Position Paper, in collaboration with EFA, highlights the most important research needs in the field of allergy to serve as key recommendations for future research funding at the national and European levels.Although allergies may involve almost every organ of the body and an array of diverse external factors act as triggers, there are several common themes that need to be prioritized in research efforts. As in many other chronic diseases, effective prevention, curative treatment and accurate, rapid diagnosis represent major unmet needs. Detailed phenotyping/endotyping stands out as widely required in order to arrange or re‐categorize clinical syndromes into more coherent, uniform and treatment‐responsive groups. Research efforts to unveil the basic pathophysiologic pathways and mechanisms, thus leading to the comprehension and resolution of the pathophysiologic complexity of allergies will allow for the design of novel patient‐oriented diagnostic and treatment protocols. Several allergic diseases require well‐controlled epidemiological description and surveillance, using disease registries, pharmacoeconomic evaluation, as well as large biobanks. Additionally, there is a need for extensive studies to bring promising new biotechnological innovations, such as biological agents, vaccines of modified allergen molecules and engineered components for allergy diagnosis, closer to clinical practice. Finally, particular attention should be paid to the difficult‐to‐manage, precarious and costly severe disease forms and/or exacerbations. Nonetheless, currently arising treatments, mainly in the fields of immunotherapy and biologicals, hold great promise for targeted and causal management of allergic conditions. Active involvement of all stakeholders, including Patient Organizations and policy makers are necessary to achieve the aims emphasized herein.

Summary: Neutrophils make up an essential part of the innate immune system, and are involved both in the initial responses to pathogens, and in orchestrating later immune responses. Neutrophils recognize pathogens through pattern‐recognition receptors (PRRs), which are activated by microbial motifs. The Nod‐like receptors (nucleotide‐binding domain leucine‐rich repeat containing family; NLRs) constitute a recently discovered group of PRRs whose role in the neutrophil immune responses is not yet characterized. The present study aimed to investigate the expression and function of NLRs in neutrophils. Neutrophils were isolated from human peripheral blood, and the presence of nucleotide‐binding oligomerization domain 1 (NOD1), NOD2 and NACHT‐LRR‐PYD‐containing protein 3 (NLRP3) was evaluated with flow cytometry and immunohistochemistry. The expression of NOD1, NOD2 and NLRP3 messenger RNA was determined using real‐time reverse transcription–polymerase chain reaction. Changes in neutrophil cytokine secretion, phenotype and migration following agonist‐induced activation were studied using enzyme‐linked immunosorbent assay, flow cytometry and a chemotaxis assay, respectively. No expression of NOD1 was found in isolated neutrophils and stimulation with the NOD1 ligand γ‐d‐glutamyl‐meso‐diaminopimelic acid induced no signs of activity. In contrast, a marked expression of NOD2 and NLRP3 was found. NOD2 activation with MurNAc‐l‐Ala‐d‐isoGln (MDP) resulted in interleukin‐8 secretion, CD62 ligand down‐regulation, CD11b up‐regulation and increased migration towards an inflammatory stimulus. NLRP3 activation with alum caused interleukin‐1β secretion and facilitated migration. Altogether, this suggests that NLRs may be a previously unknown pathway for neutrophil activation.

The human nasal epithelium is an important physical barrier, and a part of the innate immune defense that protect against pathogens. The epithelial cells recognize microbial components by pattern-recognition receptors (PRRs), and thereby trigger an immune response. Even though TLR3, TLR7, TLR9, RIG-I and MDA-5 are all known to respond to viral stimulation, their potential role in chronic airway inflammation triggered by local cytokine release remains to be established. mRNA and corresponding protein expression of TLR3, TLR7, TLR9, RIG-I and MDA-5 were analyzed in nasal biopsies and various upper airway epithelial cell lines using real-time reverse transcription PCR, immunohistochemistry and flow cytometry. Ligand induced, cytokine release, was evaluated with ELISA. Nasal biopsies were found to express TLR3, TLR7, TLR9, RIG-I and MDA-5, with the most abundant expression in the surface epithelium. These receptors were verified in primary human nasal epithelial cell (HNEC) as well as in the airway epithelial cell lines Detroit-562 and FaDu. Poly(I:C) (TLR3) and R-837 (TLR7) stimulation increased secretion of IL-6 and GM-CSF from the nasal mucosa and the epithelial cell lines. CpG (TLR9) stimulation caused release of IL-8 in the nasal mucosa and in FaDu. Poly(I:C)/LyoVec (RIG-I/MDA-5) stimulation activated the secretion of IFN-β in the nasal mucosa. A corresponding release was also detected from HNEC and Detroit-562. The nasal epithelium has the ability to recognize viral intrusion through TLR and RLR receptors, and the subsequent response might have a role in exacerbation of inflammatory diseases like allergic rhinitis and chronic rhinosinusitis.

Transcriptional profiling pinpoints the heterogeneity of T helper cells in human nasal polyps at the clonal level.