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Immunoglobulin E (IgE) is a well-known key factor in allergic airway disease; however, its central role in non-allergic airway inflammation is often underestimated. In some airway diseases, IgE is produced as a result of allergic sensitization. However, in others, IgE production occurs despite the lack of a specific allergen. Although multiple pathways contribute to the production of IgE in airway disease, it is its activity in mediating the inflammatory response that is associated with disease. Therefore, an understanding of IgE as the unifying component of upper and lower airway diseases has important implications for both diagnosis and treatment. Understanding the role of IgE in each upper and lower airway disease highlights its potential utility as a diagnostic marker and therapeutic target. Further classification of these diseases by whether they are IgE mediated or non-IgE mediated, rather than by the existence of an underlying allergic component, accounts for both systemic and localized IgE activity. Improvements in diagnostic methodologies and standardization of clinical practices with this classification in mind can help identify patients with IgE-mediated diseases. In doing so, this group of patients can receive optimal care through targeted anti-IgE therapeutics, which have already demonstrated efficacy across numerous IgE-mediated upper and lower airway diseases., (© 2021. The Author(s).)

Background: House dust mites (HDMs) are among the most important allergen sources containing many different allergenic molecules. Analysis of patients from a double-blind, placebo-controlled allergen-specific immunotherapy (AIT) study indicated that patients may benefit from AIT to different extents depending on their molecular sensitization profiles., Objective: Our aim was to investigate in a real-life setting whether stratification of patients with HDM allergy according to molecular analysis may enhance AIT success., Methods: Serum and nasal secretion samples from patients with HDM allergy (n = 24) (at baseline, 7, 15, 33, and 52 weeks) who had received 1 year of treatment with a well-defined subcutaneous AIT form (Alutard SQ 510) were tested for IgE and IgG reactivity to 15 microarrayed HDM allergen molecules with ImmunoCAP Immuno-solid-phase Allergen Chip technology. IgG subclass levels to allergens and peptides were determined by ELISA, and IgG blocking was assessed by basophil activation. In vitro parameters were related to reduction of symptoms determined by combined symptom medication score and visual analog scale score., Results: Alutard SQ 510 induced protective IgG mainly against Dermatophagoides pteronyssinus (Der p) 1 and Der p 2 and to a lesser extent to Der p 23, but not to the other important allergens such as Der p 5, Der p 7, and Der p 21, showing better clinical efficacy in patients sensitized only to Der p 1 and/or Der p 2 as compared with patients having additional IgE specificities., Conclusion: Stratification of patients with HDM allergy according to molecular sensitization profiles and molecular monitoring of AIT-induced IgG responses may enhance the success of AIT., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: In humans, both basophils and dendritic cells (DCs) express the high-affinity IgE receptor (FcεRI)., Objective: To gain more insight into the relation between serum IgE levels and FcεRI expression and IgE binding by DCs and basophils in house dust mite (HDM) allergy and during subcutaneous immunotherapy (SCIT)., Methods: We measured FcεRI, IgE and HDM allergen on DCs (conventional type 2 DCs, cDC2s; plasmacytoid dendritic cells, pDCs) and basophils by flow cytometry in 22 non-allergic vs 52 allergic subjects and upon HDM SCIT in 28 allergic subjects. IgE levels were measured in serum., Results: Serum IgE correlated differentially with FcεRI expression and IgE binding depending on cell type and allergic status. In non-allergic subjects, FcεRI/IgE surface densities increased with serum IgE to a significantly stronger degree on basophils compared to cDC2s. By contrast, in allergic subjects FcεRI/IgE surface densities increased with serum IgE to a slightly stronger degree on cDC2s compared to basophils. In addition, the data set suggests sequential loading of IgE onto FcεRI expressed by these cells (basophils>cDC2s>pDCs). Finally, HDM SCIT induced a temporary increase in serum IgE, which was paralleled by a peak in FcεRI and IgE on DCs, but not on basophils., Conclusions & Clinical Relevance: This study provides a comprehensive insight into the relation between serum IgE and FcεRI/IgE on basophils and DC subsets. The novel finding that HDM SCIT induces a temporary increase in FcεRI expression on DCs, but not on basophils, can be an incentive for future research on the potential tolerogenic role of IgE/FcεRI signalling in DCs in the setting of allergen immunotherapy., (© 2018 John Wiley & Sons Ltd.)

Background: Administration of the therapeutic anti-IgE antibody omalizumab to patients induces strong increases in IgE antibody levels., Objective: To investigate the effect of intranasal administration of major birch pollen allergen Bet v 1, omalizumab or placebo on the levels of total and allergen-specific IgE in patients with birch pollen allergy., Methods: Based on the fact that intranasal allergen application induces rises of systemic allergen-specific IgE, we performed a double-blind placebo-controlled pilot trial in which birch pollen allergic subjects were challenged intranasally with omalizumab, placebo or birch pollen allergen Bet v 1. Total and allergen-specific IgE, IgG and basophil sensitivity were measured before and 8 weeks after challenge. For control purposes, total, allergen-specific IgE levels and omalizumab-IgE complexes as well as specific IgG levels were studied in subjects treated subcutaneously with either omalizumab or placebo. Effects of omalizumab on IgE production by IL-4/anti-CD40-treated PBMCs from allergic patients were studied in vitro., Results: Intranasal challenge with Bet v 1 induced increases in Bet v 1-specific IgE levels by a median of 59.2%, and this change differed significantly from the other treatment groups (P = .016). No relevant change in allergen-specific and total IgE levels was observed in subjects challenged with omalizumab. Addition of omalizumab did not enhance IL-4/anti-CD40-induced IgE production in vitro. Significant rises in total IgE (mean IgE before: 131.83 kU/L to mean IgE after: 505.23 kU/L) and the presence of IgE-omalizumab complexes were observed after subcutaneous administration of omalizumab., Conclusion: Intranasal administration of allergen induced rises of allergen-specific IgE levels, whereas intranasal administration of omalizumab did not enhance systemic total or allergen-specific IgE levels., (© 2017 The Authors. Allergy Published by John Wiley & Sons Ltd.)

Local allergic rhinitis (LAR) is characterized by the presence of a nasal Th2 inflammatory response with local production of specific IgE antibodies and a positive response to a nasal allergen provocation test (NAPT) without evidence of systemic atopy. The prevalence has been shown to be up to 25% in subjects affected with rhinitis with persistence, comorbidity and evolution similar to allergic rhinitis. LAR is a consistent entity that does not evolve to allergic rhinitis with systemic atopy over time although patients have significant impairment in quality of life and increase in the severity of nasal symptoms over time. Lower airways can be also involved. The diagnosis of LAR is based mostly on demonstration of positive response to NAPT and/or local synthesis of specific IgE. Allergens involved include seasonal or perennial such as house dusts mites, pollens, animal epithelia, moulds (alternaria) and others. Basophils from peripheral blood may be activated by the involved allergens suggesting the spill over of locally synthesized specific IgE to the circulation. LAR patients will benefit from the same treatment as allergic patients using antihistamines, inhaled corticosteroids and IgE antagonists. Studies on immunotherapy are ongoing and will determine its efficacy in LAR in terms of symptoms improvement and evolution of the natural course of the disease., (© 2014 John Wiley & Sons Ltd.)

Background: Chronic rhinosinusitis with nasal polyps (NP) and allergic rhinitis (AR) is characterized by local Th2 inflammation and up-regulation of IgE; however, IgE in NP is 'polyclonal' and allergen specific, whereas IgE in AR is 'oligoclonal' and allergen specific. Germinal center (GC) reactions occur in AR, while only the formation of GC-like structures in NP is described. The aim of this study was to investigate the involvement of local IgE production, class switch recombination, and receptor revision in NP., Methods: We compared the levels of local IgE, germline gene transcripts, and mature Ig mRNA expression, recombination activating gene (RAG1 and RAG2), key markers of Th2 inflammation, and GC reactions in NP tissue vs AR and control tissue. Nasal mucosa was immunostained for the co-expression of RAG1 and RAG2 in B cells, plasma cells, and T cells, using dual or triple immunofluorescence (IF)., Results: In NP, local IgE level and key markers of local class switching are increased compared with AR and normal controls (NC). In NP, switch circle transcripts reveal ongoing local class switch recombination to IgE. Up to 30% of B cells, plasma cells, and T cells in nasal polyps re-express both RAG1 and RAG2, required for receptor revision. RAG1 and RAG2 mRNA concentrations are increased in NP and correlated with the magnitude of inflammation and the presence of S. aureus enterotoxin (superantigen)-specific IgE in the nasal polyp mucosa., Conclusion: Our results provide the first evidence of local receptor revision and class switching to IgE, and B-cell differentiation into IgE-secreting plasma cells in NP., (© 2012 John Wiley & Sons A/S.)

Allergic asthma and allergic rhinitis/conjunctivitis are characterized by a T(H)2-dominated immune response associated with increased serum IgE levels in response to inhaled allergens. Because IgE is a key player in the induction and maintenance of allergic inflammation, it represents a prime target for therapeutic intervention. However, our understanding of IgE biology remains fragmentary. This article puts together our current knowledge on IgE in allergic airway diseases with a special focus on the identity of IgE-secreting cells ("who"), their location ("where"), and the circumstances in which they are induced ("when"). We further consider the therapeutic implications of the insights gained., (Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: Staphylococcus aureus may modify airway disease by inducing local formation of polyclonal IgE antibodies (abs), the role of which is unknown., Methods: Nasal mucosal tissue and serum was obtained from 12 allergic rhinitis (AR) and 14 nasal polyp (NP) subjects. Skin prick tests were performed, and total and specific IgE abs to inhalant allergens and enterotoxin B were determined in serum and tissue. Tissue fragments were stimulated with anti-IgE, enterotoxin B, or grass and house dust mite allergens in different concentrations for 30 min. RBL SX38 cells were sensitized with NP homogenates containing IgE and stimulated with grass pollen extracts., Results: In AR patients, degranulation of tissue mast cells upon allergen exposure and presence of specific IgE to inhalant allergens corresponded in almost all cases. Total IgE concentrations in serum and mucosal tissue homogenates highly correlated. In contrast, in NP patients, reactivity of tissue mast cells upon allergen exposure and presence of specific IgE to inhalant allergens or Staphylococcus aureus enterotoxin B corresponded for tissue, but not for serum. Total IgE was significantly higher in tissue compared to serum and failed to show correlation. Tissue IgE to grass pollen was functional to degranulate RBL cells., Conclusion: We here demonstrate that mucosal IgE abs in NP tissue are functional and able to activate mast cells; specific IgE abs in NP tissue can be found independently of their presence in serum. We postulate that superantigen-induced polyclonal IgE in airway disease contributes to chronic inflammation by continuously activating mast cells., (© 2010 John Wiley & Sons A/S.)

Although the etiology of nasal polyposis is still not revealed, insights in the pathogenesis have largely expanded over the last years. Usually nasal polyps occur in adults, are bilateral and are characterized by a manifest tissue eosinophilia. Deposition of plasma-proteins (albumin), potentially driven by subepithelial eosinophilic inflammation, seems to be an early and key pathogenic factor in the development of nasal polyps. Accumulation and activation of eosinophils is favoured by low TGF-beta1 concentrations and overproduction of IL-5 and eotaxin. In nasal polyps high IgE concentrations are measured. Our findings indicate that this IgE is produced locally. Total IgE and the expression of specific IgE is unrelated to skin prick tests, but correlates with the degree of eosinophilia. In addition, we demonstrated the organisation of secondary lymphoid tissue in nasal polyps and a polyclonal hyper-immunoglobulinemia E, associated with the presence of IgE specific to Staph. aureus enterotoxins (SAE), colonization with Staph. aureus and increased eosinophilic inflammation in a relevant subgroup of NP patients (about 50%). In about half of the nasal polyps we thus find a local immune response against SAE. SAE can hereby act as conventional allergens, triggering T- en B-cells to produce sIgE against SAE. On the other hand, SAE can also act as superantigens and induce polyclonal B-cell activation and hyper-immunoglobulinemia. In addition, the presence of IgE antibodies to SAEs seems to be associated with the severity of asthma and nasal polyposis disease. Nasal and oral corticosteroids are currently the standard treatment for NP. This treatment however, is not always sufficient and oral corticosteroids have several side effects. Often surgery is required, which in turn is not free of complications and recurrencies. Increasing insights in the pathophysiology of NP opens perspectives for new pharmacological treatment options, with eosinophilic inflammation, IgE and Staph. aureus as potential targets.

Background: Bilateral nasal polyposis (NP) is characterized by high concentrations of IgE in NP tissue, which show no relation to the atopic status. We aimed to study the relationship between systemic and local IgE formation, nasal carriage of Staphylococcus aureus and nasal polyposis., Methods: In serum and nasal tissue homogenates from 24 NP patients and 12 controls, we determined concentrations of total IgE and IgE antibodies to inhalant allergens and S. aureus enterotoxins (SAEs; A,B,C,D,E,TSST) by ImmunoCAP. Tissue cryosections were stained for CD3, CD20, CD38, CD23, FcepsilonRI, IgE and SEA/SEB., Results: We demonstrated a higher incidence of S. aureus colonization (17/24) and IgE antibodies to SAEs in NP tissue (12/24) compared with controls (3/12 and 0/12, respectively). Total IgE and IgE antibodies in serum and NP tissue were dissociated because of local polyclonal IgE formation in NP tissue. Staining of NP tissue revealed follicular structures characterized by B and T cells, and lymphoid accumulations with diffuse plasma cell infiltration., Conclusions: We demonstrated the organization of secondary lymphoid tissue in polyp tissue and a polyclonal hyper-immunoglobulinemia E associated with the presence of IgE antibodies to SAEs, colonization with S. aureus, and tissue eosinophilia in a relevant subgroup of polyp patients.

Recent evidence suggests that Staphylococcus aureus enterotoxins (SAEs) could modify airway disease by acting as superantigens, an immune response that can be monitored by detection of IgE antibodies to SAEs. We studied the expression of total IgE and specific IgE to SAEs using the Uni-CAP system in healthy controls, smokers without COPD and COPD patients. Only 1/10 controls (10%) and 1/16 smokers (6.3%) had IgE to SAEs compared to 7/18 patients with stable COPD (38.9%) and 21/54 patients with exacerbated COPD (38.9%). The IgE levels to SAEs of the patients with stable COPD (0.18 [0.05-26.2]kUA/l) and the patients with exacerbated COPD (0.09 [0.05-18.6]kUA/l) were significantly higher than those of smokers (n = 16; 0.05 [0.05-0.82]kUA/l) and controls (n = 11; 0.05 [0.05 0.9]kUA/l, P<0.05). IgE to SAEs decreased significantly in the exacerbated patients during hospitalization (0.13 [0.05-18.3] vs. 0.05 [0.05-11]kUA/l, P<0.001) going along with a significant increase in FEV1 (38.1 [16.9-79.5] vs. 51.6 [15-80]%predicted, P<0.001). Similarly to severe asthma, we found significantly elevated IgE to SAE in COPD patients. Our data for the first time suggest differences between healthy subjects, smokers and patients with established COPD regarding the role of bacterial products and point to a possible disease modifying role of SAEs.

Background: Nasal polyposis is a multifactorial disease characterized by a chronic eosinophilic inflammation of the sinus mucosa, often associated with asthma and aspirin sensitivity. We have recently shown that the presence of IgE antibodies to Staphylococcus aureus enterotoxins (SAEs) was related to the severity of eosinophilic inflammation in nasal polyp tissue. In this study, we therefore aimed to determine, whether aspirin sensitivity was related to an immune response to SAEs, and how both criteria would be related to eosinophilic inflammation., Methods: 40 subjects with nasal polyposis (NP) were classified as aspirin-sensitive (n=13, ASNP) or aspirin-tolerant (n=27, ATNP) based on a bronchial aspirin challenge test. Homogenates prepared from nasal polyp tissue and inferior nasal turbinates from healthy subjects (n=12) were analyzed for concentrations of IL-5 by enzyme immunoassay and for ECP, total and IgE to a mix of SAEs (A, C, TSST-1) using the ImmunoCAP system., Results: Concentrations of IL-5, ECP, total IgE, and IgE to an SAE mix were significantly increased in ASNP compared with ATNP patients and controls. In addition, a subgroup analysis showed an increase in eosinophilic markers in ATNP-SAE(+) compared to ATNP-SAE(-). This relationship, however, was not found in ATNP-SAE(+) and ATNP-SAE(-) subjects, indicating that SAE immune response is overlapped or not relevant in this condition., Conclusions: Aspirin sensitivity was associated with increased concentrations of eosinophil-related mediators, as well as IgE antibodies to SAEs in nasal polyp tissue. However, a direct impact of S. aureus could not be established. It seems that aspirin sensitivity and immune reactions to SAEs are independently related to eosinophilic inflammation., (Copyright 2004 S. Karger AG, Basel)

Background: Nasal polyps (NPs) are characterized by eosinophilic inflammation and often coexist with asthma. However, the role of atopy and IgE in NP pathogenesis is unclear., Objective: We sought to determine whether there is an association between total and specific IgE to a variety of allergens in polyp and nonpolyp tissue and markers of eosinophilic inflammation or skin test results., Methods: Homogenates were prepared from nasal tissue of 20 patients with NPs and 20 patients without NPs and analyzed for concentrations of IL-5, IL-4, eotaxin, leukotriene (LT) C4/D4/E4, sCD23, and histamine (ELISA). Eosinophil cationic protein (ECP), tryptase, and total and specific IgE for inhalant allergens and Staphylococcus aureus enterotoxins were measured (ImmunoCAP)., Results: The concentrations of total IgE, IL-5, eotaxin, ECP, LTC4/D4/E4, and sCD23 were significantly higher in NP tissue compared with nonpolyp tissue. Total IgE was significantly correlated to IL-5, ECP, LTC4/D4/E4, and sCD23 and to the number of eosinophils in NPs. On the basis of the presence of specific IgE antibodies in tissue, 3 NP groups were defined. NP group 1 demonstrated no measurable specific IgE, and NP group 2 selected specific IgE. The third group demonstrated a multiclonal specific IgE, including IgE to S aureus enterotoxins, a high total IgE level, and a high prevalence of asthma., Conclusions: These studies suggest that there is an association between increased levels of total IgE, specific IgE, and eosinophilic inflammation in NPs, which may be of relevance in the pathophysiology of nasal polyposis. Similarly, the presence of specific IgE to staphylococcal enterotoxins A and B also points to a possible role of bacterial superantigens.

Chronic rhinosinusitis (CRS) is a heterogeneous group of inflammatory diseases of the nasal and paranasal cavities either accompanied by polyp formation (CRSwNP) or without polyps (CRSsNP). CRSsNP and CRSwNP are prevalent medical conditions associated with substantial impaired quality of life, reduced workplace productivity, and serious medical treatment costs. Despite recent research evidence that contributes to further unveiling the pathophysiology of these chronic airway conditions, the cause remains poorly understood and appears to be multifactorial. A diverse spectrum of alterations involving histopathology, inflammatory cell and T-cell patterns, remodeling parameters (eg, TGF-β), eicosanoid and IgE production, microorganisms, and epithelial barrier malfunctions is reported in the search to describe the pathogenesis of this heterogeneous group of upper airway diseases. Furthermore, novel evidence indicates considerable heterogeneity within the CRSwNP subgroup determining the risk of comorbid asthma. The characterization of specific disease subgroups is a challenging scientific and clinical task of utmost importance in the development of diagnostic tools and application of individualized treatments. This review focuses on recent evidence that sheds new light on our current knowledge regarding the inflammatory process of CRS to further unravel its pathogenesis. [ABSTRACT FROM AUTHOR]

Background: Staphylococcus aureus–secreted enterotoxins (SEs) may be involved in the pathophysiology of atopic diseases. Objective: We investigated the role of SEs in allergic diseases during early childhood (using the mixture of SE-specific IgEs [SE-mix] as a marker). Methods: Children (N = 510) were followed from birth to age 5 years (repeated questionnaires, IgE to inhalant and food allergens, lung function [spirometry, plethysmography], airway reactivity [dry air challenge]). We measured SE-mix specific IgE (SE-A, SE-C, toxic shock syndrome toxin 1) by using fluorescence immunoassay. Results: We found no association between rhinitis and SE-mix sensitization. Children with eczema were more frequently SE-mix–sensitized than children without (17.4% vs 8.3%; P = .02). SE-mix sensitization rate increased significantly with increasing eczema severity (no eczema, mild, moderate/severe: 8.3%, 14.8%, 42.9%; P = .003) and remained independently associated with eczema in a multivariate model adjusting for total IgE (adjusted odds ratio, 2.19; 95% CI, 1.05-4.56; P = .04). SE-mix sensitization was associated with current wheeze in the univariate but not the multivariate model. Among wheeze phenotypes, persistent wheezers were most commonly sensitized to SE-mix (never, transient, late-onset, persistent: 8.5%, 3.8%, 7.7%, 17.6%; P = .05). Among wheezers, those SE-mix–sensitized had significantly higher airway reactivity compared with those nonsensitized (mean FEV1 change, mL [95% CI]: −59 [−121, 3] vs 19 [−10.2, 48.9]; P = .04), with little difference after adjusting for atopy. Conclusion: We found differences in SE-mix IgE antibodies between healthy 5-year-old children and children with eczema and wheeze. The proportion of patients sensitized to SE-mix increases with increasing disease severity. Clinical implications: Staphylococcal enterotoxins are potential modifiers of childhood wheeze and eczema. [Copyright &y& Elsevier]

Bilateral nasal polyposis (NP) is characterized by high concentrations of IgE in NP tissue, which show no relation to the atopic status. We aimed to study the relationship between systemic and local IgE formation, nasal carriage ofStaphylococcus aureusand nasal polyposis.In serum and nasal tissue homogenates from 24 NP patients and 12 controls, we determined concentrations of total IgE and IgE antibodies to inhalant allergens andS. aureusenterotoxins (SAEs; A,B,C,D,E,TSST) by ImmunoCAP. Tissue cryosections were stained for CD3, CD20, CD38, CD23, FcεRI, IgE and SEA/SEB.We demonstrated a higher incidence ofS. aureuscolonization (17/24) and IgE antibodies to SAEs in NP tissue (12/24) compared with controls (3/12 and 0/12, respectively). Total IgE and IgE antibodies in serum and NP tissue were dissociated because of local polyclonal IgE formation in NP tissue. Staining of NP tissue revealed follicular structures characterized by B and T cells, and lymphoid accumulations with diffuse plasma cell infiltration.We demonstrated the organization of secondary lymphoid tissue in polyp tissue and a polyclonal hyper-immunoglobulinemia E associated with the presence of IgE antibodies to SAEs, colonization withS. aureus, and tissue eosinophilia in a relevant subgroup of polyp patients. [ABSTRACT FROM AUTHOR]

Background: Adult patients with nasal polyps often have comorbid asthma, adding to the serious effect on the quality of life of these patients. Nasal polyps and asthma might represent a therapeutic challenge; inflammation in both diseases shares many features, such as airway eosinophilia, local IgE formation, and a TH2 cytokine profile. Omalizumab is a human anti-IgE mAb with proved efficacy in patients with severe allergic asthma. Omalizumab could be a treatment option for patients with nasal polyps and asthma. Objective: The goal of this study was to investigate the clinical efficacy of omalizumab in patients with nasal polyps and comorbid asthma. Methods: A randomized, double-blind, placebo-controlled study of allergic and nonallergic patients with nasal polyps and comorbid asthma (n = 24) was conducted. Subjects received 4 to 8 (subcutaneous) doses of omalizumab (n = 16) or placebo (n = 8). The primary end point was reduction in total nasal endoscopic polyp scores after 16 weeks. Secondary end points included a change in sinus computed tomographic scans, nasal and asthma symptoms, results of validated questionnaires (Short-Form Health Questionnaire, 31-item Rhinosinusitis Outcome Measuring Instrument, and Asthma Quality of Life Questionnaire), and serum/nasal secretion biomarker levels. Results: There was a significant decrease in total nasal endoscopic polyp scores after 16 weeks in the omalizumab-treated group (−2.67, P = .001), which was confirmed by means of computed tomographic scanning (Lund-Mackay score). Omalizumab had a beneficial effect on airway symptoms (nasal congestion, anterior rhinorrhea, loss of sense of smell, wheezing, and dyspnea) and on quality-of-life scores, irrespective of the presence of allergy. Conclusion: Omalizumab demonstrated clinical efficacy in the treatment of nasal polyps with comorbid asthma, supporting the importance and functionality of local IgE formation in the airways. [ABSTRACT FROM AUTHOR]