Recent Journal Articles: Allergy -- Neurotransmitter.net

Recent Articles in Journal of Allergy and Clinical Immunology

Hancox RJ, Welch D, Poulton R, Taylor DR, McLachlan CR, Greene JM, Sears MR
Cigarette smoking and allergic sensitization: A 32-year population-based cohort study.
J Allergy Clin Immunol. 2007 Nov 30;
BACKGROUND: Cigarette smoke has immunosuppressant effects, but its effect on allergic sensitization is unclear. OBJECTIVE: To investigate associations between parental and personal smoking and skin prick tests (SPTs) for atopy in a population-based birth cohort of 1037 participants followed to adulthood. METHODS: Parental history of atopic disease, parental smoking, and personal smoking were obtained at multiple assessments between birth and age 32 years. Atopy was assessed by SPTs for 11 common inhaled allergens at ages 13 and 32 years. RESULTS: Children of atopic parents were less likely to have positive SPTs at age 13 years if either parent smoked (odds ratio, 0.55; P = .009). This association was not significant after adjusting for breast-feeding history, number of siblings, and childhood socioeconomic status. Subjects with atopic parents were also less likely to develop positive results to SPTs between ages 13 and 32 years if they smoked themselves (odds ratio, 0.18; P < .001). This reduction in risk remained significant after adjusting for multiple potential confounding factors. Neither parental nor personal smoking was significantly associated with allergic sensitization among subjects whose parents did not have a history of atopic disease. Few of those with positive SPT results at age 13 years had negative tests at age 32 years, and there was no evidence that this was influenced by smoking. CONCLUSION: Personal and parental smoking is associated with a reduced risk of allergic sensitization in people with a family history of atopy. [Abstract]

Justicia JL, Mullol J
Higher evidence for specific immunotherapy than reported in the ARIA update.
J Allergy Clin Immunol. 2007 Nov 30; [Abstract]

Passalacqua G, Durham SR
Reply.
J Allergy Clin Immunol. 2007 Nov 30; [Abstract]

Fantuzzi G
Adiponectin and inflammation: Consensus and controversy.
J Allergy Clin Immunol. 2007 Nov 30;
Circulating levels of adiponectin decrease with increasing visceral obesity and are lower in patients with type 2 diabetes, the metabolic syndrome, and cardiovascular disease compared with controls matched by body mass index. Several reports demonstrated anti-inflammatory effects of adiponectin. Because increased adipose tissue is associated with low-grade chronic inflammation and proinflammatory factors inhibit adiponectin production, the current hypothesis states that chronic inflammation associated with visceral obesity inhibits production of adiponectin, perpetuating inflammation. The negative correlation between adiponectin and markers of inflammation in the aforementioned conditions supports this hypothesis. In contrast with disorders typically associated with excess adiposity and positive energy balance, adiponectin levels are elevated-rather than decreased-in classic chronic inflammatory/autoimmune diseases that are unrelated to increased adipose tissue, such as rheumatoid arthritis, SLE, inflammatory bowel disease, type 1 diabetes, and cystic fibrosis. In these patients, adiponectin levels positively-rather than negatively-correlate with inflammatory markers. Furthermore, proinflammatory effects of adiponectin have been reported in tissues such as joint synovium and colonic epithelium. Thus, adiponectin is regulated in the opposite direction and may exert differential functions in classic versus obesity-associated inflammatory conditions. This article discusses this apparent paradox and presents possible alternative and/or complementary explanations. [Abstract]

Scordamaglia F, Balsamo M, Scordamaglia A, Moretta A, Mingari MC, Canonica GW, Moretta L, Vitale M
Perturbations of natural killer cell regulatory functions in respiratory allergic diseases.
J Allergy Clin Immunol. 2007 Nov 30;
BACKGROUND: Allergic diseases are characterized by abnormal responses to allergens favored by an inappropriate regulation of the T(H)1-T(H)2 polarization. Natural killer (NK) cells give rise to a complex NK/dendritic cell (DC) cross-talk that would help T(H)1 responses. OBJECTIVE: By analyzing peripheral blood NK cells from 12 patients with either allergic rhinitis or rhinitis and intermittent asthma, we evaluated whether these cells were impaired in their ability to interact with DCs. METHODS: Different circulating NK cell subsets were analyzed by flow cytofluorimetry. Mixed NK/DC cultures were performed to assess the reciprocal functional interactions. NK cells were analyzed for their ability to induce DC maturation and cytokine production, and to kill immature DCs. In addition, DCs were assessed for their ability to induce cytokine production by NK cells. RESULTS: We first analyzed the CD56(++)CD16(+/-) cells, a subset of circulating NK cells that is able to respond to DCs by proliferating and producing IFN-gamma. Our analysis revealed that this NK cell subpopulation was significantly reduced in most patients. This was reflected by reduced NK cell-mediated IFN-gamma production in response to DCs. Also, the capability of promoting DC maturation and/or killing immature DCs, a function sustained by CD56(+)CD16(+) NK cells, was reduced in most patients. CONCLUSIONS: We suggest that allergic diseases are accompanied by a partial impairment of the NK cell capability of promoting and maintaining appropriate T(H)1 responses. [Abstract]

Lanz MJ, Prendes S, Peyrou N, Toledo G, Ferrer CM
Nasal nitric oxide as a noninvasive marker in the antibiotic treatment of acute bacterial sinusitis.
J Allergy Clin Immunol. 2007 Nov 30; [Abstract]

Smith H, Wade J, Frew A
How readable are the American Academy of Allergy, Asthma & Immunology "Tips to remember" leaflets?
J Allergy Clin Immunol. 2007 Nov 30; [Abstract]

Basaga�a M, Bartolom� B, Pastor C, Torres F, Alonso R, Vivanco F, Cister�-Bah�ma A
Allergy to human seminal fluid: Cross-reactivity with dog dander.
J Allergy Clin Immunol. 2007 Nov 30;
BACKGROUND: Human seminal plasma (HSP) allergy is uncommon, with symptoms ranging from vulvovaginal pruritus to life-threatening anaphylaxis. Although several seminal plasma allergens have been reported and their molecular masses have been estimated to range between 12 and 75 kd, the prostate-specific antigen (PSA) has recently been identified as a causative allergen. Given that in a large number of cases symptoms appeared during or after the first intercourse, a cross-reactivity phenomenon might be implicated. OBJECTIVE: We sought to assess the presence of IgE cross-reactivity among proteins from dog epithelium and HSP and to attempt to identify the allergens involved. METHODS: Forty-one patients with dog epithelium allergy were selected. One of them experienced anaphylaxis in contact with her husband's seminal plasma. Skin prick tests, serum specific IgE measurements, SDS-PAGE immunoblotting, and inhibition tests were performed to study the pattern of IgE-binding proteins and the potential cross-reactivity between HSP and dog epithelium. Mass spectrometry was carried out to identify the protein involved in allergy reactions. RESULTS: Twenty-four percent of the sera from patients with dog epithelium allergy recognized an IgE-binding band of 28 kd in HSP immunoblotting. Mass spectrometry identified this band as the PSA. SDS-PAGE immunoblotting-inhibition showed a complete IgE-binding inhibition when sera from these patients were preincubated with dog dander extract. CONCLUSIONS: IgE cross-reactivity among proteins from dog dander and human PSA is demonstrated. [Abstract]

Matsumoto K, Tamari M, Saito H
Involvement of eosinophils in the onset of asthma.
J Allergy Clin Immunol. 2007 Nov 30; [Abstract]

Canino G, Vila D, Normand SL, Acosta-P�rez E, Ram�rez R, Garc�a P, Rand C
Reducing asthma health disparities in poor Puerto Rican children: The effectiveness of a culturally tailored family intervention.
J Allergy Clin Immunol. 2007 Nov 30;
BACKGROUND: Island and mainland Puerto Rican children have the highest rates of asthma and asthma morbidity of any ethnic group in the United States. OBJECTIVE: We evaluated the effectiveness of a culturally adapted family asthma management intervention called CALMA (an acronym of the Spanish for "Take Control, Empower Yourself and Achieve Management of Asthma") in reducing asthma morbidity in poor Puerto Rican children with asthma. METHODS: Low-income children with persistent asthma were selected from a national health plan insurance claims database by using a computerized algorithm. After baseline, families were randomly assigned to either the intervention or a control group. RESULTS: No significant differences between control and intervention group were found for the primary outcome of symptom-free days. However, children in the CALMA intervention group had 6.5% more symptom-free nights, were 3 times more likely to have their asthma under control, and were less likely to visit the emergency department and be hospitalized as compared to the control group. Caregivers receiving CALMA were significantly less likely to feel helpless, frustrated, or upset because of their child's asthma and more likely to feel confident to manage their child's asthma. CONCLUSION: A home-based asthma intervention program tailored to the cultural needs of low income Puerto Rican families is a promising intervention for reducing asthma morbidity. [Abstract]

Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma-Summary Report 2007.
J Allergy Clin Immunol. 2007 Nov;120(5 Suppl):S94-138.
Highlights of the National Asthma Education and Prevention Program's Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma-Full Report 2007 are presented in this EPR-3 summary report. The updated guidelines emphasize the importance of asthma control. Asthma control is the degree to which the manifestations of asthma are minimized by therapeutic intervention and the goals of therapy are met. Because asthma is highly variable, the level of control must be monitored on a periodic basis to determine whether therapy should be maintained or adjusted (stepped up if necessary, stepped down if possible). On the other hand, asthma severity is the intrinsic intensity of the disease process, most easily and directly measured in a patient not receiving long-term control therapy. For managing asthma, the recommendation is to assess severity to initiate therapy and assess control to adjust therapy. Recommendations for managing asthma include an expanded section on childhood asthma with addition of an age group 5 to 11 years old (earlier guidelines combined this group with adults). The guidelines provide new recommendations on patient education in settings beyond the physician's office, and new advice for controlling environmental factors that can cause asthma symptoms.The concepts of current impairment (frequency and intensity of symptoms, low lung function, and limitations of daily activities) and future risk (likelihood of exacerbations, progressive loss of lung function, or adverse side effects from medications) support a new approach to assessing and monitoring the patient's level of asthma control through use of multiple measures. The guidelines stress that some patients can still be at high risk for frequent exacerbations even if they have few day-to-day effects of asthma.Moreover, EPR-3 confirms the importance of teaching patients skills to self-monitor and manage asthma and to use a written asthma action plan, which should include instructions for daily treatment and ways to recognize and handle worsening asthma. New recommendations encourage expanding educational opportunities to reach patients in a variety of settings, such as pharmacies, schools, community centers, and patients' homes. A new section addresses the need for clinician education programs to improve communication with patients and to use system-wide approaches to integrate the guidelines into health care practice.The guidelines describe new evidence for using multiple approaches to limit exposure to allergens and other substances that can worsen asthma; research shows that single steps are rarely sufficient. EPR-3 also expands the section on common conditions that can affect asthma and notes that management of these conditions may help to improve asthma control.Expert Panel Report 3 continues the use of a stepwise approach to control asthma. When assessing the level of asthma control to determine the need for adjusting therapy, EPR-3 reconfirms the importance of assessing patient adherence to medication, inhaler technique, and environmental control measures before making a step up in therapy.The stepwise approach expands from 4 steps to 6 steps of care. Medications have been repositioned within these 6 steps. Recommendations on medications are updated to reflect the latest evidence on effectiveness and safety. EPR-3 reaffirms that patients with persistent asthma need both long-term control medications to control asthma and prevent exacerbations and quick-relief medication for symptoms, as needed. EPR-3 also reaffirms that inhaled corticosteroids are the most effective long-term control medication across all age groups. New recommendations on treatment options such as leukotriene receptor antagonists and cromolyn for long-term control; long-acting beta-agonists as adjunct therapy with inhaled corticosteroids; omalizumab for severe asthma; and albuterol, levalbuterol, and corticosteroids for acute exacerbations are included. [Abstract]

Huebner M, Kim DY, Ewart S, Karmaus W, Sadeghnejad A, Arshad SH
Patterns of GATA3 and IL13 gene polymorphisms associated with childhood rhinitis and atopy in a birth cohort.
J Allergy Clin Immunol. 2007 Nov 21;
BACKGROUND: GATA3 activates transcription of the T(H)2 cytokines, including IL13, an important step in the allergic inflammatory pathway. OBJECTIVE: We sought to identify associations of single nucleotide polymorphisms of the genes GATA3 and IL13 and their interactions with rhinitis and allergic sensitization during childhood. METHODS: We performed genetic association studies in a cohort of children (n = 923) who have been evaluated for the development of rhinitis and allergic sensitization by means of skin prick tests (SPTs) at age 10 years. Pyrosequencing was used to genotype 7 polymorphisms from GATA3 and 5 from IL13. A novel model-selection procedure combining logistic regression models and classification was used to study the contributions of the polymorphisms and their interactions. RESULTS: Combinations of polymorphisms and their interactions increase the risk for rhinitis and allergic sensitization at age 10 years. A model with rs1058240, rs379568, and rs4143094 (GATA3) and rs1800925 (IL13) and their interactions was selected to predict rhinitis and positive SPT responses. rs1058240 was associated with rhinitis and allergic rhinitis (P < .05), and the gene-gene interaction rs1058240:rs1800925 was associated with rhinitis (P = .043). The odds ratios for 4 genotype combinations were significant for rhinitis or SPTs (P < .044). CONCLUSION: Gene-gene interaction between GATA3 and IL13 polymorphisms can influence the risk of childhood rhinitis. Our study suggests that set associations of polymorphisms are important in studying genetic associations for complex phenotypes, such as rhinitis and atopy. [Abstract]

Leb VM, Jahn-Schmid B, Schmetterer KG, Kueng HJ, Haiderer D, Neunkirchner A, Fischer GF, Nissler K, Hartl A, Thalhamer J, Bohle B, Seed B, Pickl WF
Molecular and functional analysis of the antigen receptor of Art v 1-specific helper T lymphocytes.
J Allergy Clin Immunol. 2007 Nov 21;
BACKGROUND: Ninety-five percent of patients with mugwort allergy are sensitized to Art v 1, the sole major allergen in mugwort (Artemisia vulgaris) pollen. Sixty-nine percent of patients recognizing the single immunodominant T-cell epitope Art v 1(25-36) have an HLA-DRB1*01 phenotype. OBJECTIVE: We studied cloning and functional expression of a human alphabeta T-cell receptor (TCR) specific for Art v 1(25-36). METHODS: TCR chains were RT-PCR amplified from an Art v 1(25-36)-specific T-cell clone, retrovirally transferred, and functionally tested in Jurkat T cells or alternatively in peripheral blood T lymphocytes of nonallergic individuals. RESULTS: The alpha-chain of the TCR is composed of TRAV17 and TRAJ45 segments, and the beta-chain uses TRBV18, TRBD1, and TRBJ2-7. Analyses of 23 other Art v 1-specific T-cell clones did not reveal preferential usage of the TRAV17, TRBV18, or other TCR gene families. Efficient TCR transfer into Jurkat T cells was shown by binding of TCR Vbeta18-specific mAb and DRB1*0101/Art v 1 tetramers. Transgenic Jurkat T cells specifically recognized syngeneic EBV B cells pulsed with Art v 1(25-36) peptide and artificial antigen-presenting cells expressing invariant chain::Art v 1 fusion proteins. Moreover, transfer of the TCR into peripheral blood lymphocytes generated T cells that were Art v 1 reactive. Activation of transgenic T cells by artificial antigen-presenting cells was strictly dependent on costimulation. CONCLUSION: For the first time, a detailed molecular and functional analysis of a human allergen-specific TCR is presented. [Abstract]

Lagranderie M, Abolhassani M, Vanoirbeek J, Lefort J, Nahori MA, Lapa E Silva JR, Huerre M, Vargaftig B, Marchal G
Mycobacterium bovis BCG killed by extended freeze-drying reduces airway hyperresponsiveness in 2 animal models.
J Allergy Clin Immunol. 2007 Nov 21;
BACKGROUND: Live BCG administered intranasally to mice inhibits the development of ovalbumin (OVA)-induced eosinophilia and airway hyperresponsiveness (AHR). It is unacceptable to treat human subjects intranasally with live BCG. OBJECTIVE: We investigated whether BCG killed by extended freeze-drying (EFD) and subcutaneously injected has a protective effect in murine and guinea pig models of allergic airway inflammation. METHODS: Mice were OVA sensitized (days 0 and 7), treated subcutaneously (day 14) with EFD and live or heat-killed BCG, and then OVA challenged (day 42). OVA-sensitized mice (days 0 and 7) were challenged (day 14) and EFD treated (day 18) before OVA rechallenge (day 46) to demonstrate the capacity of EFD to reverse the established lung inflammation. Guinea pigs were OVA sensitized (days 0 and 14), treated intradermally (day 35) with EFD, and OVA challenged (days 90-105). RESULTS: In mice and guinea pigs EFD treatment reduced AHR. Among 3 BCG preparations, only EFD efficiently reduced AHR, eosinophilia, and the recruitment of dendritic cells to the lungs after OVA challenge. The protective effect of EFD is associated with production of the immunoregulatory cytokine IL-10. Moreover, EFD treatment did not induce toxic effects or delayed-type hypersensitivity to mycobacterial antigens; that is, it did not interfere with the diagnosis of tuberculosis. CONCLUSION: EFD administered subcutaneously inhibits the development of allergic airway inflammation and prevents AHR without inducing delayed-type hypersensitivity and side effects associated with live or heat-killed BCG. [Abstract]

Kanazawa H, Tochino Y, Asai K
Angiopoietin-2 as a contributing factor of exercise-induced bronchoconstriction in asthmatic patients receiving inhaled corticosteroid therapy.
J Allergy Clin Immunol. 2007 Nov 21;
BACKGROUND: Airway microcirculation has the potential to contribute to the pathogenesis of exercise-induced bronchoconstriction (EIB) in asthma. Recently, angiopoietin-1 has been found to stabilize microvessels and make them leak resistant, whereas angiopoietin-2 is an antagonist of angiopoietin-1 and enhances microvascular permeability. OBJECTIVE: We sought to examine the roles of angiopoietin-2 in EIB in asthmatic patients with inhaled corticosteroid therapy. METHODS: Levels of angiopoietin-1 and angiopoietin-2 in induced sputum were examined in 32 asthmatic patients who were receiving inhaled corticosteroid therapy for more than 6 months at the entry of this study and 14 healthy control subjects. All asthmatic patients performed an exercise test. RESULTS: The degree of eosinophilic airway inflammation did not differ significantly between asthmatic patients and healthy control subjects. Angiopoietin-1 levels were also similar in the 2 groups (asthmatic patients: median, 6.0 ng/mL [range, 2.0-10.7 ng/mL]; healthy control subjects: median, 4.2 ng/mL [range, 1.5-10.7 ng/mL]). In contrast, angiopoietin-2 levels were significantly higher in asthmatic patients than in healthy control subjects (asthmatic patients: median, 0.74 ng/mL [range, 0.3-1.2 ng/mL]; healthy control subjects: median, 0.26 ng/mL [range, 0.05-0.47 ng/mL]; P < .001). There was no significant correlation between angiopoietin-1 levels and the severity of EIB in asthmatic patients. However, angiopoietin-2 levels were significantly correlated with the severity of EIB and airway microvascular permeability index. CONCLUSION: Angiopoietin-2 levels were increased in the airways of asthmatic patients with inhaled corticosteroid therapy, and its levels were associated with the severity of EIB. [Abstract]

Flinterman AE, Akkerdaas JH, den Hartog Jager CF, Rigby NM, Fernandez-Rivas M, Hoekstra MO, Bruijnzeel-Koomen CA, Knulst AC, van Ree R, Pasmans SG
Lipid transfer protein-linked hazelnut allergy in children from a non-Mediterranean birch-endemic area.
J Allergy Clin Immunol. 2007 Nov 22;
BACKGROUND: Hazelnut allergy in birch pollen-exposed areas is usually due to cross-reactivity (Cor a 1 and 2) and is usually mild in nature (oral allergy). In areas without birches, severe reactions are more prevalent and linked to sensitization to the lipid transfer protein (LTP) Cor a 8. OBJECTIVE: We sought to investigate whether sensitization to LTP plays a role in more severe (objective) hazelnut-induced symptoms in children from a birch-endemic area. METHODS: Sensitization to Cor a 8, Cor a 2, Cor a 1, and Bet v 1 was determined by means of RASTs and immunoblotting in hazelnut-sensitized children with (n = 8) and without (n = 18) objective reactions during double-blind, placebo-controlled food challenges. Additionally, samples from 191 hazelnut-sensitized nonchallenged children were analyzed. RESULTS: Children with objective reactions during double-blind, placebo-controlled food challenge had higher IgE titers to hazelnut (P < .001) and recognized more allergens on immunoblotting (P = .001) than those without such reactions. All children with objective symptoms were sensitized to Cor a 8 (0.51-23.3 IU/mL) compared with only 1 child without objective reactions (0.90 IU/mL). In a multivariate analysis only IgE against Cor a 8 remained as an independent risk factor (undefined odds ratio; P < .0001). In the group of nonchallenged children (n = 191), the prevalence of LTP sensitization was greater than 30%. Unexpectedly, sensitization to Cor a 1 was observed in children not sensitized to Bet v 1. CONCLUSION: Sensitization to hazelnut LTP is a risk factor for objective symptoms in children from a birch-endemic area. [Abstract]

Allam JP, Peng WM, Appel T, Wenghoefer M, Niederhagen B, Bieber T, Berg� S, Novak N
Toll-like receptor 4 ligation enforces tolerogenic properties of oral mucosal Langerhans cells.
J Allergy Clin Immunol. 2007 Nov 22;
BACKGROUND: Despite high bacterial colonization, acute infections are rare in the oral mucosa, implicating tolerogenic predominance. Bacterial antigens like LPSs are recognized by innate immunity receptors such as Toll-like receptor 4 (TLR4), associated with LPS receptor (CD14). OBJECTIVES: Toll-like receptor 4 agonist monosphoryl lipid A has been successfully used as adjuvant in subcutaneous immunotherapy, suggesting reinforcement of allergen-specific tolerance. Recently sublingual immunotherapy (SLIT) has been shown to be an effective alternative to subcutaneous immunotherapy. We observed CD14 expression on human oral Langerhans cells (oLCs), representing a major target of SLIT. However, not much is known about TLR4 expression and its effect on oLCs. METHODS: Cell suspensions were obtained by trypsinization of human oral mucosa and analyzed by flow cytometry, RT-PCR, cytometric bead arrays, ELISA, and mixed lymphocyte reactions. RESULTS: We could show that oLCs express TLR4, and its ligation by monosphoryl lipid A upregulated expression of coinhibitory molecules B7-H1 and B7-H3 while surface expression of costimulatory molecule CD86 was concomitantly decreased. Furthermore, TLR4 ligation on oLCs increased their release of the anti-inflammatory cytokine IL-10 and decreased their stimulatory capacity toward T cells. Moreover, TLR4-ligation on oLCs induced IL-10, TGF-beta1, Forkhead box protein 3, IFN-gamma, and IL-2 production in T cells. CONCLUSION: In view of these data, TLR4-ligation on oLCs might not only play a role in pathogen recognition for efficient immunity but also contribute to the tolerogenic state predominating in the oral cavity. [Abstract]

Yokoi H, Choi OH, Hubbard W, Lee HS, Canning BJ, Lee HH, Ryu SD, von Gunten S, Bickel CA, Hudson SA, Macglashan DW, Bochner BS
Inhibition of FcvarepsilonRI-dependent mediator release and calcium flux from human mast cells by sialic acid-binding immunoglobulin-like lectin 8 engagement.
J Allergy Clin Immunol. 2007 Nov 22;
BACKGROUND: Sialic acid-binding immunoglobulin-like lectins (Siglecs) are a family of glycan-binding inhibitory receptors, and among them, Siglec-8 is selectively expressed on human eosinophils, basophils, and mast cells. On eosinophils, Siglec-8 engagement induces apoptosis, but its function on mast cells is unknown. OBJECTIVE: We sought to study the effect of Siglec-8 engagement on human mast cell survival and mediator release responses. METHODS: Human mast cells were generated from CD34(+) precursors. Apoptosis was studied by using flow cytometry. Mast cell mediator release or human lung airway smooth muscle contraction was initiated by FcvarepsilonRI cross-linking with or without preincubation with Siglec-8 or control antibodies, and release of mediators was analyzed along with Ca(++) flux. RBL-2H3 cells transfected with normal and mutated forms of Siglec-8 were used to study how Siglec-8 engagement alters mediator release. RESULTS: Siglec-8 engagement failed to induce human mast cell apoptosis. However, preincubation with Siglec-8 mAbs significantly (P < .05) inhibited FcvarepsilonRI-dependent histamine and prostaglandin D(2) release, Ca(++) flux, and anti-IgE-evoked contractions of human bronchial rings. In contrast, release of IL-8 was not inhibited. Siglec-8 ligation was also shown to inhibit beta-hexosaminidase release and Ca(++) flux triggered through FcvarepsilonRI in RBL-2H3 cells transfected with full-length human Siglec-8 but not in cells transfected with Siglec-8 containing a tyrosine to phenylalanine point mutation in the membrane-proximal immunoreceptor tyrosine-based inhibitory motif domain. CONCLUSION: These data represent the first reported inhibitory effects of Siglec engagement on human mast cells. [Abstract]

Saffar AS, Dragon S, Ezzati P, Shan L, Gounni AS
Phosphatidylinositol 3-kinase and p38 mitogen-activated protein kinase regulate induction of Mcl-1 and survival in glucocorticoid-treated human neutrophils.
J Allergy Clin Immunol. 2007 Nov 22;
BACKGROUND: Glucocorticoids have been shown to inhibit human neutrophil apoptosis, with implications that this might help accentuate neutrophilic inflammation. OBJECTIVE: The aim of this study was to investigate the molecular mechanisms involved in glucocorticoid-mediated inhibition of primary human neutrophil apoptosis. METHODS: Primary human neutrophils were isolated from peripheral blood of healthy volunteers and cultured in vitro with dexamethasone. RESULTS: Here we confirm that dexamethasone, a classical glucocorticoid, significantly inhibited apoptosis of primary human neutrophils. This inhibition was not dependent on transrepression of proapoptotic molecules but was associated with induction of antiapoptotic Mcl-1. Remarkably, glucocorticoid-mediated enhancement of Mcl-1 and survival were significantly suppressed by pharmacologic inhibition of p38 mitogen-activated protein kinase or phosphatidylinositol 3-kinase. Inhibition of the above kinases also blocked glucocorticoid-induced maintenance of mitochondrial transmembrane potential and suppression of caspases. CONCLUSION: Phosphatidylinositol 3-kinase and p38 mitogen-activated protein kinase are protein kinases that regulate the prosurvival effect of glucocorticoids on human neutrophils. [Abstract]

Schroeder JT, Chichester KL, Bieneman AP
Toll-like receptor 9 suppression in plasmacytoid dendritic cells after IgE-dependent activation is mediated by autocrine TNF-alpha.
J Allergy Clin Immunol. 2007 Nov 22;
BACKGROUND: Functional significance for the alphagamma(2) variant of the high-affinity IgE receptor (FcvarepsilonRI) reportedly expressed on human dendritic cell subtypes remains poorly understood. Studies show that immature plasmacytoid dendritic cells (pDCs) secrete large quantities of TNF-alpha and IL-6 when directly stimulated with anti-IgE antibody. This mode of activation, however, reduces Toll-like receptor 9 (TLR9) expression in pDCs and their ability to mount an IFN-alpha response when subsequently activated with oligodeoxynucleotide containing CpG. OBJECTIVE: To investigate the mechanisms underlying this IgE-dependent suppression of TLR9 and innate immune responsiveness in pDCs by focusing on autocrine cytokine responses. METHODS: pDCs were isolated from blood by using blood dendritic cell antigen 4 selection. Cytokine responses to anti-IgE antibody-dependent and/or CpG-dependent stimulation were measured by using ELISA. TLR9 expression was determined by using quantitative RT-PCR and Western blotting. RESULTS: The time required for downregulating TLR9 expression in pDCs after anti-IgE stimulation correlated with the induction and duration of TNF-alpha secreted by these cells. Pretreatment of pDCs with recombinant TNF-alpha (but not IL-6 or IL-10) markedly suppressed TLR9 expression. Functional response to CpG (ie, IFN-alpha induction) was also inhibited with TNF-alpha pretreatment (inhibitory concentration(50) = approximately 200 pg/mL). Finally, an antibody that neutralizes TNF-alpha activity completely restored TLR9 expression during anti-IgE stimulation and significantly improved IFN-alpha secretion on subsequent activation with CpG. CONCLUSION: Autocrine TNF-alpha secretion resulting from IgE/FcvarepsilonRI-dependent activation plays a critical role in suppressing TLR9-dependent responses in pDCs that normally promote T(H)1 activity. [Abstract]

Brightling C, Berry M, Amrani Y
Targeting TNF-alpha: A novel therapeutic approach for asthma.
J Allergy Clin Immunol. 2007 Nov 22;
Approximately 5% to 10% of patients with asthma have severe disease that is refractory or poorly responsive to inhaled corticosteroid therapy. These patients represent an important unmet clinical need because they experience considerable morbidity and mortality and consume a disproportionately large amount of health care resources. TNF-alpha is a proinflammatory cytokine that has been implicated in many aspects of the airway pathology in asthma. Evidence is emerging to suggest that it might play an important role in severe refractory disease. The development of novel TNF-alpha antagonists has allowed us to test the role of this cytokine in vivo. Preliminary studies have demonstrated an improvement in asthma quality of life, lung function, and airway hyperresponsiveness and a reduction in exacerbation frequency in patients treated with anti-TNF-alpha therapy. However, there is marked heterogeneity in response, suggesting that benefit is likely to be reserved to a small subgroup. Importantly, where efficacy is reported, this also needs to be considered in the context of concerns about the safety of anti-TNF-alpha therapies. Therefore the challenge for clinicians is to evaluate the risk/benefit ratio of these therapies in individual patients with asthma. [Abstract]

Bittner C, Grassau B, Frenzel K, Baur X
Identification of wheat gliadins as an allergen family related to baker's asthma.
J Allergy Clin Immunol. 2007 Nov 22;
BACKGROUND: Flour is still one of the most common causes of occupational asthma worldwide. Thus far, little is known about the relevant allergens causing baker's asthma. Therefore the reliability of current diagnostic procedures is insufficient. Only few of the suspected causative wheat allergens have been hitherto characterized on the molecular level. OBJECTIVE: The aim was to identify and characterize unknown wheat allergens related to baker's asthma to improve the reliability of diagnostic procedures. METHODS: A wheat pJuFo cDNA phage display library was created and screened for IgE binding to wheat proteins with pooled sera from patients with baker's asthma. After identifying an alphabeta-gliadin, the frequency of sensitization was investigated by means of ELISA screening of 153 bakers' sera with the recombinant alphabeta-gliadin. Furthermore, the allergenicity of native total gliadin (alphabeta, gamma, omega) was analyzed by means of ImmunoCAP. RESULTS: One cDNA clone was identified as an alphabeta-gliadin. Serum IgE antibodies to the recombinant allergen were found in 12% of bakers with occupational asthma. Of the asthmatic bakers, 33% showed sensitization to native total gliadin; 4% of them had negative results on routine IgE testing with wheat extract. CONCLUSIONS: Gliadins represent a newly discovered family of inhalable allergens in baker's asthma. This finding demonstrates that water-insoluble proteins might also represent causative allergens. [Abstract]

Maneechotesuwan K, Supawita S, Kasetsinsombat K, Wongkajornsilp A, Barnes PJ
Sputum indoleamine-2, 3-dioxygenase activity is increased in asthmatic airways by using inhaled corticosteroids.
J Allergy Clin Immunol. 2007 Nov 22;
BACKGROUND: Indoleamine-2, 3-dioxygenase (IDO), a tryptophan-degrading enzyme, plays a key role in the regulation of T-lymphocyte function. IDO inhibits eosinophilic inflammation in a murine asthma model, but little is known about its role in asthmatic patients or the effects of corticosteroids on this key regulatory enzyme. OBJECTIVE: We studied IDO activity and the effect of inhaled corticosteroids (ICSs) in patients with asthma and how this correlated with eosinophilic inflammation. METHODS: After a 1-week run-in period on no therapy, 34 asthmatic patients were treated with only short-acting beta(2)-agonists as required or an ICS or an ICS in combination with a long-acting beta(2)-agonist, which were required for asthma control, and the treatment was continued for a further 4 weeks. Each patient underwent sputum induction at the end of the run-in and treatment periods. Sputum supernatant specimens were analyzed for IDO activity and kynurenine concentrations by using HPLC. RESULTS: All patients with mild intermittent and mild-to-moderate persistent asthma had low baseline IDO activity in induced sputum compared with that seen in age-matched nonasthmatic subjects. The IDO activity was markedly enhanced by either ICS (P = .03) or ICS/long-acting beta(2)-agonist (P < .0001) treatment, and this increase negatively correlated with sputum eosinophils but was positively associated with an increase in IL-10-positive macrophages. CONCLUSION: ICSs might exert their anti-inflammatory activity in asthmatic airways, at least in part, through the upregulation of IDO activity associated with increased IL-10 secretion from macrophages. [Abstract]

Ueda T, Niimi A, Matsumoto H, Takemura M, Yamaguchi M, Matsuoka H, Jinnai M, Chin K, Minakuchi M, Cheng L, Shirakawa T, Mishima M
TGFB1 promoter polymorphism C-509T and pathophysiology of asthma.
J Allergy Clin Immunol. 2007 Nov 22;
BACKGROUND: TGF-beta1 can modulate airway inflammation and exaggerate airway remodeling. A polymorphism of a promoter region of TGFB1, C-509T, might be associated with the development of asthma, but its pathophysiologic relevance remains poorly understood. OBJECTIVE: We investigated relations of the C-509T polymorphism to airflow obstruction, sputum eosinophilia, and airway wall thickening, as assessed by means of computed tomography, in 85 patients with stable asthma. METHODS: The CC, CT, and TT genotypes were examined by means of PCR and restriction enzyme fragment length polymorphism. At a selected bronchus, 3 indices of airway wall thickness were measured with an automatic method. RESULTS: The CC, CT, and TT genotypes were found in 22, 46, and 17 patients, respectively. Serum TGF-beta1 levels were significantly associated with the polymorphism and were increased in the CT/TT genotypes. FEV(1) and sputum eosinophil percentages were also significantly associated with the polymorphism and were both decreased in the CT/TT genotypes. The polymorphism was unrelated to airway wall thickness. CONCLUSION: In addition to increased serum TGF-beta1 levels, the T allele of the C-509T polymorphism is related to increased airflow obstruction but attenuated eosinophilic inflammation. The former relation is not attributed to thickening of the central airway walls. The latter relation might reflect the anti-inflammatory effect of TGF-beta1. The C-509T polymorphism has a complex role in asthma pathophysiology, presumably because of the diverse functions of TGF-beta1 and its various interactions with cells and humoral factors in vivo. [Abstract]

Schmechel D, Green BJ, Blachere FM, Janotka E, Beezhold DH
Analytical bias of cross-reactive polyclonal antibodies for environmental immunoassays of Alternaria alternata.
J Allergy Clin Immunol. 2007 Nov 22;
BACKGROUND: Alternaria alternata is recognized as an important aeroallergen indoors and outdoors, and exposure to the fungus has been identified as a risk factor for asthma. Two recent publications concluded that 95% to 99% of American homes contained detectable amounts of Alternaria antigens when analyzed with a polyclonal antibody (pAb)-based ELISA. OBJECTIVES: We investigated the cross-reactivity of the commercially available pAbs that were used in those studies. METHODS: Reactivity to 24 fungal species commonly found in indoor environments was analyzed by inhibition ELISA by using solid-phase A alternata antigen. The pAbs were also tested by immunoblotting and halogen immunoassay for a subgroup of fungi. RESULTS: Spores of 7 fungi including species of Alternaria, Ulocladium, Stemphylium, Epicoccum, Drechslera, and Exserohilum strongly inhibited the binding of the pAbs when tested by ELISA. Six other fungi reacted in the ELISA at a lower level, and 11 fungal species including several Penicillium, Aspergillus, Fusarium, and Cladosporium species failed to show inhibition. The immunoblots and the halogen immunoassay staining confirmed the cross-reactivity patterns of the ELISA. CONCLUSION: The pAbs against A alternata were found to cross-react broadly with related and nonrelated fungi. The prevalence data previously reported for A alternata should be considered to be fungal-reactive rather than A alternata-specific. [Abstract]

Levesque MC, Hauswirth DW, Mervin-Blake S, Fernandez CA, Patch KB, Alexander KM, Allgood S, McNair PD, Allen AS, Sundy JS
Determinants of exhaled nitric oxide levels in healthy, nonsmoking African American adults.
J Allergy Clin Immunol. 2007 Nov 23;
BACKGROUND: Asthma is a significant cause of morbidity and mortality for African Americans. Fraction of exhaled nitric oxide (FeNO) levels are increased in patients with asthma, and airway levels of nitric oxide metabolites regulate airway inflammation and airway diameter. More needs to be known about the factors that regulate FeNO. There is a need for FeNO reference values for African Americans. OBJECTIVE: We sought to establish reference values and identify factors associated with FeNO levels in healthy African American adults. METHODS: FeNO levels were measured in 895 healthy, nonsmoking African Americans between the ages of 18 and 40 years. FeNO measurements were repeated in 84 subjects. Factors potentially associated with FeNO were measured, including blood pressure, height, weight, and serum total IgE, eosinophil cationic protein, C-reactive protein, and nitrate levels. Data on respiratory symptoms, including upper respiratory tract infection (URI) symptoms, were collected. Univariate and multivariate analyses of the relationship between these variables and FeNO levels were performed. RESULTS: In healthy, nonsmoking African Americans FeNO levels were stable during repeated measurements (intraclass correlation coefficient, 0.81). Sex (P < .0001), serum total IgE levels (P < .0001), and current URI symptoms (P = .0002) contributed significantly to FeNO variability but together accounted for less than 50% of the variation in FeNO levels. CONCLUSION: The high correlation between repeated measurements of FeNO and the low correlation coefficients of known factors associated with FeNO suggest that other factors might contribute substantially to variability of FeNO levels in African Americans. [Abstract]

Woszczek G, Chen LY, Nagineni S, Kern S, Barb J, Munson PJ, Logun C, Danner RL, Shelhamer JH
Leukotriene D(4) induces gene expression in human monocytes through cysteinyl leukotriene type I receptor.
J Allergy Clin Immunol. 2007 Oct 26;
BACKGROUND: Cysteinyl leukotrienes (CysLTs) are important mediators of innate immune responsiveness and chronic inflammatory diseases. CysLTs acting through CysLT receptors can influence the migration and activity of cells, such as eosinophils, monocytes, and dendritic cells. OBJECTIVE: We sought to determine the gene expression signature of human monocytes in response to CysLTs and to elucidate the signaling pathways involved in monocyte activation. METHODS: Gene expression was analyzed by using oligonucleotide microarrays. Responsiveness to CysLTs was assessed by using real-time PCR, calcium flux, kinase activation, and chemotaxis assays. RESULTS: CysLT type 1 receptor (CysLTR(1)) transcript 1 is predominantly expressed in human monocytes, and CysLTs signal through CysLTR(1) in these cells. Several immediate-early genes, including early growth response 2 and 3, FBJ murine osteosarcoma viral oncogene homolog B, activating transcription factor 3, and nuclear receptor subfamily 4 were significantly induced by leukotriene (LT) D(4). This effect was mediated by CysLTR(1) coupled to the G protein alpha inhibitory subunit, activation of phospholipase C, and inositol-1,4,5-triphosphate and store-operated calcium channels. LTD(4) induced p38 mitogen-activated protein kinase phosphorylation, a pathway also involved in the regulation of immediate-early gene expression in monocytes. LTD(4) stimulated monocyte chemotactic activity that was fully blocked by a selective CysLTR(1) inhibitor, MK571, and pertussis toxin, suggesting that CysLTR(1) coupled to the G protein alpha inhibitory subunit is a dominant functional pathway in human monocytes. CONCLUSION: Our data show that CysLTs acting through CysLTR(1) can significantly influence the activation and migration of human monocytes and that these effects can be fully inhibited by CysLTR(1) antagonists. CLINICAL IMPLICATIONS: Antileukotriene therapies are likely to significantly block the proinflammatory functions of human monocytes. [Abstract]

Casale TB, Romero FA, Spierings EL
Intranasal noninhaled carbon dioxide for the symptomatic treatment of seasonal allergic rhinitis.
J Allergy Clin Immunol. 2007 Oct 26;
BACKGROUND: Noninhaled intranasal carbon dioxide (CO(2)) has been shown to be effective in the abortive treatment of migraine headache. Migraine headache is associated with trigeminal neuronal activation and release of calcitonin gene-related peptide, events also implicated in allergic rhinitis. Intranasal CO(2) might inhibit trigeminal neuronal activation and suppress the release of calcitonin gene-related peptide. OBJECTIVE: We studied whether noninhaled intranasal CO(2) would be effective in the treatment of seasonal allergic rhinitis. METHODS: We conducted a single-center, randomized, double-blind, placebo-controlled, parallel-group study. Treatment consisted of either CO(2) (verum) or air (placebo) at a 2:1 ratio administered in each nostril for 60 seconds per nostril at a flow rate of 10 mL/s. The primary efficacy end point was the change from baseline in total nasal symptom score (TNSS), the sum of congestion, rhinorrhea, itching, and sneezing scored on a 0- to 5-point scale, at 30 minutes. RESULTS: Eighty-nine subjects received treatment, 60 with CO(2) and 29 with placebo, and all subjects completed the study. CO(2) resulted in a statistically significant improvement in TNSS at 30 minutes over placebo (absolute changes of 5.0 for CO(2) and 2.2 for placebo, P = .00019). Improvement from baseline in TNSS (CO(2) vs placebo) was statistically significant at 10 minutes and remained so for 24 hours. CONCLUSION: Two 60-second intranasal CO(2) treatments resulted in rapid (10 minutes) and sustained (24 hours) relief of seasonal allergic rhinitis symptoms. CLINICAL IMPLICATIONS: Noninhaled intranasal CO(2) has potential as a safe and effective treatment for seasonal allergic rhinitis. [Abstract]

Salamon P, Shoham NG, Puxeddu I, Paitan Y, Levi-Schaffer F, Mekori YA
Human mast cells release oncostatin M on contact with activated T cells: Possible biologic relevance.
J Allergy Clin Immunol. 2007 Oct 26;
BACKGROUND: We have recently demonstrated that mast cells can be activated by heterotypic adhesion to activated T cells. OBJECTIVE: We sought to perform gene expression profiling on human mast cells activated by either IgE cross-linking or by T cells and to characterize one of the cytokines, oncostatin M (OSM). METHODS: Gene expression profiling was done by means of microarray analysis, OSM expression was validated by means of RT-PCR, and the product was measured by means of ELISA in both the LAD 2 human mast cell line and in cord blood-derived human mast cells. Immunocytochemistry was used to localize OSM in human mast cells, and its biologic activity was verified by its effect on the proliferation of human lung fibroblasts. RESULTS: OSM was expressed and released specifically on T cell-induced mast cell activation but not on IgE cross-linking. OSM was localized to the cytoplasm, and its expression was inhibited by dexamethasone and mitogen-activated protein kinase inhibitors. OSM was also found to be biologically active in inducing lung fibroblast proliferation that was partially but significantly inhibited by anti-OSM mAb. In vivo mast cells were found to express OSM in both biopsy specimens and bronchoalveolar lavage fluid from patients with sarcoidosis. CONCLUSION: The production of OSM by human mast cells might represent one link between T cell-induced mast cell activation and the development of a spectrum of structural changes in T cell-mediated inflammatory processes in which mast cells have been found to be involved. CLINICAL IMPLICATIONS: Mast cells might serve as a target for treating T cell-mediated fibrotic processes. [Abstract]

Wang M, Karlsson C, Olsson C, Adlerberth I, Wold AE, Strachan DP, Martricardi PM, Aberg N, Perkin MR, Tripodi S, Coates AR, Hesselmar B, Saalman R, Molin G, Ahrn� S
Reduced diversity in the early fecal microbiota of infants with atopic eczema.
J Allergy Clin Immunol. 2007 Oct 26;
BACKGROUND: It might be that early intestinal colonization by bacteria in westernized infants fails to give rise to sufficient immune stimulation to support maturation of regulatory immune mechanisms. OBJECTIVE: The purpose of the present study was to characterize the very early infantile microbiota by using a culture-independent approach and to relate the colonization pattern to development of atopic eczema in the first 18 months of life. METHODS: Fecal samples were collected from 35 infants at 1 week of age. Twenty infants were healthy, and 15 infants were given diagnoses of atopic eczema at the age of 18 months. The fecal microbiota of the infants was compared by means of terminal restriction fragment length polymorphism (T-RFLP) and temporal temperature gradient gel electrophoresis (TTGE) analysis of amplified 16S rRNA genes. RESULTS: By means of T-RFLP analysis, the median number of peaks, Shannon-Wiener index, and Simpson index of diversity were significantly less for infants with atopic eczema than for infants remaining healthy in the whole group and for the Swedish infants when AluI was used for digestion. The same was found when TTGE patterns were compared. In addition, TTGE analysis showed significantly less bands and lower diversity indices for the British atopic infants compared with those of the control subjects. CONCLUSION: There is a reduced diversity in the early fecal microbiota of infants with atopic eczema during the first 18 months of life. CLINICAL IMPLICATIONS: This finding, if confirmed in larger patients and control populations, might inspire future strategies for primary prevention of IgE-mediated atopic eczema. [Abstract]

Kelly A, Bowen H, Jee YK, Mahfiche N, Soh C, Lee T, Hawrylowicz C, Lavender P
The glucocorticoid receptor beta isoform can mediate transcriptional repression by recruiting histone deacetylases.
J Allergy Clin Immunol. 2007 Oct 26;
BACKGROUND: The glucocorticoid receptor (GR) is able to participate in regulation of transcription by a variety of mechanisms, one of which involves DNA binding and recruitment of regulatory cofactors. The best-studied forms of the receptor are the 777-amino-acid alpha and the 742-amino-acid beta variants. The beta isoform, which does not bind cortisol in human subjects, has been proposed to be a dominant-negative inhibitor of the transcriptional activation-competent GRalpha isoform. OBJECTIVE: GRalpha has roles in both transcriptional activation and repression. We wished to determine the influence of GRbeta on genes that are normally transcriptionally repressed by glucocorticoids. We studied IL5 and IL13, which both contribute to the asthmatic phenotype. METHODS: We used transient transfection systems and coimmunoprecipitation experiments to determine whether GRbeta has repressive activity on the promoters of the human IL5 and IL13 genes. RESULTS: GRbeta is able to act as a transcriptional repressor of cytokine genes and mediates its function through the recruitment of histone deacetylase complexes. CONCLUSION: GRalpha and GRbeta act in a similar manner on IL5 and IL13 promoters, serving to repress transcription. In this circumstance GRbeta does not act as a dominant-negative inhibitor of GRalpha. CLINICAL IMPLICATIONS: Our data suggest that if GRbeta contributes toward glucocorticoid resistance by acting as a dominant-negative inhibitor of GRalpha function, then its influence does not lie at genes such as IL5 and IL13. GRbeta might have a more important role at genes that are normally activated by glucocorticoids. [Abstract]

Real FG, Svanes C, Omenaas ER, Ant� JM, Plana E, Jarvis D, Janson C, Neukirch F, Zemp E, Dratva J, Wjst M, Svanes K, Leynaert B, Sunyer J
Lung function, respiratory symptoms, and the menopausal transition.
J Allergy Clin Immunol. 2007 Oct 26;
BACKGROUND: There is limited information on potential changes in respiratory health when women enter the menopausal transition. OBJECTIVE: We sought to investigate whether the menopausal transition is related to lung function and asthma and whether body mass index (BMI) modifies associations. METHODS: Four thousand two hundred fifty-nine women from 21 centers (ECRHS II, 2002) responded to a questionnaire concerning women's health. Women aged 45 to 56 years not using exogenous sex hormones (n = 1274) were included in the present analysis. Lung function measurements (n = 1120) and serum markers of hormonal status (follicle-stimulating hormone, luteinizing hormone, and estradiol; n = 710) were available. Logistic and linear regression analyses were adjusted for BMI, age, years of education, smoking status, center, and height. RESULTS: Women not menstruating for the last 6 months (n = 432, 34%) had significantly lower FEV(1) values (-120 mL [95% CI, -177 to -63]), lower forced vital capacity values (-115 mL [95% CI, -181 to -50]), and more respiratory symptoms (odds ratio [OR], 1.82 [95% CI, 1.27-2.61]) than those menstruating regularly. Results were similar when restricting analyses to those who never smoked. Associations were significantly stronger in women with BMIs of less than 23 kg/m(2) (respiratory symptoms: OR, 4.07 [95% CI, 1.88-8.80]; FEV(1) adjusted difference: -166 [95% CI, -263 to -70]) than in women with BMIs of 23 to 28 kg/m(2) (respiratory symptoms: OR, 1.10 [95% CI, 0.61-1.97], P(interaction): .04; FEV(1) adjusted difference, -54 [95% CI, -151 to 43], P(interaction) = .06). CONCLUSIONS: Menopause is associated with lower lung function and more respiratory symptoms, especially among lean women. CLINICAL IMPLICATIONS: Clinicians should be aware of increased asthma risk and lower lung function in women reaching menopause. These problems appeared to be less pronounced among women with a BMI of approximately 25 kg/m(2). [Abstract]

Julius P, Lommatzsch M, Kuepper M, Bratke K, Faehndrich S, Luttmann W, Virchow JC
Safety of segmental allergen challenge in human allergic asthma.
J Allergy Clin Immunol. 2007 Oct 26;
BACKGROUND: Segmental allergen challenge is widely used to study mechanisms of human allergic asthma. Despite the relatively large dissemination, limited information is available about the safety of this method. OBJECTIVE: Observational, retrospective study to report the adverse events of segmental allergen challenge in a large group of volunteers with asthma. METHODS: In total, 78 cases from several studies performed between 1994 and 2007 were pooled for this analysis. Volunteers underwent allergen challenge using either a fixed dose of allergen (7 cases) or an individually standardized allergen dose defined by an inhaled allergen test before the challenge (71 cases). A subgroup of 13 volunteers underwent repeated challenges, with more than 6 months between the challenges. RESULTS: With a fixed dose instilled during bronchoscopy, 43% of the participants developed wheezing and coughing, requiring 2-6 puffs of a ss(2)-agonist after segmental allergen challenge. In volunteers with individually standardized doses, a ss(2)-agonist was required in only 19% of the cases. No severe adverse events occurred in all cases studied. Volunteers who underwent repeated challenges did not develop more adverse events than those who underwent 1 challenge. CONCLUSIONS: Segmental allergen challenge is a safe tool to study the mechanisms of human allergic asthma, even when repeated challenges are performed in the same patient. It is associated with only a few, tolerable adverse events, especially when the dose of allergen is standardized individually. CLINICAL IMPLICATIONS: This retrospective analysis confirms that segmental allergen challenge is a safe tool in human asthma research. [Abstract]

P�gorier S, Arouche N, Dombret MC, Aubier M, Pretolani M
Augmented epithelial endothelin-1 expression in refractory asthma.
J Allergy Clin Immunol. 2007 Dec;120(6):1301-7.
BACKGROUND: Airway remodeling in patients with severe steroid-refractory asthma might result from a reduced ability of steroid therapy to limit the transcription of remodeling factors by the bronchial epithelium. OBJECTIVE: We sought to compare the levels of transcripts encoding remodeling factors in bronchial epithelium of healthy volunteers and of asthmatic patients with either steroid-sensitive or steroid-refractory disease and to correlate these levels with hallmarks of airway remodeling. METHODS: By means of real-time quantitative PCR, we assessed the levels of 14 transcripts encoding remodeling factors, matrix metalolproteinases, and extracellular matrix proteins in laser-capture microdissected bronchial epithelium of healthy volunteers, patients with mild steroid-untreated asthma, and patients with steroid-sensitive and steroid-refractory asthma (n = 8-10 in each group). Histologic features of airway remodeling and endothelin-1 (EDN1) immunolocalization were determined by using frozen specimens. RESULTS: Patients with steroid-refractory asthma had greater levels of EDN1 transcripts (4.1-fold increase, P = .026) and protein (P = .0009) in their bronchial epithelium compared with patients with steroid-sensitive asthma. EDN1 mRNA levels and protein expression in asthmatic patients were negatively correlated with prebronchodilator and postbronchodilator FEV(1) value (r(2) >/= 0.193, P </= .03), and they were positively related to airway smooth muscle areas (r(2) = 0.253, P = .01 and r(2) = 0.281, P = .005 for EDN1 mRNA and protein expression, respectively). CONCLUSION: Increased EDN1 synthesis by the bronchial epithelium characterizes severe refractory asthma and correlates with airway remodeling and airflow obstruction. CLINICAL IMPLICATIONS: Targeting EDN1 might represent a novel therapeutic strategy for severe steroid-refractory asthma. [Abstract]

Cox L, Platts-Mills TA, Finegold I, Schwartz LB, Simons FE, Wallace DV
American Academy of Allergy, Asthma & Immunology/American College of Allergy, Asthma and Immunology Joint Task Force Report on omalizumab-associated anaphylaxis.
J Allergy Clin Immunol. 2007 Dec;120(6):1373-7.
The American Academy of Allergy, Asthma & Immunology and the American College of Allergy, Asthma and Immunology Executive Committees formed the Omalizumab Joint Task Force with the purpose of reviewing the Genentech Xolair (omalizumab) clinical trials and postmarketing surveillance data on anaphylaxis and anaphylactoid reactions. Using the definition of anaphylaxis proposed at a 2005 multidisciplinary symposia, the Omalizumab Joint Task Force concluded that 35 patients had 41 episodes of anaphylaxis associated with Xolair (omalizumab) administration between June 1, 2003, and December 31, 2005. With 39,510 patients receiving Xolair (omalizumab) during the same period of time, this would correspond to an anaphylaxis-reporting rate of 0.09% of patients. Of those 36 events for which the time of reaction was known, 22 (61%) reactions occurred in the first 2 hours after one of the first 3 doses. Five (14%) of the events after the fourth or later doses occurred within 30 minutes. Considering the timing of these 36 events, an observation period of 2 hours for the first 3 injections and 30 minutes for subsequent injections would have captured 75% of the anaphylactic reactions. The OJTF report provides recommendations for physicians who prescribe Xolair (omalizumab) on (1) the suggested wait periods after administration and (2) patient education regarding anaphylaxis. [Abstract]

Recent Articles in Clinical and Experimental Allergy: Journal of the British Society for Allergy and Clinical Immunology

Flicker S, Steinberger P, Eibensteiner PB, Lebecque S, Kraft D, Valenta R
Molecular characterization of a human immunoglobulin G4 antibody specific for the major birch pollen allergen, Bet v 1.
Clin Exp Allergy. 2007 Dec 7; .
Background Allergen-specific IgG4 antibodies induced by specific immunotherapy are thought to represent a protective immune response. Objective Our aim was the molecular characterization of a human IgG4 antibody (BAB5) specific for the major birch pollen allergen Bet v 1 that was derived from an immunotherapy-treated patient. Methods The cDNA coding for BAB5 was obtained by reverse transcriptase-PCR from the BAB5-producing cell line, compared with the germ line sequences and was expressed as a soluble antibody fragment in Escherichia coli. The epitope specificity and cross-reactivity of BAB5 were investigated with recombinant and synthetic Bet v 1 fragments and Bet v 1 homologous allergens from pollen. The ability of BAB5 to block allergic patients IgE was determined by competition experiments and sandwich ELISA. Results BAB5 is an affinity-matured Bet v 1-specific IgG4 antibody that reacts exclusively with Bet v 1 but not with Bet v 1-related allergens. Unlike an earlier-described monoclonal IgG1-blocking antibody, BAB1, which had been isolated from the same patient, BAB5 did not block allergic patients' IgE reactivity to Bet v 1. Conclusion Our study demonstrates that not all allergen-specific IgG antibodies inhibit IgE recognition of allergens and can contribute to the success of immunotherapy. The epitope specificity and affinity of IgG antibodies but not their isotype are decisive for their protective activity. [Abstract]

Pereira-Santos MC, Baptista AP, Melo A, Alves RR, Soares RS, Pedro E, Pereira-Barbosa M, Victorino RM, Sousa AE
Expansion of circulating Foxp3(+)CD25(bright) CD4(+) T cells during specific venom immunotherapy.
Clin Exp Allergy. 2007 Dec 7;
Background Venom immunotherapy (VIT) induces long-lasting immune tolerance to hymenoptera venom antigens, but the underlying mechanisms are not yet clarified. Regulatory T cells are thought to play an important role in allergic diseases and tolerance induction during specific immunotherapy. Aim Characterize longitudinally the impact of VIT on the pool of circulating regulatory T cells. Methods Fourteen hymenoptera venom-allergic patients with severe reactions (grades III-IV) were studied before, 6 and 12 months after starting ultra-rush VIT. Freshly isolated peripheral blood mononuclear cells were surface stained with a panel of markers of T cell differentiation and intracellularly for CTLA-4 and Foxp3 and analysed by flow cytometry. foxp3 mRNA was quantified by real-time PCR. VIT responses were assessed by measuring specific IgG4 and IgE levels. Eleven individuals with no history of insect venom allergy were studied as controls. Results VIT induces a significant progressive increase in both the proportion and the absolute numbers of regulatory T cells defined as CD25(bright) and/or Foxp3(+) CD4(+) T cells. These changes are not related to alterations in the expression of activation markers or imbalances in the na�ve/memory T cell compartments. foxp3 mRNA levels also increased significantly during VIT. Of note, the increase in circulating regulatory T cell counts significantly correlates with the venom-specific IgG4/IgE ratio shift. Conclusion VIT is associated with a progressive expansion of circulating regulatory T cells, supporting a role for these cells in tolerance induction. [Abstract]

Takeuchi H, Zaman K, Takahashi J, Yunus M, Chowdhury HR, Arifeen SE, Baqui A, Wakai S, Iwata T
High titre of anti-Ascaris immunoglobulin E associated with bronchial asthma symptoms in 5-year-old rural Bangladeshi children.
Clin Exp Allergy. 2007 Dec 7;
Background Increasing interest has arisen whether helminthic infections protect against asthma and allergy. The prevalence of wheezing among Bangladeshi children is higher in rural areas where helminthic infectious burden is greater, which is contrary to the general assumption. Objective We therefore examined the association between Ascaris infection, serum level of anti-Ascaris IgE, which should be investigated differently from the infection, and wheezing in 5-year-old children from rural Bangladesh. Methods A total of 219 children who reported wheezing during the previous 12 months and 122 randomly selected age-matched individuals who had never experienced wheezing were tested for serum levels of total and specific Ascaris, Dermatophagoides pteronyssinus, alternaria and cockroach IgEs, and for intestinal helminth infection as well. Results Anti-Ascaris IgE levels were significantly and independently associated with current wheezing during the previous 12 months [odds ratio (OR) per log(e) increment is 1.31 (95% confidence interval (CI) 1.08-1.60), P=0.007], a history of at least four episodes of wheezing [OR per log(e) increment is 1.52 (95% CI 1.18-1.96), P=0.001], wheezing with sleep disturbances [OR per log(e) increment is 1.35 (95% CI 1.10-1.64), P=0.011] and wheezing with speech disturbances [OR per log(e) increment is 1.57 (95% CI 1.19-2.08), P=0.001]. These were adjusted for gender, pneumonia history, parental asthma, Trichuris infection, use of dry leaves as fuel and other specific IgE levels. The prevalence of Ascaris infection by the presence of wheezing was not significantly different (76% vs. 72%, respectively). Conclusion We conclude that a high titre of anti-Ascaris IgE is associated with an increased risk of asthma symptoms among 5-year-old rural Bangladeshi children with a high helminthic infectious load. [Abstract]

Liu X, Feng J, Xu ZR, Wang YZ, Liu JX
Oral allergy syndrome and anaphylactic reactions in BALB/c mice caused by soybean glycinin and beta-conglycinin.
Clin Exp Allergy. 2007 Dec 7;
Background Soybean protein is used in a number of food products but is also a common cause of food allergy. Soybean glycinin and beta-conglycinin represent up to one-third of protein in the soybean. Many reports have indicated that glycinin and beta-conglycinin have been characterized as major soybean allergens involved in food hypersensitivity. Objective To investigate oral allergy syndrome and anaphylactic reactions in BALB/c mice caused by soybean glycinin and beta-conglycinin with an intragastric feeding protocol without using an adjuvant. Methods BALB/c mice were sensitized by gavages with glycinin and beta-conglycinin, and allergen-specific IgE and IgG1 responses were studied by a passive cutaneous anaphylaxis assay. Serum histamine release and blood pressure were measured according to other methods. Epithelium and mast cell dye used the method of light microscopy. Results Sensitization with soybean allergens induced high levels of antigen-specific IgE and IgG1 and increased serum histamine in BALB/c mice. Percentiles of intact mast cell of small intestine in mice sensitized with glycinin and beta-conglyinin significantly decreased for 28 days. Degranulation of mast cells and damage of the epithelium in the small intestine of mice sensitized with globulins were observed. The level of blood pressure in sensitized mice reached a minimum at 3 h. Conclusion Soybean-specific IgE and IgG1 antibodies increased, with high levels of histamine release, severe degranulation of mast cells and damage of the epithelium of small intestine in mice sensitized with glycinin and beta-conglyinin. [Abstract]

Nagakura T, Ogino S, Okubo K, Sato N, Takahashi M, Ishikawa T
Omalizumab is more effective than suplatast tosilate in the treatment of Japanese cedar pollen-induced seasonal allergic rhinitis.
Clin Exp Allergy. 2007 Dec 7;
Background Seasonal allergic rhinitis (SAR) induced by Japanese cedar pollens is a major problem in Japan. Omalizumab, a humanized monoclonal anti-IgE antibody, improves symptoms associated with SAR, but a comparative study with an anti-allergy drug h