C. Barnig

Lipoxin A4 Regulates Natural Killer Cell and Type 2 Innate Lymphoid Cell Activation in Asthma

The pro-resolving mediator lipoxin A4 regulates natural killer cells and type 2 innate lymphoid cells in severe asthma. ILCs Catch Their Breath Focusing on your breath is one of the most basic meditation techniques. But for people with asthma, breathing can be anything but relaxing. Asthma is a chronic inflammatory disease, but attacks can be triggered by everything from allergens to cold to exercise. However, much still remains to be learned about the dysregulation that allows this inflammation to continue. Now, Barnig et al. suggest that differences in innate lymphoid cells (ILCs) may contribute to asthma pathogenesis. The authors look at two types of ILCs—natural killer (NK) cells and type 2 ILCs (ILC2s)—in the context of severe asthma. They find that NK cells may down-modulate the airway inflammatory response by inducing eosinophil apoptosis, whereas ILC2s promote airway inflammation through the secretion of interleukin-13 (IL-13). Intriguingly, despite their disparate function, both NK cells and ILC2s express the receptor for lipoxin A4, which functions in resolving inflammation. Indeed, lipoxin A4 increased the ability of NK cells to induce eosinophil apoptosis and decreased IL-13 production from the ILC2 population. Furthermore, lipoxin A4 production was decreased in severe asthmatics, suggesting this as a new line of potential therapies. Increasing lipoxin A4 may help severe asthmatics breathe easy. Asthma is a prevalent disease of chronic inflammation in which endogenous counterregulatory signaling pathways are dysregulated. Recent evidence suggests that innate lymphoid cells (ILCs), including natural killer (NK) cells and type 2 ILCs (ILC2s), can participate in the regulation of allergic airway responses, in particular airway mucosal inflammation. We have identified both NK cells and ILC2s in human lung and peripheral blood in healthy and asthmatic subjects. NK cells were highly activated in severe asthma, were linked to eosinophilia, and interacted with autologous eosinophils to promote their apoptosis. ILC2s generated antigen-independent interleukin-13 (IL-13) in response to the mast cell product prostaglandin D2 alone and in a synergistic manner with the airway epithelial cytokines IL-25 and IL-33. Both NK cells and ILC2s expressed the pro-resolving ALX/FPR2 receptors. Lipoxin A4, a natural pro-resolving ligand for ALX/FPR2 receptors, significantly increased NK cell–mediated eosinophil apoptosis and decreased IL-13 release by ILC2s. Together, these findings indicate that ILCs are targets for lipoxin A4 to decrease airway inflammation and mediate the catabasis of eosinophilic inflammation. Because lipoxin A4 generation is decreased in severe asthma, these findings also implicate unrestrained ILC activation in asthma pathobiology.

Sublingual-swallow immunotherapy with standardized 3-grass pollen extract: a double-blind, placebo-controlled study

BACKGROUND Sublingual immunotherapy (SLIT) is accepted as a safe and effective route for the treatment of grass pollen allergy, but clarification of its clinical and biological efficacy requires more study. OBJECTIVE To evaluate the efficacy, safety, and compliance of SLIT with a standardized 3-grass pollen extract in patients with grass pollen seasonal allergic rhinoconjunctivitis, with or without mild asthma. METHODS This multicenter, randomized, double-blind study included 127 patients (aged 12-41 years; mean age, 24.9 years) with grass pollen seasonal allergic rhinoconjunctivitis, with or without mild asthma. They received either SLIT with a high-dose, standardized, 3-grass pollen extract or placebo for 10 months before and during the grass pollen season. The efficacy evaluation compared weekly clinical scores (defined as the sum of the symptom score and rescue medication score) to measure rhinoconjunctivitis and asthma for the first 8 weeks of the pollen season. We also evaluated safety and compliance and measured changes in anti-Dactylis specific IgG4 antibody levels. RESULTS There was a trend in favor of the study group in the mean adjusted clinical score. The groups were not comparable on inclusion (P = .02): the SLIT group included more subjects with asthma and had a higher mean IgG4 serum level. Additional exploration according to subgroups with and without asthma found that among the patients without asthma, the SLIT group had a significantly better clinical score (P = .045). Anti-Dactylis specific IgG4 levels increased significantly in the SLIT group. CONCLUSION SLIT with a standardized, high-dose, 3-grass pollen extract is safe and significantly improves the clinical score in patients with hay fever and without asthma during the pollen season.

EAACI consensus statement for investigation of work‐related asthma in non‐specialized centres

Work‐related asthma (WRA) is a relevant problem in several countries, is cause of disability and socioeconomic consequences for both the patient and the society and is probably still underdiagnosed. A correct diagnosis is extremely important to reduce or limit the consequences of the disease. This consensus document was prepared by a EAACI Task Force consisting of an expert panel of allergologists, pneumologists and occupational physicians from different European countries. This document is not intended to address in detail the full diagnostic work‐up of WRA, nor to be a formal evidence‐based guideline. It is written to provide an operative protocol to allergologists and physicians dealing with asthma useful for identifying the subjects suspected of having WRA to address them to in‐depth investigations in a specialized centre. No evidence‐based system could be used because of the low grade of evidence of published studies in this area, and instead, ‘key messages’ or ‘suggestions’ are provided based on consensus of the expert panel members.

Niox® and Niox Mino®: comparison of exhaled NO in grass pollen allergic adult volunteers

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Innate immunity is a key factor for the resolution of inflammation in asthma

The resolution of inflammation is an integral and natural part of the physiological response to tissue injury, infection and allergens or other noxious stimuli. Resolution is now recognised as an active process with highly regulated cellular and biochemical events. Recent discoveries have highlighted that innate inflammatory cells have bimodal effector functions during the inflammatory response, including active roles during the resolution process. Several mediators displaying potent pro-resolving actions have recently been uncovered. Lipoxin A4, the lead member of this new class of pro-resolving mediators, has anti-inflammatory actions on type 2 innate lymphoid cells and pro-resolving actions through natural killer cells in asthma immunobiology. Eosinophils are also able to control crucial aspects of resolution through the generation of pro-resolving mediators. Uncontrolled asthma has been associated with a defect in the generation of specialised pro-resolving mediators, including lipoxin A4 and protectin D1. Thus, bioactive stable analogue mimetics of these mediators that can harness endogenous resolution mechanisms for inflammation may offer new therapeutic strategies for asthma and airway inflammation associated diseases. Innate inflammatory cells control crucial aspects of resolution of the inflammatory response in asthma http://ow.ly/Hj0yl

Indoor dust and air concentrations of endotoxin in urban and rural environments.

Studies in European children from a farming background have shown that these children have a reduced risk of asthma and atopic sensitization compared to their urban counterparts. It has been suggested that this might be due to exposure to high levels of endotoxin in the farming environment. The aim of this study was to compare indoor endotoxin concentrations in air and dust samples from randomly selected urban and rural dwellings. In the rural area, endotoxins were analysed in farmhouses and nonfarmhouses as well as housing characteristics, lifestyle factors and agricultural practices likely to influence air and dust endotoxin levels. Endotoxin levels were significantly higher in floor (6600 ± 6100 vs 3600 ± 5600 and 3800 ± 17 000 ng g−1; P < 0·001) and mattress dust (2900 ± 4100 vs 1100 ± 2400 and 800 ± 2600 ng g−1; P < 0·001) from farmhouses compared to other rural and urban homes. However, no difference was observed between endotoxin concentrations in the air of urban and rural houses, and airborne endotoxin levels did not correlate to dust levels. Lack of ventilation and direct entry into the house were correlated with an increase in dust endotoxin levels. These results confirm that dairy farming is associated with high exposure to endotoxins in indoor dust samples. No difference was observed between indoor airborne concentrations between urban and rural houses. These results suggest that measuring endotoxin in dust is the most relevant method to assess endotoxin exposure.

Natural killer cell–mediated inflammation resolution is disabled in severe asthma

Severe asthma is characterized by decreased NK cell cytotoxicity, and corticosteroids further disable NK cell function. NK cells in severe asthma—Failed resolution Anti-inflammatory corticosteroids are a first line of defense against many types of asthma, but patients with severe asthma do not frequently respond to this therapy. Duvall et al. now report that this lack of response may be due in part to defects in natural killer (NK) cells, which are important mediators of inflammation resolution. They found that NK cells from patients with severe asthma had impaired killing and that corticosteroid exposure further inhibited the function of these cells, whereas the proresolving mediator LXA4 preserved NK cell effector mechanisms. Therefore, corticosteroids may be a counterproductive therapy in patients with severe asthma, and specifically activating NK cells may provide an alternate therapeutic target. Severe asthma is typically characterized by chronic airway inflammation that is refractory to corticosteroids and associated with excess morbidity. Patients were recruited into the National Heart, Lung, and Blood Institute–sponsored Severe Asthma Research Program and comprehensively phenotyped by bronchoscopy. Bronchoalveolar lavage (BAL) cells were analyzed by flow cytometry. Compared with healthy individuals (n = 21), patients with asthma (n = 53) had fewer BAL natural killer (NK) cells. Patients with severe asthma (n = 29) had a marked increase in the ratios of CD4+ T cells to NK cells and neutrophils to NK cells. BAL NK cells in severe asthma were skewed toward the cytotoxic CD56dim subset, with significantly increased BAL fluid levels of the cytotoxic mediator granzyme A. The numbers of BAL CD56dim NK cells and CCR6−CCR4− T helper 1–enriched CD4+ T cells correlated inversely with lung function [forced expiratory volume in 1 s (FEV1) % predicted] in asthma. Relative to cells from healthy controls, peripheral blood NK cells from asthmatic patients had impaired killing of K562 myeloid target cells despite releasing more cytotoxic mediators. Ex vivo exposure to dexamethasone markedly decreased blood NK cell lysis of target cells and cytotoxic mediator release. NK cells expressed airway lipoxin A4/formyl peptide receptor 2 receptors, and in contrast to dexamethasone, lipoxin A4–exposed NK cells had preserved functional responses. Together, our findings indicate that the immunology of the severe asthma airway is characterized by decreased NK cell cytotoxicity with increased numbers of target leukocytes, which is exacerbated by corticosteroids that further disable NK cell function. These failed resolution mechanisms likely contribute to persistent airway inflammation in severe asthma.

Transfer of peanut allergy following lung transplantation: a case report.

This case study describes a patient who developed peanut allergy following lung transplantation. A 54-year-old woman underwent bilateral lung transplantation on June 2009 owing to severe chronic obstructive pulmonary disease. She had no history of food allergy before transplantation. The donor, however, was a 20-year-old man who was fatally injured during an automobile accident; he was allergic to peanuts. At 3 months after transplantation, the lung recipient presented with acute dyspnea and urticaria 15 minutes after consuming food containing peanut derivatives. Pre- and posttransplantation recipient blood samples analyzed for the presence of IgE antibodies specific for peanut allergens confirmed that the allergy had been passively transfered as a consequence of transplantation. Food allergy following solid organ transplantation is thought to be rare, mostly occurring in children. Two mechanisms may explain the observations described for the patient reported in this study: de novo development of peanut allergies after transplantation, or passive transfer of peanut allergies from a peanut-sensitized organ donor. This case report documenting pre- and posttransplantation IgE status in a lung transplantation case suggested that the allergic status of organ donors should be thoroughly assessed before transplantation, and potential allergy transfer risks must be discussed with the transplant team and the patient.

House dust mite control measures for asthma

The recently published paper in your jour-nal by Gotzsche and Johansen (1) hascaught our attention. We would like to addsome comments.In this newly updated meta-analysis onhouse dust mite control measures forasthma, 44 trials with a total of 3302subjects were included. When comparedwith the last meta-analysis published by thesame authors in 2004 (2), the newly addedstudies were seen to be based on reductionmethods concentrated only on mattressesand bed covers. It has been demonstratedby Frederick in 1997 (3) and more recentlyby Woodcook et al. (4) that house dustmite reduction measures performed only onthe beddings were not able to decrease themite-allergen exposure. Consequently, it isdifficult to state that mite-allergen reduc-tion is not clinically efficient and should notbe recommended as it has been showed thatthese methods are not able to decreasesignificantly the mite-allergen exposure.It is surprising, that the two multifacetedallergen-reduction studies (5, 6) have notbeen taken into consideration for thismeta-analysis as the conclusion of theprevious meta-analysis suggested thatglobal allergen reduction had to be per-formed (2). These two studies, which gath-ered 937 children for the first one (5) and274 for the second one (6), demonstratedthe efficacy of global allergen reduction onallergen exposure and on clinical outcomesin moderate to severe asthma. In the firststudy published by Morgan et al. in 2004(5), the reduction of allergen exposure wasobtained 1 and 2 years after the interven-tion for Dermatophagoides farinae (Der f 1)in the bed and on the bedroom floor andfor Dermatophagoides pteronyssinus (Der p1) and cockroach on the floor. A significantreduction of days with symptoms was alsoobtained when compared with the controlgroup and the reduction of dust mite (Derf 1) and cockroach allergen levels on thebedroom floor was significantly correlatedwith reduced complications of asthma. Inthe second multifaceted study published in2005 by Krieger et al. (6), it was alsodemonstrated that global reduction mea-sures were clinically more efficient thansingle reduction measures.Moreover, these two studies (5, 6)clearly demonstrated the role of indoortechnicians, performing home visits toachieve a global allergen reduction, andconfirmed the results of the French study(7). Brandt et al. (8) underlined also veryrecently the role of indoor techniciansand recommended that public healthprograms should consider the use oftrained field workers such as medicalindoor environment counselors to preventthe progression of allergic asthma andrhinitis.In conclusion, this last meta-analysis byGotzsche and Johansen on house dust mitecontrol measures for asthma clearly dem-onstrated that specific house dust mitecontrol measures for asthma only concen-trated on the bedding were not efficient onallergen exposure and clinical symptoms.So, we think that it is not yet useful toperform every 4 years a new meta-analysisbased on single mite-allergen reductionmeasures for asthma and suggest for thenext meta-analysis to include multi-facetedstudies.F. De Blay, C. Barnig, M. OttDivision of Asthma and Allergy –Department of Chest Diseases UniversityHospital Strasbourg, Strasbourg, France

Circulating Human Eosinophils Share a Similar Transcriptional Profile in Asthma and Other Hypereosinophilic Disorders.

Eosinophils are leukocytes that are released into the peripheral blood in a phenotypically mature state and are capable of being recruited into tissues in response to appropriate stimuli. Eosinophils, traditionally considered cytotoxic effector cells, are leukocytes recruited into the airways of asthma patients where they are believed to contribute to the development of many features of the disease. This perception, however, has been challenged by recent findings suggesting that eosinophils have also immunomodulatory functions and may be involved in tissue homeostasis and wound healing. Here we describe a transcriptome-based approach–in a limited number of patients and controls—to investigate the activation state of circulating human eosinophils isolated by flow cytometry. We provide an overview of the global expression pattern in eosinophils in various relevant conditions, e.g., eosinophilic asthma, hypereosinophilic dermatological diseases, parasitosis and pulmonary aspergillosis. Compared to healthy subjects, circulating eosinophils isolated from asthma patients differed in their gene expression profile which is marked by downregulation of transcripts involved in antigen presentation, pathogen recognition and mucosal innate immunity, whereas up-regulated genes were involved in response to non-specific stimulation, wounding and maintenance of homeostasis. Eosinophils from other hypereosinophilic disorders displayed a very similar transcriptional profile. Taken together, these observations seem to indicate that eosinophils exhibit non-specific immunomodulatory functions important for tissue repair and homeostasis and suggest new roles for these cells in asthma immunobiology.