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Abstract: Nasal allergen challenge (NAC) is an important tool to diagnose allergic rhinitis. In daily clinical routine, experimentally, or when measuring therapeutic success clinically, nasal allergen challenge is fundamental. It is further one of the key diagnostic tools when initiating specific allergen immunotherapy. So far, national recommendations offered guidance on its execution; however, international divergence left many questions unanswered. These differences in the literature caused EAACI to initiate a task force to answer unmet needs and find a consensus in executing nasal allergen challenge. On the basis of a systematic review containing nasal allergen challenges of the past years, task force members reviewed evidence, discussed open issues, and studied variations of several subjective and objective assessment parameters to propose a standardized way of a nasal allergen challenge procedure in clinical practice. Besides an update on indications, contraindications, and preparations for the test procedure, main recommendations are a bilaterally challenge with standardized allergens, with a spray device offering 0.1 mL per nostril. A systematic catalogue for positivity criteria is given for the variety of established subjective and objective assessment methods as well as a schedule for the challenge procedure. The task force recommends a unified protocol for NAC for daily clinical practice, aiming at eliminating the previous difficulty of comparing NAC results due to unmet needs. [ABSTRACT FROM AUTHOR]

Summary: 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. [ABSTRACT FROM AUTHOR]

Abstract: 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. [ABSTRACT FROM AUTHOR]

Abstract: Innate lymphoid cells (ILC) represent a group of lymphocytes that lack specific antigen receptors and are relatively rare as compared to adaptive lymphocytes. ILCs play important roles in allergic and nonallergic inflammatory diseases due to their location at barrier surfaces within the airways, gut, and skin, and they respond to cytokines produced by activated cells in their local environment. Innate lymphoid cells contribute to the immune response by the release of cytokines and other mediators, forming a link between innate and adaptive immunity. In recent years, these cells have been extensively characterized and their role in animal models of disease has been investigated. Data to translate the relevance of ILCs in human pathology, and the potential role of ILCs in diagnosis, as biomarkers and/or as future treatment targets are also emerging. This review, produced by a task force of the Immunology Section of the European Academy of Allergy and Clinical Immunology (EAACI), encompassing clinicians and researchers, highlights the role of ILCs in human allergic and nonallergic diseases in the airways, gastrointestinal tract, and skin, with a focus on new insights into clinical implications, therapeutic options, and future research opportunities. [ABSTRACT FROM AUTHOR]

Since its discovery, the understanding of stem/progenitor cells raised dramatically in the last decade. Their regenerative potential is important to develop new therapeutic applications, but the identification advanced much faster than our understanding of stem/progenitor cells. In nasal polyposis, little is known about stem cells/progenitor cells and their ability. However, the further characterization of stem cells/progenitor cells may provide new treatment options for combating nasal polyposis. This review highlights the knowledge of the current literature about stem cells/progenitor cells in nasal polyposis and how this may be exploited in the development of novel treatment strategies. [ABSTRACT FROM AUTHOR]

This EAACI position paper aims at providing a state-of-the-art overview on nonallergic rhinitis ( NAR). A significant number of patients suffering from persistent rhinitis are defined as nonallergic noninfectious rhinitis ( NANIR) patients, often denominated in short as having NAR. NAR is defined as a symptomatic inflammation of the nasal mucosa with the presence of a minimum of two nasal symptoms such as nasal obstruction, rhinorrhea, sneezing, and/or itchy nose, without clinical evidence of endonasal infection and without systemic signs of sensitization to inhalant allergens. Symptoms of NAR may have a wide range of severity and be either continuously present and/or induced by exposure to unspecific triggers, also called nasal hyperresponsiveness ( NHR). NHR represents a clinical feature of both AR and NAR patients. NAR involves different subgroups: drug-induced rhinitis, (nonallergic) occupational rhinitis, hormonal rhinitis (including pregnancy rhinitis), gustatory rhinitis, senile rhinitis, and idiopathic rhinitis ( IR). NAR should be distinguished from those rhinitis patients with an allergic reaction confined to the nasal mucosa, also called 'entopy' or local allergic rhinitis ( LAR). We here provide an overview of the current consensus on phenotypes of NAR, recommendations for diagnosis, a treatment algorithm, and defining the unmet needs in this neglected area of research. [ABSTRACT FROM AUTHOR]

Precision medicine ( PM) is increasingly recognized as the way forward for optimizing patient care. Introduced in the field of oncology, it is now considered of major interest in other medical domains like allergy and chronic airway diseases, which face an urgent need to improve the level of disease control, enhance patient satisfaction and increase effectiveness of preventive interventions. The combination of personalized care, prediction of treatment success, prevention of disease and patient participation in the elaboration of the treatment plan is expected to substantially improve the therapeutic approach for individuals suffering from chronic disabling conditions. Given the emerging data on the impact of patient stratification on treatment outcomes, European and American regulatory bodies support the principles of PM and its potential advantage over current treatment strategies. The aim of the current document was to propose a consensus on the position and gradual implementation of the principles of PM within existing adult treatment algorithms for allergic rhinitis ( AR) and chronic rhinosinusitis ( CRS). At the time of diagnosis, prediction of success of the initiated treatment and patient participation in the decision of the treatment plan can be implemented. The second-level approach ideally involves strategies to prevent progression of disease, in addition to prediction of success of therapy, and patient participation in the long-term therapeutic strategy. Endotype-driven treatment is part of a personalized approach and should be positioned at the tertiary level of care, given the efforts needed for its implementation and the high cost of molecular diagnosis and biological treatment. [ABSTRACT FROM AUTHOR]

The article focuses on a pilot randomized clinical trial. on probiotics-impregnated bedding covers for house dust mite allergic rhinitis (AR). AR affects up to one-third of the adult population and causes illness and disability world-wide. Main symptoms include sneezing, rhinorrhea and nasal obstruction.

This report has been prepared by the European Academy of Allergy and Clinical Immunology Task Force on Allergic Rhinitis (AR) comorbidities. The aim of this multidisciplinary European consensus document is to highlight the role of multimorbidities in the definition, classification, mechanisms, recommendations for diagnosis and treatment of AR and to define the needs in this neglected area by a literature review. AR is a systemic allergic disease and is generally associated with numerous multi-morbid disorders, including asthma, eczema, food allergies, eosinophilic oesophagitis (EoE), conjunctivitis, chronic middle ear effusions, rhinosinusitis, adenoid hypertrophy, olfaction disorders, obstructive sleep apnea, disordered sleep and consequent behavioural and educational effects. This report provides up-todate usable information to: (1) improve the knowledge and skills of allergists, so as to ultimately improve the overall quality of patient care; (2) to increase interest in this area and (3) to present a unique contribution to the field of upper inflammatory disease. [ABSTRACT FROM AUTHOR]

Background The majority of grass pollen-sensitized rhinitis patients develops allergic symptoms when exposed to the causal allergen and shows a positive nasal allergen provocation test ( NAPT). Chronic rhinosinusitis with nasal polyposis ( CRSw NP) patients, also characterized by eosinophilic inflammation and local IgE production, can suffer from comorbid inhalant allergy, but may show a different response to allergens. Objective We aimed to explore the allergic response to grass pollen allergens by NAPT in grass pollen-sensitized CRSw NP patients. Methods Twelve grass pollen-sensitized CRSw NP patients underwent NAPT with grass pollen and were compared with 12 grass pollen allergic rhinitis patients, 12 control patients and 12 CRSw NP patients without grass pollen sensitization. A positive NAPT was based on change in nasal airflow and symptoms. Further, VAS scores of different symptoms were noted before and after NAPT. Biomarkers such as total IgE, grass pollen-specific IgE and tryptase were measured in serum and nasal secretions. Results NAPT was positive in 6 of 12 of the grass pollen-sensitized CRSw NP patients, and another four patients developed allergic symptoms not fulfilling the criteria of positivity. In contrast, all patients with allergic rhinitis developed a positive provocation test, whereas in the control group one of the patients and in the non-sensitized CRSw NP group two of the patients developed a positive provocation test. Conclusion and clinical relevance These results show that allergen exposure induces an attenuated clinical response in patients with CRSw NP and sensitization to grass pollen as compared with grass pollen allergic rhinitis patients. [ABSTRACT FROM AUTHOR]

Calcineurin inhibitors (CNI), used frequently in solid organ transplant patients, are known to inhibit T cell proliferation, but their effect on humoral immunity is far less studied. Total and naive B cells from healthy adult donors were cultured in immunoglobulin (Ig)A- or IgG/IgE-promoting conditions with increasing doses of cyclosporin, tacrolimus, rapamycin or methylprednisolone. The effect on cell number, cell division, plasmablast differentiation and class-switching was tested. To examine the effect on T follicular helper (Tfh) cell differentiation, naive CD4+ T cells were cultured with interleukin (IL)-12 and titrated immunosuppressive drug (IS) concentrations. Total B cell function was not affected by CNI. However, naive B cell proliferation was inhibited by cyclosporin and both CNI decreased plasmablast differentiation. Both CNI suppressed IgA, whereas only cyclosporin inhibited IgE class-switching. Rapamycin had a strong inhibitory effect on B cell function. Strikingly, methylprednisolone, increased plasmablast differentiation and IgE class-switching from naive B cells. Differentiation of Tfh cells decreased with increasing IS doses. CNI affected humoral immunity directly by suppressing naive B cells. CNI, as well as rapamycin and methylprednisolone, inhibited the in-vitro differentiation of Tfh from naive CD4+ T cells. In view of its potent suppressive effect on B cell function and Tfh cell differentiation, rapamycin might be an interesting candidate in the management of B cell mediated complications post solid organ transplantation. [ABSTRACT FROM AUTHOR]

Background Post-transplant food allergy (LTFA) is increasingly observed after paediatric liver transplantation (LT). Although the immunopathology of LTFA remains unclear, immunoglobulin (Ig) E seems to be implicated. Objective To study humoral and cellular immunity in paediatric LT patients in search for factors associated with LTFA, and compare with healthy controls (HC) and non-transplant food-allergic children (FA). Methods We studied serum Ig levels in 29 LTFA, 43 non-food-allergic LT patients (LTnoFA), 21 FA patients and 36 HC. Serum-specific IgA and IgE against common food allergens in LTFA, IgA1, IgA2 and joining-chain-containing polymeric IgA (pIgA) were measured. Peripheral blood mononuclear cells were analysed by flow cytometry for B and T cell populations of interest. Results Serum IgA and specific IgA were higher in LTFA compared to LTnoFA. LTFA patients had the highest proportion of circulating T follicular helper cells (cTfh). The percentage of cTfh correlated positively with serum IgA. Unique in LTFA was also the significant increase in serum markers of mucosal IgA and the decrease in the Th17 subset of CXCR5- CD4+ cells compared to HC. Both LT patients exhibited a rise in IgA+ memory B cells and plasmablasts compared to HC and FA. Conclusions LT has an impact on humoral immunity, remarkably in those patients developing FA. The increase in serum markers of mucosal IgA, food allergen-specific IgA and cTfh cells observed in LTFA, point towards a disturbance in intestinal immune homoeostasis in this patient group. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The allergen challenge test has been the mainstay of diagnosis of allergic diseases for a long time since it offers a direct proof of the clinical relevance of a particular allergen for the allergic disease symptoms and severity. Standardisation and availability for daily practice (including safety issues) are still to be refined but most of the challenge tests have safely crossed the border from research tools to diagnostic tests available for daily practice for a well trained clinical staff. [ABSTRACT FROM AUTHOR]

Background Edema represents a key feature of nasal polyp ( NP) disease. Members of the vascular endothelial growth factor ( VEGF) family may be involved, but the precise role of VEGF-A, VEGF-B, placental growth factor (Pl GF), and their receptors VEGFR1 and VEGFR2 in NP edema formation remains elusive. Objective Exploring the expression of VEGF family members and their receptors and their correlation with clinical, radiological, and edema markers in NP. Methods The expression of VEGF- A, VEGF- B, Pl GF, VEGFR1, and VEGFR2 was measured in NP ( n = 23) and control tissue ( n = 22) at mRNA and protein level. Edema was evaluated by measuring albumin levels and wet/dry ratios. Computed tomography ( CT) scans were scored using the Lund-Mackay scoring system. IL-5 mRNA expression was determined by real-time RT- PCR. Cell suspensions from NP ( n = 10) and control tissue ( n = 12) were stimulated in vitro with IL-1β or TNFα. Results mRNA expression of VEGFR1 and VEGF- B was significantly higher in NP compared with control tissue. Expression levels of VEGF- B and VEGFR1 significantly correlated with NP albumin content ( VEGF- B: P = 0.0208; VEGFR1: P = 0.0293), CT scan scores ( VEGF- B: P = 0.0075; VEGFR1: P = 0.0068), and IL-5 mRNA ( VEGF- B: P = 0.0027; VEGFR1: P = 0.0001). In vitro stimulation of control and NP tissue cell suspensions with IL-1β or TNFα significantly reduced the expression of VEGFR2 in control tissue, without altering VEGFR1 and VEGF- B expression. hVEGF- B induced nitric oxide production in NP macrophages ( P < 0.05). Conclusion Expression levels of VEGFR1 and VEGF- B correlate with edema and clinical markers of NP disease and therefore represent potential therapeutic targets. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

State-of-the-art documents like ARIA and EPOS provide clinicians with evidence-based treatment algorithms for allergic rhinitis ( AR) and chronic rhinosinusitis ( CRS), respectively. The currently available medications can alleviate symptoms associated with AR and RS. In real life, a significant percentage of patients with AR and CRS continue to experience bothersome symptoms despite adequate treatment. This group with so-called severe chronic upper airway disease ( SCUAD) represents a therapeutic challenge. The concept of control of disease has only recently been introduced in the field of AR and CRS. In case of poor control of symptoms despite guideline-directed pharmacotherapy, one needs to consider the presence of SCUAD but also treatment-related, diagnosis-related and/or patient-related factors. Treatment-related issues of uncontrolled upper airway disease are linked with the correct choice of treatment and route of administration, symptom-oriented treatment and the evaluation of the need for immunotherapy in allergic patients. The diagnosis of AR and CRS should be reconsidered in case of uncontrolled disease, excluding concomitant anatomic nasal deformities, global airway dysfunction and systemic diseases. Patient-related issues responsible for the lack of control in chronic upper airway inflammation are often but not always linked with adherence to the prescribed medication and education. This review is an initiative taken by the ENT section of the EAACI in conjunction with ARIA and EPOS experts who felt the need to provide a comprehensive overview of the current state of the art of control in upper airway inflammation and stressing the unmet needs in this domain. [ABSTRACT FROM AUTHOR]

Background Free light chain ( FLC) concentrations are demonstrated to be increased in different inflammatory disorders and are proposed to mediate mast cell-dependent immune responses. A role for mast cells is suggested in chronic rhinosinusitis with nasal polyposis ( CRSw NP), which is characterized by a local Th2 inflammatory response. However, clear mast cell-activating factors are not always apparent. In this study, the presence of FLCs in CRS patients with or without nasal polyps ( CRSw/ sNP) was investigated and the effect of different treatments on FLC expression was analyzed. Methods Nasal tissue, nasal secretion, and serum of control patients, patients with CRSw NP, and CRSs NP were analyzed for the presence of kappa and lambda FLC. The expression of FLCs in nasal polyp tissue was investigated using immunohistochemistry. In addition, FLC was measured in serum and nasal secretion of nasal polyp patients treated with methylprednisolone, doxycycline, anti- IL-5, or placebo. Results Free light chain concentrations were increased in nasal secretion and mucosal tissue homogenates in patients with chronic rhinosinusitis, and this effect was most prominent in CRSw NP patients. Immunohistochemical analysis confirmed the increased FLC concentrations in nasal polyp tissue. In CRSw NP patients, treatment with methylprednisolone or anti- IL-5 resulted in the reduction in systemic or local FLC concentrations, respectively. Conclusion The presence of FLC in CRSw NP and CRSs NP suggests a possible role in mediating the local immune reaction in the paranasal cavities. Furthermore, the decrease in local FLCs after treatment with anti- IL-5 presumes that IL-5 creates an environment that favors FLC production. [ABSTRACT FROM AUTHOR]

Background A distinct set of inflammatory and remodelling factors have been found elevated in chronic rhinosinusitis. Objective The investigation of their expression in early stage disease may reveal early events in this common disease. Methods Sinonasal mucosal samples from nine patients with early stage CRSsNP were taken from the inferior and middle turbinates, the uncinate process, maxillary sinus, anterior ethmoid, bulla ethmoidalis and the posterior ethmoid and measured for TGF-beta 1 and it's receptors, MPO protein as well as pro-inflammatory cytokines (TNF-alpha and IL-1beta) and the Th1 cell signature (IFN-gamma and T-bet). As outcome parameter for TGF-beta signalling collagen deposition was analysed. Inferior turbinates from patients undergoing (rhino-) septoplasty were collected as controls. Results TGF-beta 1 protein concentrations were significantly increased in the maxillary sinuses (P = 0.006), the uncinate process (P = 0.01), the anterior ethmoid including the bulla ethmoidalis (P = 0.005) and the posterior ethmoid (P = 0.037) when compared to the inferior and middle turbinates. Collagen deposition was significantly increased in the maxillary sinus when compared to the inferior turbinates (P = 0.008). In contrast, mRNA for TGF-beta receptors, Th1 related markers (IFN-gamma and T-bet), pro-inflammatory cytokines (IL-1 beta and TNF-alpha), and MPO protein as neutrophil marker were expressed at all locations but showed no significant differences between the various locations. TGF-beta 1 mRNA expression in inferior turbinates of CRSsNP was significantly higher when compared to inferior turbinates of controls (P = 0.017). The pro-inflammatory cytokines and Th1-related cytokines did not show an upregulation in inferior turbinates of CRSsNP when compared to controls. Conclusions In early stage chronic sinus disease, TGF-beta protein is expressed in significantly higher concentrations within the paranasal sinuses when compared to turbinates, whereas pro-inflammatory, neutrophilic and Th1 markers did not show any difference. These findings suggest that TGF-beta plays a central role in the initiation of CRSsNP, and represents a major target for further research and future intervention. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background Staphylococcus aureus Enterotoxin B (SEB) has immunomodulatory effects in allergic airway disease. The potential contribution of SEB to the sensitization process to allergens remains obscure. Objective In order to study the effects of staphylococcal-derived toxins on the sensitization to ovalbumin (OVA) and induction of allergic airway inflammation, we have combined the nasal application of OVA with different toxins. Methods Nasal applications of OVA and saline, SEA, SEB, toxic shock syndrome toxin (TSST)-1, protein A or lipopolysaccharide (LPS) were performed on alternate days from day 0 till 12. On day 14, mice were killed for the evaluation of OVA-specific IgE, cytokine production by mediastinal lymph node (MLN) cells and bronchial hyperreactivity (BHR) to inhaled metacholine. The effect of SEB on dendritic cell (DC) migration and maturation, and on T cell proliferation was evaluated. Results Concomitant endonasal application of OVA and SEB resulted in OVA-specific IgE production, whereas this was not found with SEA, TSST-1, protein A, LPS or OVA alone. Increased DC maturation and migration to the draining lymph nodes were observed in OVA/SEB mice, as well as an increased T cell proliferation. Bronchial inflammation with an influx of eosinophils and lymphocytes was demonstrated in OVA/SEB mice, together with hyperresponsiveness and the production of IL-4, IL-5, IL-10 and IL-13 by MLN stimulated with OVA. Conclusions Our data demonstrate that SEB facilitates sensitization to OVA and consecutive bronchial inflammation with features of allergic asthma. This is likely due to augmentation of DC migration and maturation, as well as the allergen-specific T cell proliferation upon concomitant OVA and SEB application. Cite this as: W. Huvenne, I. Callebaut, M. Plantinga, J. A. J. Vanoirbeek, O. Krysko, D. M. A. Bullens, P.Gevaert, P. Van Cauwenberge, B. N. Lambrecht, J. L. Ceuppens, C. Bachert and P. W. Hellings, Clinical & Experimental Allergy, 2010 (40) 1079–1080. [ABSTRACT FROM AUTHOR]

Background: T-regulatory cells (Treg) are important in balancing immune responses and maintaining peripheral tolerance. Current evidence suggests that asthma is characterized by a relative deficiency in Treg, allowing T helper 2 cells to expand. In this study, we aimed to evaluate circulating Treg, defined by the protein FOXP3, in both control subjects and patients with stable asthma. Methods: Peripheral blood mononuclear cells (PBMC) of control ( n = 14) and asthmatic patients ( n = 29) were labeled for CD4, CD25, and intracellular FOXP3 and analyzed using flow cytometry. In CD3/CD28 stimulated PBMC, the effects of dexamethasone on the transcription factors T-bet, GATA-3, FOXP3, and RORc2 and representative cytokines were studied. Results: In control subjects and asthmatic patients, numbers of peripheral blood CD4+CD25high and CD4+CD25highFOXP3+ T-cells were similar. However, FOXP3 protein expression within CD4+CD25high T-cells was significantly decreased in asthmatic patients. There was a tendency for increased FOXP3 expression within CD4+CD25high T-cells in glucocorticosteroid-treated patients when compared to steroid-naive asthmatic patients. In stimulated PBMC, dexamethasone treatment increased the anti-/proinflammatory transcription ratios of FOXP3/GATA-3, FOXP3/T-bet, and FOXP3/RORc2. Conclusion: Asthmatic patients have decreased FOXP3 protein expression within their CD4+CD25high Treg. Our findings also suggest that treatment with inhaled glucocorticosteroids in asthmatics might increase this FOXP3 protein expression within the CD4+CD25high T-cell population. [ABSTRACT FROM AUTHOR]

Background: Given the key role of interleukin-5 (IL-5) in eosinophil function, we investigated the regulated expression of the membrane-anchored (TM-IL-5Rα) isoform, or a secreted (SOL IL-5Rα) isoform, on both protein and transcript level in vitro and in vivo. Methods: A real-time PCR, FACS and ELISA were established to determine IL-5Rα isoform expression in peripheral blood and nasal tissue from control subjects and nasal polyp (NP) patients with or without asthma. Human peripheral blood eosinophils were incubated with IL-5 and were analyzed for SOL-IL-5Rα and TM-IL-5Rα mRNA and protein levels in comparison with CD-69 expression. Results: SOL-IL-5Rα and TM-IL-5Rα mRNA and protein expression was significantly increased in NP vs controls. In polyp tissue, SOL-IL-5Rα expression correlated to disease severity and eosinophils counts, whereas TM-IL-5Rα levels were inversely correlated to eosinophils counts and SOL-IL-5Rα expression. FACS analysis revealed increased CD-69 and decreased TM-IL-5Rα expression in NP tissue eosinophils vs blood eosinophils. Incubation of blood eosinophils with IL-5 caused up-regulation of CD-69 and down-regulation of TM-IL-5Rα after 2 and 24 h. Conclusion: The expression of SOL-IL-5Rα and TM-IL-5Rα differs according to the eosinophil activation state and localization in the body (blood vs tissue) and may therefore be involved in the fine-tuning of the eosinophil homeostasis. Exposure of eosinophils to IL-5 reduces their responsiveness to IL-5 by regulated expression of the IL-5Rα isoforms. Since, TM-IL-5Rα is down-regulated and SOL-IL-5Rα (antagonistic) is upregulated in NP tissue, our findings are important to understand the clinical trials with anti-IL-5 in humans. [ABSTRACT FROM AUTHOR]

Chronic rhinosinusitis is one of the most common health care challenges, with significant direct medical costs and severe impact on lower airway disease and general health outcomes. The diagnosis of chronic rhinosinusitis (CRS) currently is based on clinical signs, nasal endoscopy and CT scanning, and therapeutic recommendations are focussing on 2 classes of drugs, corticosteroids and antibiotics. A better understanding of the pathogenesis and the factors amplifying mucosal inflammation therefore seems to be crucial for the development of new diagnostic and therapeutic tools. In an effort to extend knowledge in this area, the WP 2.7.2 of the GA2LEN network of excellence currently collects data and samples of 1000 CRS patients and 250 control subjects. The main objective of this project is to characterize patients with upper airway disease on the basis of clinical parameters, infectious agents, inflammatory mechanisms and remodeling processes. This collaborative research will result in better knowledge on patient phenotypes, pathomechanisms, and subtypes in chronic rhinosinusitis. This review summarizes the state of the art on chronic rhinosinusitis and nasal polyposis in different aspects of the disease. It defines potential gaps in the current research, and points to future research perspectives and targets. [ABSTRACT FROM AUTHOR]

Background Chronic rhinosinusitis (CRS) with nasal polyps (NP) represents a persistent inflammation often characterized by local hyper-immunoglobulinaemia and the presence of specific IgE to Staphylococcus aureus enterotoxins (SAEs). We aimed to study the systemic and local production of Igs in relation to plasma cells, B cells and specific IgE to SAEs. Methods Concentrations of IgE, IgG, IgM, IgA, IgG subclasses and specific IgE to SAE were determined on tissue homogenates and serum from 15 CRS patients with NP, 15 CRS without NP and 10 control patients. Tissue cryo-sections were stained for CD19, CD20 and CD138 to demonstrate B and plasma cells. Results IgA, IgG and IgE concentrations were significantly higher in tissue homogenates, but not in serum, of NP compared with CRS and control subjects. NP with specific IgE to SAEs had significantly higher concentrations of IgG and IgE, and also showed a significantly higher fraction of IgG4 ( P=0.003) and a lower fraction of IgG2 ( P=0.04) than those without specific IgE production. Furthermore, naïve CD19+ B cell and plasma cell counts (CD138+) were significantly higher in NP tissue compared with controls or CRS. Conclusions The difference in IgE, IgG and IgA expression between NP tissue and serum, supported by increased numbers of plasma cells, suggests a local production of these Igs in NP in response to a chronic microbial trigger. The local immune response to SAE is associated with a further increased production of IgE and IgG, and a shift in IgG subclasses. [ABSTRACT FROM AUTHOR]

Background: Chronic rhinosinusitis (CRS) clinically is a heterogeneous group of sinus diseases, which may cover different disease entities, or may represent a disease continuum. Studying inflammatory cells and mediators in clearly defined disease subgroups may lead to a better differentiation of chronic sinus diseases. Methods: Sinonasal mucosal tissue from 10 nasal polyp (NP) patients, 13 cystic fibrosis patients (CF-NP), eight CRS subjects without polyps, and nine control patients were stained for CD3, CD25, CD68, CD20, myeloperoxidase (MPO), CD138 and tissue homogenates were assayed for eotaxin, interleukin (IL)-1 β, IL-2sR α, IL-5, interferon (IFN)- γ, IL-8, transforming growth factor (TGF)- β1, tumor necrosis factor- α, and MPO by enzyme-linked immunosorbent assay or UNICAP system. Results: Nasal polyp and CF-NP showed increased numbers and activation of T cells, while only NP displayed an increase in plasma cells. Nasal polyp had significantly higher levels of eosinophilic markers [eosinophils, eotaxin, and eosinophil cationic protein (ECP)] compared with CRS, controls and CF-NP. Chronic rhinosinusitis was characterized by a Th1 polarization with high levels of IFN- γ and TGF- β, while NP showed a Th2 polarization with high IL-5 and immunoglobulin (Ig) E concentrations. Nasal polyp and CF-NP were discriminated by edema from CRS and controls, with CF-NP displaying a very prominent neutrophilic inflammation. Conclusion: Based on cellular and mediator profiles, we suggest that CRS, NP, and CF-NP are distinct disease entities within the group of chronic sinus diseases. [ABSTRACT FROM AUTHOR]

Background The role of bacterial enterotoxins like Staphylococcus aureus enterotoxin B (SEB) in allergic asthma remains unknown. We used a mouse model of airway allergy to study the effects of nasal or bronchial contact with SEB on bronchial allergic inflammation. Methods The features of allergic asthma were induced in ovalbumin (OVA)-sensitized mice (days 1–13) by repeated exposures to nebulized OVA (days 33–37). Nasal or bronchial application of SEB was performed on three occasions (days 33–35–37), and the effects on bronchial inflammation, IgE titres and expression levels of mRNA for T helper type 2 cytokines and other inflammatory mediators were evaluated. Results Both nasal and bronchial SEB enhanced the allergen-induced bronchial inflammation, as reflected by more eosinophilic inflammation in the airway lumen and in bronchial tissue. Aggravation of experimental asthma correlated with higher expression of mRNA for IL-5, IL-4, IFN-γ, IL-12 p40, eotaxin-1 and TGF-β in bronchi. In addition, nasal SEB elevated concentrations of IL-4, IL-5 and IFN-γ in serum and bronchial SEB increased titres of OVA-specific and total IgE in serum. Conclusion Our data illustrate the potential of both nasal as well as bronchial SEB to aggravate several features of allergic asthma in a mouse model. [ABSTRACT FROM AUTHOR]

The dysfunction of the mucosal interface of the upper respiratory tract in cystic fibrosis (CF) patients is clinically visible by the development of nasal polyps (NP) at a young age. Innate defence markers and inflammatory mediators in NP from patients with CF were compared with non-cystic fibrosis nasal polyps (non-CF-NP) to determine a possible different immunological background in macroscopically similar tissue.Surgical samples were obtained from patients with non-CF-NP, cystic fibrosis patients with nasal polyps (CF-NP) and control patients (CO). With real time PCR, the mRNA expression of humanβ defensins (HBD) 2 and 3, toll-like receptors (TLR) 2 and 4 and the macrophage mannose receptor (MMR) were measured. On homogenates of the surgical samples eotaxin, myeloperoxidase (MPO), IL-5 and IL-8 protein content was measured using commercial ELISA kits; IgE and eosinophilic cationic protein (ECP) were measured by the Unicap system.In CF-NP we found a statistically significant higher mRNA expression of HBD 2 compared with non-CF-NP and CO and of TLR 2 compared with non-CF-NP. In the non-CF-NP group, MMR mRNA expression was significantly elevated compared with CO and CF-NP. For TLR 4 mRNA expression no statistically significant differences were found between groups. IL-5 was below detection level in all CO and CF-NP, but was measurable in 80% of the non-CF-NP. MPO and IL-8 concentrations were significantly higher in CF-NP compared with CO and non-CF-NP, whereas ECP, eotaxin and IgE were significantly higher in the non-CF-NP group.We here demonstrate that CF-NP and non-CF-NP not only differ in terms of inflammatory mediator profile, but also in terms of innate markers. [ABSTRACT FROM AUTHOR]

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: The role of infectious agents in the onset and maintenance of chronic sinus disease is still not fully understood. Macrophage mannose receptor (MMR), an innate pattern recognizing receptor, capable of phagocytosis of invaders and signal transduction for proinflammatory mechanisms, might be of importance in immune interactions in chronic sinus disease. Methods: We examined the MMR in sinonasal airway mucosa to evaluate its possible role in chronic rhinosinusitis (CS) and nasal polyposis (NPs). Surgical samples from patients with sinonasal disease were investigated with real-time RT-PCR for quantification of MMR mRNA expression, and the presence and location of MMR-positive cells was analysed by immunohistochemistry. Results: Quantification of MMR mRNA showed a statistically significant higher expression in NPs compared to CS without NP and controls. Immunohistochemistry revealed expression of MMR in all tissue samples; however, in NP we found an enhanced positive cellular staining including cell aggregates. Conclusions: We could demonstrate for the first time that the expression of MMR is significantly upregulated in NP compared to patients with CS without NP or turbinate tissue of controls. Macrophages expressing MMR, accumulated in cell aggregates in NPs, play a possible key role in pathogen-macrophage interaction in NP disease. [ABSTRACT FROM AUTHOR]

Background: Measurement of innate markers in nasal mucosa, tonsils and adenoids might lead to new views about the role of innate immunity in the upper airway. In this study, the expression of human β-defensins (HBD) 2 and 3 and toll-like receptors (TLR) 2 and 4 in various upper airway diseases was investigated. Methods: Surgical samples from patients with tonsillar disease (n = 18), hypertrophic adenoids (n = 10) and sinonasal disease (n = 30) (chronic sinusitis, nasal polyps, turbinate mucosa as controls) were investigated by immunohistochemistry. Quantification of HBD-2 and 3 mRNA, TLR-2 and 4 mRNA expression was performed by real-time polymerase chain reaction (PCR). Results: Immunohistochemistry revealed a strong expression of HBD-2 in tonsillar tissue. Quantification of HBD-2 and HBD-3 mRNA showed a more than tenfold higher expression in tonsillar tissue than in adenoids, whereas in nasal biopsies, only negligible defensin expression could be measured. No significant differences were found for TLR-4 between the various tissues, whereas TLR-2 expression in adenoids was significantly lower compared with other tissues. Conclusion: These results demonstrate a strong defensin expression in tonsillar tissue compared with nasal and paranasal mucosa and adenoids. Toll-like receptor expression in all these tissues illustrates a possibly important immunological sentinel function of upper airway mucosa. [ABSTRACT FROM AUTHOR]

Background: Alternative splicing of the interleukin-5 receptor alpha (IL-5Rα )-subunit leads to the generation of a signalling, membrane-anchored (TM) isoform, or a secreted [soluble (SOL)], antagonistic variant. Given the key role of IL-5 in eosinophil function, we investigated SOL IL-5Rα expression pattern in an eosinophil-associated disease such as nasal polyposis (NP). Methods: An SOL IL-5Rα enzyme-linked immunosorbent assay and quantitative real-time polymerase chain reaction (PCR) were established and applied in serum, nasal secretion and nasal tissue of controls (n = 12), and NP patients (n = 42) with or without asthma. Results: Analysis of serum, nasal secretion, and nasal tissue samples revealed that SOL IL-5Rα protein concentrations were significantly increased in NP vs control tissue. Within the NP group, there was a significant up-regulation of SOL IL-5Rα in patients with systemic airway disease. These findings were confirmed at the mRNA level, using an optimized real-time reverse-transcriptase PCR procedure. Conclusions: This report demonstrates SOL IL-5Rα transcript and protein up-regulation in NP. Soluble IL-5Rα differentiates nasal polyps with or without concomitant asthma. As SOL IL-5Rα is strongly up-regulated for disease and has antagonistic properties in vitro , our studies shed new light on the mechanisms of specific immunomodulatory therapies, such as anti-IL-5. [ABSTRACT FROM AUTHOR]

Background: This paper reports a study on the concentrations of the pro-inflammatory cytokines IL-18 and IL-1β in nasal secretions of allergic rhinitis patients in relation to ECP and nasal symptoms. Methods: We measured IL-18 and IL-1β concentrations using ELISA, and eosinophilic cationic protein (ECP) using the CAP system, in nasal secretions of 15 seasonal allergic rhinitis (SAR) patients at six visits throughout the pollen season. Pollen exposure, nasal and ocular symptoms were monitored daily. Furthermore, we measured IL-18, IL-1β and ECP concentrations in nasal secretions of 19 controls and 20 symptomatic persistent allergic rhinitis (PAR) patients with house dust mite allergy. Results: In SAR, the increase of IL-18, IL-1β and ECP paralleled the pollen flight with a time delay. IL-18 and IL-1β significantly increased during the pollen season compared to baseline, and differently from ECP, remained elevated until 4 weeks after the season. In PAR, the concentrations of IL-18 and ECP, but not IL-1β, were significantly higher compared to controls, with IL-18 concentrations also being significantly higher than in SAR. Conclusion: This is the first study to demonstrate the up-regulation of IL-18 in nasal secretions in allergic rhinitis. The persistence of elevated IL-18 concentrations until after the season and the high concentrations in PAR compared to SAR suggests its role in persistent allergic inflammation. [ABSTRACT FROM AUTHOR]

Deals with the role of Staphylococcus aureus (S. aureus) enterotoxins in airway diseases. Parts of the body where the S. aureus is often found; Characteristics of Staphylococcus superantigens.

Allergic rhinitis (AR) affects 23–30% of the European population with equal prevalence reported in Belgium. Despite guidelines on the correct use of effective treatment, up to 40% of AR patients remain uncontrolled. Allergen immunotherapy (AIT) has been shown to improve the level of control up to 84% of patients being controlled by AIT. Recently, new guidelines for AIT have been published, supporting the clinical evidence for effectiveness of various subcutaneous and sublingual products for AIT in patients who are allergic to airborne allergens. AIT in AR patients not only reduces nasal and/or ocular symptoms but also induces tolerance and has preventive potential. Adoption of AIT into daily clinical practice in Belgium and other European countries is hampered primarily by reimbursement issues of each of the single products but also by several patient- and physician-related factors. Patients need to be better informed about the effectiveness of AIT and the different routes of administration of AIT. Physicians dealing with AR patients should inform patients on tolerance-inducing effects of AIT and are in the need of a harmonized and practical guide that supports them in selecting eligible patients for AIT, in choosing evidence-based AIT products and in following treatment protocols with proven efficacy. Therefore, a stepwise and holistic approach is needed for better adoption of AIT in the real-life setting in Belgium. [ABSTRACT FROM AUTHOR]