Showing papers in "Clinical & Experimental Allergy in 2008"

Eosinophils: Biological Properties and Role in Health and Disease

Abstract: Eosinophils are pleiotropic multifunctional leukocytes involved in initiation and propagation of diverse inflammatory responses, as well as modulators of innate and adaptive immunity. In this review, the biology of eosinophils is summarized, focusing on transcriptional regulation of eosinophil differentiation, characterization of the growing properties of eosinophil granule proteins, surface proteins and pleiotropic mediators, and molecular mechanisms of eosinophil degranulation. New views on the role of eosinophils in homeostatic function are examined, including developmental biology and innate and adaptive immunity (as well as their interaction with mast cells and T cells) and their proposed role in disease processes including infections, asthma, and gastrointestinal disorders. Finally, strategies for targeted therapeutic intervention in eosinophil-mediated mucosal diseases are conceptualized.

Pathogenesis of Asthma

Abstract: While asthma is considered an inflammatory disorder of the conducting airways, it is becoming increasingly apparent that the disease is heterogeneous with respect to immunopathology, clinical phenotypes, response to therapies, and natural history. Once considered purely an allergic disorder dominated by Th2-type lymphocytes, IgE, mast cells, eosinophils, macrophages, and cytokines, the disease also involves local epithelial, mesenchymal, vascular and neurologic events that are involved in directing the Th2 phenotype to the lung and through aberrant injury-repair mechanisms to remodeling of the airway wall. Structural cells provide the necessary "soil" upon which the "seeds" of the inflammatory response are able to take root and maintain a chronic phenotype and upon which are superimposed acute and subacute episodes usually driven by environmental factors such as exposure to allergens, microorganisms, pollutants or caused by inadequate antiinflammatory treatment. Greater consideration of additional immunologic and inflammatory pathways are revealing new ways of intervening in the prevention and treatment of the disease. Thus increased focus on environmental factors beyond allergic exposure (such as virus infection, air pollution, and diet) are identifying targets in structural as well as immune and inflammatory cells at which to direct new interventions.

A meta‐analysis of the association between Caesarean section and childhood asthma

Abstract: Summary Background Children born by Caesarean section have modified intestinal bacterial colonization and consequently may have an increased risk of developing asthma under the hygiene hypothesis. The results of previous studies that have investigated the association between Caesarean section and asthma have been conflicting. Objective To review published literature and perform a meta-analysis summarizing the evidence in support of an association between children born by Caesarean section and asthma. Methods MEDLINE, Web Science, Google Scholar and PubMed were searched to identify relevant studies. Odds ratio (OR) and 95% confidence interval (CI) were calculated for each study from the reported prevalence of asthma in children born by Caesarean section and in control children. Meta-analysis was then used to derive a combined OR and test for heterogeneity in the findings between studies. Results Twenty-three studies were identified. The overall meta-analysis revealed an increase in the risk of asthma in children delivered by Caesarean section (OR=1.22, 95% CI 1.14, 1.29). However, in this analysis, there was evidence of heterogeneity (I2=46%) that was statistically significant (P<0.001). Restricting the analysis to childhood studies, this heterogeneity was markedly decreased (I2=32%) and no longer attained statistical significance (P=0.08). In these studies, there was also evidence of an increase (P<0.001) in the risk of asthma after Caesarean section (OR=1.20, 95% CI 1.14, 12.6). Conclusion In this meta-analysis, we found a 20% increase in the subsequent risk of asthma in children who had been delivered by Caesarean section.

Caesarean delivery and risk of atopy and allergic disesase: meta-analyses

Abstract: Summary Background Studies of delivery by caesarean section (c-section) and the offspring's risk of allergic diseases are of current interest due to concerns about the increased use of c-section in many countries. However, previous studies have reported inconsistent findings. Objective We investigated whether delivery by c-section is associated with an increased risk of atopy and allergic disease by reviewing the literature, performing a meta-analysis, and assessing publication bias. Methods We used a systematic literature search of MEDLINE (1966 to May 2007). Six common allergic outcomes were included: food allergy/food atopy, inhalant atopy, eczema/atopic dermatitis, allergic rhinitis, asthma, and hospitalization for asthma. For each outcome a meta-analysis was performed, where a summary odds ratio (OR) was calculated taking into account heterogeneity between the study-specific relative risks. Publication bias was assessed using the funnel plot method. Results We identified 26 studies on delivery by c-section and one or more of the six allergic outcomes. C-section was associated with an increased summary OR of food allergy/food atopy (OR 1.32, 95% CI 1.12–1.55; six studies), allergic rhinitis (OR 1.23, 95% CI 1.12–1.35; seven studies), asthma (OR 1.18, 95% CI 1.05–1.32; 13 studies), and hospitalization for asthma (OR 1.21, 95% CI 1.12–1.31; seven studies), whereas there was no association with inhalant atopy (OR 1.06, 95% CI 0.82–1.38; four studies) and eczema/atopic dermatitis (OR 1.03, 95% CI 0.98–1.09; six studies). Funnel plots indicated that the association with food allergy/food atopy could be difficult to interpret due to publication bias. For each significant association with an allergic outcome, only 1–4% of cases were attributable to c-section. Conclusion Delivery by c-section is associated with a moderate risk increase for allergic rhinitis, asthma, hospitalization for asthma, and perhaps food allergy/food atopy, but not with inhalant atopy or atopic dermatitis. The increased use of c-section during the last decades is unlikely to have contributed much to the allergy epidemic observed during the same period.

Allergens to wheat and related cereals

Abstract: Wheat is one of the major crops grown, processed and consumed by humankind and is associated with both intolerances (notably coeliac disease) and allergies. Two types of allergy are particularly well characterized. The first is bakers' asthma, which results from the inhalation of flour and dust during grain processing. Although a number of wheat proteins have been shown to bind IgE from patients with bakers' asthma, there is no doubt a well-characterized group of inhibitors of alpha-amylase (also called chloroform methanol soluble, or CM, proteins) are the major components responsible for this syndrome. The second well-characterized form of allergy to wheat proteins is wheat-dependent exercise-induced anaphylaxis (WDEIA), with the omega(5)-gliadins (part of the gluten protein fraction) being the major group of proteins which are responsible. Other forms of food allergy have also been reported, with the proteins responsible including gluten proteins, CM proteins and non-specific lipid transfer proteins. Processing of wheat and of related cereals (barley and rye, which may contain related allergens) may lead to decreased allergenicity while genetic engineering technology offers opportunities to eliminate allergens by suppressing gene expression.

Effects of climate change on environmental factors in respiratory allergic diseases

Abstract: A body of evidence suggests that major changes involving the atmosphere and the climate, including global warming induced by human activity, have an impact on the biosphere and the human environment. Studies on the effects of climate change on respiratory allergy are still lacking and current knowledge is provided by epidemiological and experimental studies on the relationship between asthma and environmental factors, such as meteorological variables, airborne allergens and air pollution. However, there is also considerable evidence that subjects affected by asthma are at an increased risk of developing obstructive airway exacerbations with exposure to gaseous and particulate components of air pollution. It is not easy to evaluate the impact of climate change and air pollution on the prevalence of asthma in general and on the timing of asthma exacerbations. However, the global rise in asthma prevalence and severity suggests that air pollution and climate changes could be contributing. Pollen allergy is frequently used to study the interrelationship between air pollution, rhinitis and bronchial asthma. Epidemiological studies have demonstrated that urbanization, high levels of vehicle emissions and westernized lifestyle are correlated to an increase in the frequency of pollen-induced respiratory allergy, prevalent in people who live in urban areas compared with those who live in rural areas. Meteorological factors (temperature, wind speed, humidity, etc.) along with their climatological regimes (warm or cold anomalies and dry or wet periods, etc.), can affect both biological and chemical components of this interaction. In addition, by inducing airway inflammation, air pollution overcomes the mucosal barrier priming allergen-induced responses. In conclusion, climate change might induce negative effects on respiratory allergic diseases. In particular, the increased length and severity of the pollen season, the higher occurrence of heavy precipitation events and the increasing frequency of urban air pollution episodes suggest that environmental risk factors will have a stronger effect in the following decades.

Impact of maternal atopy and probiotic supplementation during pregnancy on infant sensitization: a double‐blind placebo‐controlled study

Abstract: Summary Background The effects of breastfeeding and probiotics on infant sensitization still remain discrepant. Objective To explore probable explanatory factors in infant sensitization and the protective effect of probiotics. Methods Altogether 171 mother–infant pairs from an ongoing placebo-controlled double-blind study with nutrition modulation by dietary counselling and probiotic supplementation were studied. Skin prick testing was done in infants at 6 and 12 months and in mothers at third trimester of pregnancy. The breast milk concentrations of cytokines TGF-β2, soluble CD14, IFN-γ, TNF-α, IL-10, IL-6, IL-4 and IL-2 were measured. Results The risk of sensitization increased in infants with allergic mothers breastfeeding over 6 months [odds ratio (OR=4.83, P=0.005)], or exclusively breastfeeding over 2.5 months (OR=3.4, P=0.018). Probiotic supplementation had a protective effect against sensitization in infants with a high hereditary risk due to maternal sensitization (OR=0.3, P=0.023). The concentration of TGF-β2 tended to be higher in the colostrum of the mothers in the probiotic group as compared with those on placebo (probiotic/placebo ratio=1.50, P=0.073). A similar result was obtained in the subgroup of allergic mothers (probiotic/placebo ratio=1.56, P=0.094). Conclusion Infants of atopic mothers, specifically when breastfed exclusively over 2.5 months or totally over 6 months, had a higher risk of sensitization at the age of 12 months. This risk could be reduced by the use of probiotics during pregnancy and lactation, partly by resulting in a beneficial composition of the breast milk.

Supplementation with Lactobacillus rhamnosus or Bifidobacterium lactis probiotics in pregnancy increases cord blood interferon-γ and breast milk transforming growth factor-β and immunoglobin A detection

Abstract: Summary Background This study explored the effects of maternal probiotic supplementation on immune markers in cord blood (CB) and breast milk. Methods CB plasma and breast milk samples were collected from a cohort of women who had received daily supplements of either 6 × 109 CFU/day Lactobacillus rhamnosus HN001 (n=34), 9 × 109 CFU/day Bifidobacterium lactis HN019 (n=35) or a placebo (n=36) beginning 2–5 weeks before delivery and continuing for 6 months in lactating women. CB plasma and breast milk (collected at 3–7 days, 3 months and 6 months postpartum) were assayed for cytokines (IL-13, IFN-γ, IL-6, TNF-α, IL-10, TGF-β1) and sCD14. Breast milk samples were also assayed for total IgA. Results Neonates of mothers who received a probiotic had higher CB IFN-γ levels (P=0.026), and a higher proportion had detectable blood IFN-γ levels, compared with the placebo group (P=0.034), although levels were undetectable in many infants. While this pattern was evident for both probiotics, when examined separately only the L. rhamnosus HN001 group showed statistically significant higher IFN-γ levels (P=0.030) compared with the placebo group. TGF-β1 levels were higher in early breast milk (week 1) from the probiotic groups (P=0.028). This was evident for the B. lactis HN019 group (P=0.041) with a parallel trend in the L. rhamnosus HN001 group (P=0.075). Similar patterns were seen for breast milk IgA, which was more readily detected in breast milk from both the B. lactis HN019 (P=0.008) and the L. rhamnosus HN001 group (P=0.011). Neonatal plasma sCD14 levels were lower in the B. lactis HN019 group compared with the placebo group (P=0.041). Conclusion The findings suggest that supplementation with probiotics in pregnancy has the potential to influence fetal immune parameters as well as immunomodulatory factors in breast milk.

Food allergy QoL questionnaire for children aged 0-12 years : content, construct, and cross-cultural validity

Abstract: Summary Background To date, there is no food allergy-specific questionnaire that allows parents to report children's health-related QoL (HRQL) from the child's perspective. Objective The aim of this study was to develop a sensitive, multi-dimensional measure to assess parental perception of HRQL in children aged 0–12 years with food allergy. Methods The Food Allergy QoL – Parent Form (FAQLQ-PF) was developed and validated in four stages: (1) item generation using focus groups, expert opinion, and literature review; (2) item reduction, using clinical impact and factor analysis; (3) internal and test–retest reliability and construct validity were evaluated using relevant scales of the Child Health Questionnaire (CHQ)-28 and the disease-specific food allergy independent measure (FAIM); and (4) cross-cultural and content validity was examined by administering the questionnaire in a US sample. Results Stage 1: Saturation was reached at 110 items. Stage 2: The reduced instrument has 14 items for children <4 years and 26 and 30 items for children aged 4–6 years and 7–12 years, respectively. Factor analysis revealed three subscales: emotional impact, food anxiety, and social and dietary limitations, accounting for 68% of the variance. Stage 3: Cronbach's α >0.7 for subscales and total score. Construct validity was demonstrated by significant correlations between relevant scales of the CHQ-28 and FAQLQ-PF subscales (r=0.69–0.77, P<0.01), and between FAQLQ-PF subscales and the FAIM. Sensitivity was shown by significant within-group differences in a sample of 124 food-allergic children. Stage 4: The FAQLQ-PF was validated in a sample of US children, Cronbach's α >0.7 for subscales and total score. Construct validity was demonstrated by significant correlations between FAQLQ-PF and the FAIM (parent report) and between the FAQLQ-PF and the FAIM (child report). No differences were observed between the US and Irish scores. Conclusion The FAQLQ-PF is psychometrically robust, with excellent reliability and validity.

Probiotics in infancy induce protective immune profiles that are characteristic for chronic low-grade inflammation

Abstract: Summary Background Probiotics are widely studied both in the treatment and prevention of allergic diseases, but their mode of action is poorly known. Objective Our aim was to examine the effect of probiotic bacteria on in vivo cytokine, antibody, and inflammatory responses in allergy-prone infants. Methods In a randomized double-blind study, probiotic bacteria or placebo were given for 1 month before delivery to mothers and for 6 months to infants with a family history of allergy. Plasma samples were analysed for C-reactive protein (CRP), total IgA and IgE, food-specific IgA, IgG, and IgE, IL-2, IL-4, IL-6, IL-10, TNF-α, and IFN-γ. We analysed the associations of immunological and inflammatory parameters at age 6 months with probiotic treatment and allergic phenotype at 2 years. Results Infants receiving probiotic bacteria had higher plasma levels of CRP (P=0.008), total IgA (P=0.016), total IgE (P=0.047), and IL-10 (P=0.002) than infants in the placebo group. Increased plasma CRP level at age 6 months was associated with a decreased risk of eczema [odds ratio (OR) 0.41 [95% confidence interval (CI) 0.17–0.99], P=0.046], and with a decreased risk of allergic disease [OR 0.38 (95% CI 0.16–0.87), P=0.023] at age 2 years, when adjusted with probiotic use. Conclusion The association of CRP with a decreased risk of eczema at 2 years of age in allergy-prone children supports the view that chronic, low-grade inflammation protects from eczema. Probiotic-induced low-grade inflammation was characterized by elevation of IgE, IgA, and IL-10, the changes typically observed in helminth infection-associated induction of regulatory mechanisms. The findings emphasize the role of chronic microbial exposure as an immune modulator protecting from allergy.

IL‐13 induced increases in nitrite levels are primarily driven by increases in inducible nitric oxide synthase as compared with effects on arginases in human primary bronchial epithelial cells

Abstract: Summary Background Exhaled nitric oxide is increased in asthma, but the mechanisms controlling its production, including the effects of T-helper type 2 (Th2) cytokines, are poorly understood. In mouse and submerged human epithelial cells, Th2 cytokines inhibit expression of inducible nitric oxide synthase (iNOS). Arginases have been proposed to contribute to asthma pathogenesis by limiting the arginine substrate available to NOS enzymes, but expression of any of these enzymes has not been extensively studied in primary human cells. Objectives We hypothesized that primary human airway epithelial cells in air–liquid interface (ALI) culture would increase iNOS expression and activity in response to IL-13, while decreasing arginase expression. Methods iNOS and arginase mRNA (real-time PCR) and protein expression (Western blot and immunofluorescence) as well as iNOS activity (nitrite levels) were measured in ALI epithelial cells cultured from bronchial brushings of normal and asthmatic subjects following IL-13 stimulation. Results IL-13 up-regulated iNOS mRNA primarily at a transcriptional level in epithelial cells. iNOS protein and activity also increased, arginase1 protein expression decreased while arginase 2 expression did not change. The changes in iNOS protein correlated strongly with changes in nitrites, and inclusion of arginase (1 or 2) did not substantially change the relationship. Interestingly, iNOS mRNA and protein were not correlated. Conclusions These results contrast with many previous results to confirm that Th2 stimuli enhance iNOS expression and activity. While arginase 1 protein decreases in response to IL-13, neither arginase appears to substantially impact nitrite levels in this system.

Clinical effects of immunotherapy with genetically modified recombinant birch pollen Bet v 1 derivatives

Abstract: Summary Background Birch pollen and pollen from related trees of the Fagales order are a major cause of allergic rhinitis, conjunctivitis, and asthma through the spring season in northern and central Europe. Objective To investigate the clinical effects of injection immunotherapy with genetically modified derivatives of major birch pollen allergen Bet v 1 on pollen-induced allergic symptoms. Methods A three-arm double-blind placebo-controlled immunotherapy study was conducted with one pre-seasonal course of treatment using two derivatives of Bet v 1, namely a recombinant Bet v 1 trimer and an equimolar mixture of two recombinant Bet v 1 fragments together representing the whole protein sequence. Analysis of local and systemic adverse events was performed for 124 patients who had received at least one dose of medication. Clinical efficacy was monitored by symptom medication scores and interval scoring in the per protocol-treated population (n=84). In addition, skin and nasal provocation responses and allergen-specific antibodies were assessed. Results There were trends towards improvement in the subjects' well-being and clinical symptoms (nasal scores), although comparisons with a placebo group did not show statistical significance in the main end-point, the combined symptom medication score. Reductions in skin and nasal sensitivity were observed for some subjects with a trend for the Bet v 1 trimer to be more effective than the fragments. Treatment induced strong IgG1 and IgG4 allergen-specific antibody responses. Local injection-site reactions were most frequent in the trimer group affecting 59.5% of patients as opposed to 37.8% and 30.6% in the fragment and placebo groups, respectively. Systemic reactions were elicited more frequently by fragments. A large proportion of adverse side-effects appeared hours following injections, and might be attributable to concurrent exposure to related pollens. Conclusion Single courses of injection immunotherapy with Bet v 1 allergen derivatives showed trends towards improved well-being and reduced reactivity to specific allergen provocation, but did not yield significant improvement in the combined symptom medication score in this study.

Profilin sensitization detected in the office by skin prick test: a study of prevalence and clinical relevance of profilin as a plant food allergen.

Abstract: Background Profilin, a pan-allergen present in all eukaryotic cells, is one of the main causes of cross-sensitization between pollen and plant-derived foods, but its clinical relevance as a food allergen is still debated. Objective To investigate the prevalence of profilin sensitization in a pollen-allergic population and its clinical relevance as a food allergen. Methods Two hundred consecutive patients with pollen allergy underwent skin prick tests (SPT) with purified natural date palm profilin (Pho d 2; 50 microg/mL; Alk Abello, Madrid, Spain). Those reporting adverse reactions to foods (confirmed by SPT with either commercial food extracts or fresh foods) underwent SPT with an apple extract containing uniquely Mal d 1 (2 microg/mL; ALK-Abello), and with a commercial peach extract containing uniquely lipid transfer protein (LTP 30 microg/mL; ALK-Abello). Results Sixty patients (30%) showed skin reactivity to date palm profilin, Pho d 2. All were sensitized to grass pollen, and most of them reacted to birch, mugwort, ragweed and plantain pollen as well. SPT with pellitory and cypress scored negative in a high proportion of profilin reactors [26/60 (43%) and 33/60 (55%), respectively]. More than one half (34/60 [57%]) of profilin reactors had food allergy; 21 of these were monosensitized to profilin, 11 were sensitized to both profilin and Bet v 1 homologous protein, one to both profilin and LTP, and one to all the three allergens. The large majority of profilin-allergic patients reported oral allergy syndrome as the only food-induced symptom and were able to tolerate the offending foods if they were cooked or otherwise processed. Twenty-eight of 34 reported reactivity to two or more plant-derived foods. Rosaceae, tree nuts, melon and watermelon, tomato, pineapple, citrus fruits and banana were the more frequently offending foods. Conclusion Profilin should be considered a clinically relevant food allergen. Allergy to melon, watermelon, tomato, banana, pineapple and orange may be considered as a marker of profilin hypersensitivity. This study underlines the clinical importance of being able to diagnose hypersensitivity to single food allergenic proteins by SPT, particularly when the relevant food allergen sources contain several allergens that show different chemical/physical features and, hence, completely different risk profiles.

Association of serum interleukin-33 level and the interleukin-33 genetic variant with Japanese cedar pollinosis.

Abstract: Summary Background IL-33, an IL-1-like cytokine, is a ligand for IL1RL1, which is an important effector molecule of type 2 T helper responses. Although IL-33/IL1RL1 interaction has been suggested to be important in induction of allergic airway inflammation, serum levels of IL-33 and the genetic influences of the polymorphisms of IL-33 in human allergic diseases are unclear. Objective The aim of this study was to examine whether the serum IL-33 level and polymorphisms in IL-33 are associated with Japanese cedar (JC) pollinosis, the most common form of allergic rhinitis, and a major public health problem, in Japan. Methods We performed linkage disequilibrium (LD) mapping of the gene using the HapMap database, and two selected tag single nucleotide polymorphisms were genotyped. We conducted an association study of IL-33 (JC pollinosis, n=170; normal controls, n=100) and measured the IL-33 levels in sera of the 270 subjects by ELISA. Results Serum levels of IL-33 were significantly higher in patients with JC pollinosis (P=0.0018) than in controls. In genetic association analysis, we found a positive association between the polymorphism and JC pollinosis (P=0.048). Conclusion Our results support a role for IL-33 in the pathogenesis of JC pollinosis.

Immunoregulatory roles of eosinophils: a new look at a familiar cell

Abstract: Summary Eosinophils are usually considered as end-stage degranulating effector cells of innate immunity. However, accumulating evidence has revealed additional roles for eosinophils that are immunoregulatory in nature in both the adaptive and innate arms of immunity. Specifically, eosinophils have key immunoregulatory roles as professional antigen-presenting cells and as modulators of CD4+ T cell, dendritic cell, B cell, mast cell, neutrophil, and basophil functions. This review addresses the emerging immunoregulatory roles of eosinophils with a focus on recent data that support this new paradigm. Recognizing both the effector and immunoregulatory functions of eosinophils will enable a fuller understanding of the roles of eosinophils in allergic airways inflammation and may be pertinent to therapies that target eosinophils both for their acute and ongoing immunomodulatory functions.

Oral delivery of Lactobacillus casei Shirota modifies allergen-induced immune responses in allergic rhinitis.

Abstract: Summary Background Changes in the composition of the gut microbiota have been implicated in the pathogenesis of allergic disorders, suggesting beneficial interactions between the intestinal immune system and specific bacterial strains. Lactobacilli are naturally present within the complex gastrointestinal microbiota of humans and they are currently present in many probiotic supplements. Objective We sought to investigate the role that Lactobacillus casei Shirota (LcS) may play in modulating seasonal allergic rhinitis (SAR). Methods The study format was double-blinded, placebo-controlled with 10 SAR sufferers in each group. We have documented and compared changes in immune status arising through the daily ingestion of a milk drink with or without live LcS, over a period of 5 months. Pre-, peak- and post-grass pollen season blood samples were collected for determination of plasma total IgE and grass pollen-specific IgG and IgE levels by an enzyme immunoassay. At the same time, cytokine levels were determined by flow cytometric bead array technology following culture of peripheral blood mononuclear cells for 6 days in the presence or absence of specific grass pollen antigens. Results Volunteers treated with LcS showed a significant reduction in levels of antigen-induced IL-5, IL-6 and IFN-γ production compared with volunteers supplemented with placebo. Meanwhile, levels of specific IgG increased and IgE decreased in the probiotic group. Conclusion Changes in antigen-induced production of cytokines were observed in patients treated with probiotics. These data show that probiotic supplementation modulates immune responses in allergic rhinitis and may have the potential to alleviate the severity of symptoms.

Update on mechanisms of allergen injection immunotherapy.

Abstract: The incidence of allergic diseases is increasing at an alarming rate, particularly in countries with a western lifestyle. Currently in the UK, approximately one quarter of the population suffers from seasonal allergic rhinitis. Most patients can be treated with conventional pharmacotherapy on an 'as needed' symptomatic basis whereas allergen immunotherapy represents a useful treatment approach in carefully selected patients with severe, IgE-mediated disease. Allergen immunotherapy can deliver improvements in hayfever symptoms over and above that which can be achieved by pharmacotherapy. In addition, unlike pharmacotherapy, allergen immunotherapy provides long-term clinical benefits. These include long-term disease remission, prevention of new atopic sensitisations and a reduction in disease progression from rhinitis to asthma. This review provides a comprehensive update on the mechanisms of allergen injection immunotherapy, recent data on the mechanisms of sublingual allergen immunotherapy is also included.

Early infection with Trichuris trichiura and allergen skin test reactivity in later childhood.

Abstract: Summary Background Allergic diseases cause a large and increasing burden in developed countries and in urban centres in middle-income countries. The causes of this increase are unknown and, currently, there are no interventions to prevent the development of allergic diseases. The ‘hygiene hypothesis’ has tried to explain the increase through a reduction in the frequency of childhood infections causing a failure to program the immune system for adequate immune regulation. Intestinal helminth parasites are prevalent in childhood in developing countries and are associated with a lower prevalence of allergen skin test reactivity and asthma. Objectives To investigate whether children who had intestinal helminth infections during early childhood have a lower prevalence of allergen skin test reactivity later in childhood. Methods We re-visited a population of 1055 children from whom stool samples had been collected for detection of intestinal helminth infections for another study, and collected new stool samples and performed allergen skin prick testing. Information on potential confounding variables was collected. Results Children with heavy infections with Trichuris trichiura in early childhood had a significantly reduced prevalence of allergen skin test reactivity in later childhood, even in the absence of T. trichiura infection at the time of skin testing in later childhood. Conclusion Early heavy infections with T. trichiura may protect against the development of allergen skin test reactivity in later childhood. Novel treatments to program immune-regulation in early childhood in a way that mimics the effects of early infections with T. trichiura may offer new strategies for the prevention of allergic disease.

Heterogeneity of commercial timothy grass pollen extracts

Abstract: Summary Background The diagnosis and specific immunotherapy of allergy is currently performed with allergen extracts prepared from natural allergen sources. Objective To analyse commercial timothy grass pollen allergen extracts used for in vivo diagnosis regarding their qualitative and quantitative allergen composition and in vivo biological activity. Methods Antibodies specific for eight timothy grass pollen allergens (Phl p 1, Phl p 2, Phl p 4, Phl p 5, Phl p 6, Phl p 7, Phl p 12, Phl p 13) were used to detect these allergens in timothy grass pollen extracts from four manufacturers by immunoblotting. ELISA assays were developed and used to quantify the three major allergens (Phl p 1, Phl p 2, Phl p 5) in the extracts. The magnitude of skin responses to the four extracts was studied by skin prick testing in 10 grass pollen-allergic patients. Results The allergen extracts showed broad variations in protein compositions and amounts (24.1‐197.7mg/mL extract). Several allergens could not be detected in certain extracts or appeared degraded. A considerable variability regarding the contents of major allergens was found (Phl p 1: 32‐384ng/mL; Phl p 2: 1128‐6530ng/mL, Phl p 5: 40‐793ng/mL). Heterogeneous skin test results were obtained with the extracts in grass pollen-allergic patients. Conclusions Timothy grass pollen extracts from different manufacturers exhibit a considerable heterogeneity regarding the presence of individual allergens and hence yield varying in vivo test results. Problems related to the use of natural grass pollen allergen extracts may be circumvented by using defined recombinant grass pollen allergens.

Human blood dendritic cells from allergic subjects have impaired capacity to produce interferon‐α via toll‐like receptor 9

Abstract: Summary Background High-affinity IgE receptor (FcɛRI) expression on blood dendritic cells reportedly correlates with serum IgE levels. Our studies demonstrate that plasmacytoid dendritic cells (pDCs) secrete pro-inflammatory cytokines (IL-6, TNF-α) following FcɛRI stimulation – a mode of activation that simultaneously reduces expression of Toll-like receptor 9 (TLR9). Whether or not TLR9 and/or FcɛRI levels and their function on dendritic cells relate to allergic status is unknown. Objective The aim of this study is to compare the innate (TLR9-mediated) immune response of human pDCs to TLR9 and FcɛRIα receptor expression in allergic and non-allergic subjects. Methods Basophil-depleted mononuclear cell fractions containing pDCs were prepared from peripheral blood of allergic and non-allergic subjects. Intracellular TLR9 and surface FcɛRIα expression in blood dendritic cell antigen-2-positive cells were determined by flow cytometry. Activating anti-IgE antibody, anti-FcɛRIα antibody, and TLR9 agonist were used to stimulate cell suspensions, with cytokine levels determined by ELISA. Results No difference in the frequency of pDCs was detected among allergic (n=9) vs. non-allergic (n=11) subjects (P=0.261). While there was also no difference in the baseline expression of TLR9, pDCs from allergic subjects produced sixfold less IFN-α when stimulated with CpG (P=0.002). Conversely, there was higher FcɛRIα expression (P=0.01) on the pDCs of allergic subjects. Conclusions Impaired TLR9-dependent immune responses in human pDCs are associated with allergic status and inversely correlated with FcɛRIα expression. This impaired innate immune response among dendritic cells of allergic subjects may lead to more targeted therapeutic approaches and could provide a better understanding of the mechanisms underlying conventional and CpG-based immunotherapy.

Allergic asthma: a tale of many T cells.

Abstract: Asthma is a common immune-mediated disorder characterized by reversible airway inflammation, mucus production, and variable airflow obstruction with airways hyperresponsiveness (AHR). In most cases the airway inflammation characteristic of asthma is thought to result from an allergic-type reaction to an inhaled substance from the environment (so-called allergic asthma). In allergic asthma, allergen exposure stimulates eosinophilic inflammation of the airways associated with infiltration of T cells. Although the recruitment of eosinophils into the airways is an important component in the pathogenesis of asthma, the trafficking of T lymphocytes into the airways is now believed to establish and orchestrate the asthmatic inflammatory response. This review explores the roles of various T cell subsets in the pathogenesis of allergic airway inflammation and highlights the contributions of these cells in regulating asthma.

Non-immediate reactions to β-lactams: diagnostic value of skin testing and drug provocation test

Abstract: Summary Background β-Lactam (BL) antibiotics can induce non-immediate skin reactions, frequently manifested as exanthema or urticaria. The time between drug intake and the reaction appearance is generally 24–48 h. Because the mechanisms involved are not completely understood, diagnostic tests for these reactions have still to be fully validated. Objective To evaluate the role of skin and drug provocation tests (DPTs) in the diagnosis of patients with non-immediate reactions to BL. Methods We evaluated a group of 22 patients who developed maculopapular exanthema or urticarial exanthema after BL intake. Diagnosis was confirmed by DPT with BL. Intradermal/patch testing was performed with benzylpenicilloyl, minor determinant mixture, amoxicillin (AX), ampicillin (AMP) and the culprit drug in patients and in 22 negative controls. Immunohistochemical studies were done in the affected skin at the acute phase of the reaction and after a delayed positive skin test/DPT. IFN-γ and IL-4 were quantified in peripheral mononuclear cells, obtained during the positive response to DPT and after resolution of the symptoms. Results From the total number of cases, 12 patients developed urticarial exanthema and 10 maculopapular exanthema after DPT. Only two of the 22 patients (9%) had a positive delayed intradermal skin test: one to AX/AMP and the other to cloxacillin. Biopsies showed a mononuclear CD4, CD8 infiltrate and activated and memory cells. The cytokine expression showed a Th1 pattern in patients, in contrast with the Th0 pattern in controls. Conclusion In patients with non-immediate reactions to BLs (maculopapular exathema or urticarial exanthema), the sensitivity of skin testing is low and DPT may be required to establish the diagnosis. The reproducibility of the reactions and the cytokine pattern expressed during the acute episode support a T cell-induced non-immediate response.

Fatty acid composition abnormalities in atopic disease: evidence explored and role in the disease process examined

Abstract: Summary There is a hypothesis causally linking excess intake of n-6 polyunsaturated fatty acids (PUFAs) to atopic disease. Under most dietary conditions, the main precursor of eicosanoids is the n-6 PUFA arachidonic acid (AA). AA-derived eicosanoids play many roles in sensitization to allergens and in allergic inflammation. Long chain n-3 PUFAs inhibit AA incorporation into cell membranes and inhibit AA metabolism to eicosanoids. It is hypothesized that atopy is associated with a higher n-6 PUFA status and with a low n-3 PUFA status. However, measurements of fatty acid composition do not provide a clear picture that such fatty acid abnormalities exist in atopy with no really clear pattern of altered status of a particular fatty acid or a particular fatty acid family. There are few reports of elevated linoleic acid in atopy. Some studies report lower amounts of the n-6 PUFAs, including AA, and of long chain n-3 PUFAs in atopy, although observations on this are not consistent. Taken together these data clearly do not support the hypothesis that atopy is somehow associated with a high exposure to, and status of, n-6 PUFAs. Intervention studies with n-3 PUFAs in pregnant women, infants and children suggest some clinical benefits, although how long lasting these are remains to be determined. The observation that there may be low AA status in atopy suggests that fish oil intervention, which targets AA status and metabolism, may not be ideal and that a combination of fish oil with some longer chain n-6 PUFAs may be more efficacious WEB/URL: PM:18665842;

A double-blind placebo-controlled birch allergy vaccination study II: correlation between inhibition of IgE binding, histamine release and facilitated allergen presentation

Abstract: Summary Background The pathogenesis of IgE-mediated allergic disease is closely related to the production of T-helper type 2 (Th2) cytokines, which lead to IgE production pivotal for activation of mast cells and basophils. Proliferating T cells along with eosinophils expanded and attracted by Th2 cytokines are major contributors to the late-phase reaction. The activation of these Th2 cells is strongly enhanced by CD23-mediated IgE facilitated allergen presentation (FAP). Objective The present study aims to investigate the effect of specific immunotherapy (SIT)-induced allergen-specific non-IgE antibodies (blocking antibodies) on IgE binding to allergen, histamine release (HR) and CD23-mediated allergen uptake in antigen-presenting cells. Methods Competition between IgE and non-IgE for allergen binding was studied by Advia Centaur antibody measurements, passively sensitized basophils were used to study HR and IgE-facilitated binding of allergen to B cells (FAP) was studied by flow cytometry. FAP measurements were performed both with and without the addition of a reference IgE serum, which was included to obtain optimal complex formation. The serum samples were obtained from birch pollen immunotherapy (n=21) or placebo control patients (n=21) before and after 1 and 2 years of treatment. Results Statistically significant reduction of all parameters investigated was observed after 1 year of treatment and the effect was maintained during the second year of treatment. There was a clear correlation between the two FAP measurements and between each of them and the level of T cell activation reported upon previously. Moreover, strong correlations were found between changes in FAP, IgE binding and HR. Conclusion The present study clearly demonstrates that SIT induces changes in the composition of serum antibodies that inhibit IgE binding, HR and FAP to a similar extent. This suggests that these measurements, individually or in combination, may be used to monitor the immunological effect of SIT, even though direct correlations to changes in clinical parameters could not be demonstrated.

Comparison of two basophil activation markers CD63 and CD203c in the diagnosis of amoxicillin allergy

Abstract: Summary Background To confirm allergy to b-lactam (BL), a basophil activation test in flow cytometry based on CD63 up-regulation was described. CD203c is a more recent basophil activation marker and up to day there is no consensus about which marker is the more sensitive one. CD203c has not yet been evaluated in the diagnosis of BL allergy. Objective The aim of the study was to compare the reliability of CD203c to CD63 for the diagnosis of amoxicillin (AX) allergy, which is nowadays the most frequent BL allergy. Methods Twenty-seven patients with an immediate positive skin test (ST) to AX, 20 had had anaphylaxis with AX and 7 had urticaria and/or angioedema, were compared with 14 controls with no allergy to BL and to six patients with delayed positive ST to AX. Results In the anaphylaxis group, AX induced up-regulation of CD203c in the basophils of 12 patients out of 20 (60%) and of CD63 in four patients (20%) (Po0.02). Two patients out of seven with urticaria or angioedema had a positive result with CD203c and CD63. In patients who had anaphylaxis, ampicillin (AMP) induced CD203c up-regulation in eight out of 12 (67%) patients tested, and CD63 up-regulation in 4 out of 12 (33%) (all patients who had anaphylaxis could not be tested with AMP). False-positive results were observed with CD203c as well as CD63, and for 10 patients indeed this was confirmed by a negative drug provocation test. The origin of conflicting results between CD63 and CD203c might be at least the targeting of basophils based on anti-IgE labelling. Among IgE 1 gated cells, by means of CD33, a marker of monocytes, a contamination up to 50% by monocytes was detected. In contrast to CD63, CD203c is an activation marker specific of basophils with a basal low-level expression in resting basophils. Thus, IgE and CD203c double targeting of basophils avoids the contamination by monocytes. Conclusion CD203c seems to be a more sensitive activation marker of basophils than CD63 for the diagnosis of amoxicillin allergy.

Effects of dog ownership in early childhood on immune development and atopic diseases

Abstract: SummaryBackground Exposure to pets in childhood has been associated with a reduced risk ofwheezing and atopy.Objective Our objective was to determine whether the effects of pet exposure on immunedevelopment and atopy in early childhood can be explained by alterations in exposure toinnate immune stimuli in settled dust.Methods Two hundred and seventy-five children at increased risk of developing allergicdiseases were evaluated to age 3 years for pet ownership, blood cell cytokine responses, andatopy. Can f 1, Fel d 1, endotoxin, ergosterol, and muramic acid were measured in settled dustfrom 101 homes.Results Dog exposure at birth was associated with decreased atopic dermatitis (AD) (12% vs.27%; P=0.004) and wheezing (19% vs. 36%; P=0.005) in year 3. The rates of AD (23%) andwheezing (42%) in year 3 were relatively high in children who acquired dogs after birth. Theprevalence of dog sensitization (10–12%) did not vary according to dog exposure. Can f 1levels in bedroom dust were positively associated with IL-10 (r=0.26; P=0.01), IL-5 (r=0.34,Po0.001),andIL-13(r=0.28;P=0.004)responsesatage1,andIL-5(r=0.24;P=0.022)andIL-13(r=0.25;P=0.015)responsesatage3.Incontrast,endotoxinwasassociatedwithIFN-g(r=0.31; P=0.002) and IL-13 (r=0.27; P=0.01) responses at age 3 but not at age 1, andsimilar relationships were present for muramic acid. Adjustment for levels of innate immunestimuli in house dust did not significantly affect the relationships between Can f 1 andcytokine responses.ConclusionsExposuretodogsininfancy,andespeciallyaroundthetimeofbirth,isassociatedwith changes in immune development and reductions in wheezing and atopy. These findingsare not explained by exposure to endotoxin, ergosterol, or muramic acid.Keywords atopic dermatitis, cytokines, dogs, pets, wheezingSubmitted 30 August 2007; revised 14 March 2008; accepted 17 March 2008

Asthma and allergic symptoms in relation to house dust endotoxin: Phase Two of the International Study on Asthma and Allergies in Childhood (ISAAC II).

Abstract: BACKGROUND: Several studies have consistently reported inverse associations between exposure to endotoxin in house dust and atopy. With regard to the association between house dust endotoxin and as ...

Toll‐like receptor 2 agonist Pam3CSK4 enhances the induction of antigen‐specific tolerance via the sublingual route

Abstract: Summary Background Sublingual immunotherapy (SLIT) has been established in humans as a safe and efficacious treatment for type I respiratory allergies. Objective In this study, we compared three Toll-like receptor (TLR) 2 ligands (Pam3CSK4, Porphyromonas gingivalis lipopolysaccharide and lipoteichoic acid) as potential adjuvants for sublingual allergy vaccines. Methods These molecules were tested in co-cultures of adjuvant-pre-treated dendritic cells (DCs) with murine naive CD4+ T lymphocytes. Patterns of cytokine production, phenotype, proliferation and gene expression were analysed by ELISA, cytofluorometry and quantitative PCR, respectively. TLR2 ligands were subsequently tested in a model of SLIT in BALB/c mice sensitized with ovalbumin (OVA). Results Among the three TLR2 ligands tested, the synthetic lipopeptide Pam3CSK4 is the most potent inducer of IL-12p35 and IL-10 gene expression in murine bone marrow-derived DCs, as well as in purified oral myeloid DCs. Only Pam3CSK4-treated DCs induce IFN-γ and IL-10 secretion by naive CD4+ T cells. Sublingual administration of Pam3CSK4 together with the antigen in BALB/c mice sensitized to OVA decreases airway hyperresponsiveness as well as OVA-specific T-helper type 2 (Th2) responses in cervical lymph nodes dramatically. Conclusion Pam3CSK4 induces Th1/regulatory T cell responses, and as such, is a valid candidate adjuvant for sublingual allergy vaccines.

Phenotypes of food hypersensitivity and development of allergic diseases during the first 8 years of life.

Abstract: Summary Background Longitudinal data from population-based studies on the development and persistence of food hypersensitivity (FHS) during childhood are almost absent. Methods A population-based birth cohort was established, and information on various exposures and symptoms of allergic disease were obtained from questionnaires when the children were 2 months, 1, 2, 4 and 8 years of age. Complete data were available on 3104 children. Children with reported FHS and doctor's diagnosis of food allergy (RDFA) were identified and allocated into transient, intermittent, late-onset and persistent phenotypes. Food allergen-specific IgE-antibodies (abs) to a mix of six common food allergens (fx5®) were analysed at 4 and 8 years of age in 1857 children. Results The overall prevalence of reported FHS in combination with RDFA should be 3.1% at 1 year to 7.6% at 8 years of age. However, reactions to milk, egg, fish and wheat decreased, whereas an increase was seen for peanuts and tree nuts. Reported reactions to egg, peanuts or tree nuts early in life, as well as IgE-abs to food allergens at the age of 4, increased the risk of FHS at 8 years of age. Furthermore, FHS at young ages increased the risk for asthma, eczema and allergic rhinitis at 8 years of age, even when adjustments were made for children with these symptoms during the first 2 years of life. Conclusion The increasing prevalence of FHS up to the age of 8 years probably reflects an increasing prevalence of allergy to birch pollen and pollen-related reactions to foods. Reactions to egg, peanuts and tree nuts early in life increase the risk of FHS at 8 years. Furthermore, reported FHS at young ages, even though transient, seems to increase the risk for other allergic diseases at 8 years of age.

Loss of classical transient receptor potential 6 channel reduces allergic airway response

Abstract: Summary Background Non-selective cation influx through canonical transient receptor potential channels (TRPCs) is thought to be an important event leading to airway inflammation. TRPC6 is highly expressed in the lung, but its role in allergic processes is still poorly understood. Objective The purpose of this study was to evaluate the role of TRPC6 in airway hyperresponsiveness (AHR) and allergic inflammation of the lung. Methods Methacholine-induced AHR was assessed by head-out body plethysmography of wild type (WT) and TRPC6−/− mice. Experimental airway inflammation was induced by intraperitoneal ovalbumin (OVA) sensitization, followed by OVA aerosol challenges. Allergic inflammation and mucus production were analysed 24 h after the last allergen challenge. Results Methacholine-induced AHR and agonist-induced contractility of tracheal rings were increased in TRPC6−/− mice compared with WT mice, most probably due to compensatory up-regulation of TRPC3 in airway smooth muscle cells. Most interestingly, when compared with WT mice, TRPC6−/− mice exhibited reduced allergic responses after allergen challenge as evidenced by a decrease in airway eosinophilia and blood IgE levels, as well as decreased levels of T-helper type 2 (Th2) cytokines (IL-5, IL-13) in the bronchoalveolar lavage. However, lung mucus production after allergen challenge was not altered by TRPC6 deficiency. Conclusions TRPC6 deficiency inhibits specific allergic immune responses, pointing to an important immunological function of this cation channel in Th2 cells, eosinophils, mast cells and B cells.