Showing papers in "The Journal of Allergy and Clinical Immunology in 2006"

Second symposium on the definition and management of anaphylaxis: summary report--Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium.

Abstract: There is no universal agreement on the definition of anaphylaxis or the criteria for diagnosis. In July 2005, the National Institute of Allergy and Infectious Disease and Food Allergy and Anaphylaxis Network convened a second meeting on anaphylaxis, which included representatives from 16 different organizations or government bodies, including representatives from North America, Europe, and Australia, to continue working toward a universally accepted definition of anaphylaxis, establish clinical criteria that would accurately identify cases of anaphylaxis with high precision, further review the evidence on the most appropriate management of anaphylaxis, and outline the research needs in this area.

Asthma Control Test: Reliability, validity, and responsiveness in patients not previously followed by asthma specialists

Abstract: Background The development of the Asthma Control Test (ACT), a short, simple, patient-based tool for identifying patients with poorly controlled asthma, was recently described in patients under the routine care of an asthma specialist. Objectives We sought to evaluate the reliability and validity of the ACT in a longitudinal study of asthmatic patients new to the care of an asthma specialist. Methods Patients (n = 313) completed the ACT and the Asthma Control Questionnaire (ACQ) at 2 physician visits (4-12 weeks apart). Pulmonary function was measured, and asthma specialists rated asthma control. Results Internal consistency reliability of the ACT was 0.85 (baseline) and 0.79 (follow-up). Test-retest reliability was 0.77. Criterion validity was demonstrated by significant correlations between baseline ACT scores and baseline specialists' ratings of asthma control ( r = 0.52, P r = −0.89, P P r = 0.44, P r = −0.69, P 1 values ( r = 0.29, P Conclusions The ACT is reliable, valid, and responsive to changes in asthma control over time in patients new to the care of asthma specialists. A cutoff score of 19 or less identifies patients with poorly controlled asthma. Clinical implications In a clinical setting the ACT should be a useful tool to help physicians identify patients with uncontrolled asthma and facilitate their ability to follow patients' progress with treatment.

Toll-like receptor function and signaling.

Abstract: Mammals sense pathogen invasion through pattern-recognition receptors. A group of transmembrane proteins, Toll-like receptors (TLRs), play critical roles as pattern-recognition receptors. They are mainly expressed on antigen-presenting cells, such as macrophages or dendritic cells, and their signaling activates antigen-presenting cells to provoke innate immunity and to establish adaptive immunity. Each TLR has common effects, such as inflammatory cytokine induction or upregulation of costimulatory molecule expression, but also has its specific function, exemplified by type I IFN-inducing ability. These immunoadjuvant effects are not only critical in antimicrobial immunity but are also involved in manifestations of autoimmunity. Furthermore, some TLR agonists are now promising therapeutic tools for various immune disorders, including allergy. Therefore understanding molecular mechanisms on TLRs should be quite useful in the development of therapeutic maneuvers against allergy and autoimmune diseases.

IL-31: A new link between T cells and pruritus in atopic skin inflammation

Abstract: Background IL-31 is a novel T-cell–derived cytokine that induces severe pruritus and dermatitis in transgenic mice, and signals through a heterodimeric receptor composed of IL-31 receptor A and oncostatin M receptor. Objective To investigate the role of human IL-31 in pruritic and nonpruritic inflammatory skin diseases. Methods The expression of IL-31 was analyzed by quantitative real-time PCR in skin samples of healthy individuals and patients with chronic inflammatory skin diseases. Moreover, IL-31 expression was analyzed in nonlesional skin of atopic dermatitis patients after allergen or superantigen exposure, as well as in stimulated leukocytes. The tissue distribution of the IL-31 receptor heterodimer was investigated by DNA microarray analysis. Results IL-31 was significantly overexpressed in pruritic atopic compared with nonpruritic psoriatic skin inflammation. Highest IL-31 levels were detected in prurigo nodularis, one of the most pruritic forms of chronic skin inflammation. In vivo , staphylococcal superantigen rapidly induced IL-31 expression in atopic individuals. In vitro , staphylococcal enterotoxin B but not viruses or T H 1 and T H 2 cytokines induced IL-31 in leukocytes. In patients with atopic dermatitis, activated leukocytes expressed significantly higher IL-31 levels compared with control subjects. IL-31 receptor A showed most abundant expression in dorsal root ganglia representing the site where the cell bodies of cutaneous sensory neurons reside. Conclusion Our findings provide a new link among staphylococcal colonization, subsequent T-cell recruitment/activation, and pruritus induction in patients with atopic dermatitis. Taken together, these findings show that IL-31 may represent a novel target for antipruritic drug development.

Periostin: A novel component of subepithelial fibrosis of bronchial asthma downstream of IL-4 and IL-13 signals

Abstract: Background Subepithelial fibrosis is a cardinal feature of bronchial asthma. Collagen I, III, and V; fibronectin; and tenascin-C are deposited in the lamina reticularis. Extensive evidence supports the pivotal role of IL-4 and IL-13 in subepithelial fibrosis; however, the precise mechanism remains unclear. We have previously identified the POSTN gene encoding periostin as an IL-4/IL-13–inducible gene in bronchial epithelial cells. Periostin is thought to be an adhesion molecule because it possesses 4 fasciclin I domains. Objective We explore the possibility that periostin is involved in subepithelial fibrosis in bronchial asthma. Methods We analyzed induction of periostin in lung fibroblasts by IL-4 or IL-13. We next analyzed expression of periostin in patients with asthma and in ovalbumin-sensitized and ovalbumin-inhaled mice. Furthermore, we examined the binding ability of periostin to other extracellular matrix proteins. Results Both IL-4 and IL-13 induced secretion of periostin in lung fibroblasts independently of TGF-β. Periostin colocalized with other extracellular matrix proteins involved in subepithelial fibrosis in both asthma patients and ovalbumin-sensitized and ovalbumin-inhaled wild-type mice, but not in either IL-4 or IL-13 knockout mice. Periostin had an ability to bind to fibronectin, tenascin-C, collagen V, and periostin itself. Conclusion Periostin secreted by lung fibroblasts in response to IL-4 and/or IL-13 is a novel component of subepithelial fibrosis in bronchial asthma. Periostin may contribute to this process by binding to other extracellular matrix proteins. Clinical implications Periostin induced by IL-4/IL-13 shows promise in inhibiting subepithelial fibrosis in bronchial asthma.

Use of intravenous immunoglobulin in human disease: A review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology

Abstract: Human immunoglobulin prepared for intravenous administration (IGIV) has a number of important uses in the treatment of disease. Some of these are in diseases for which acceptable treatment alternatives do not exist. In this review we have evaluated the evidence underlying a wide variety of IGIV uses and make specific recommendations on the basis of these data. Given the potential risks and inherent scarcity of IGIV, careful consideration of the indications for and administration of IGIV is warranted.

Loss-of-function variations within the filaggrin gene predispose for atopic dermatitis with allergic sensitizations

Abstract: Background Atopic dermatitis (AD) is a chronic inflammatory skin disease with a strong genetic background. One of the characteristic features of AD and causative factor for the disease is an impaired epidermal skin barrier based on a primary defect of epidermal differentiation. Objectives Recently, 2 loss-of-function mutations (R501X and 2282derl4) in the filaggrin gene (FLG) that cause ichthyosis vulgaris, one of the most common inherited skin disorders of keratinization, have been reported to be strong predisposing factors for AD. Methods We evaluated the association of the loss-of-function mutations R501X and 2282del4 within the FLG gene in a large collection of 476 well-characterized white German families with AD by using the transmission-disequilibrium test. Results Our family-based approach revealed prominent associations between the 2 loss-of-function FLG mutations and AD, as previously observed in a traditional Mendelian linkage analysis and case-control cohort analysis approach. In addition, we observed associations of the FLG mutations in particular with the extrinsic subtype of AD, which is characterized by high total serum IgE levels and concomitant allergic sensitizations. Furthermore, FLG mutations are significantly associated with palmar hyperlinearity in patients with AD, which represents a shared feature of AD and ichthyosis vulgaris. Conclusion Together these data implicate that FLG is the first really strong genetic factor identified in a common complex disease. Clinical implications These findings underline the crucial role of the skin barrier in preventing allergic sensitization.

The role of the mast cell in the pathophysiology of asthma.

Abstract: There is compelling evidence that human mast cells contribute to the pathophysiology of asthma. Mast cells, but not T cells or eosinophils, localize within the bronchial smooth muscle bundles in patients with asthma but not in normal subjects or those with eosinophilic bronchitis, a factor likely to be important in determining the asthmatic phenotype. The mechanism of mast cell recruitment by asthmatic airway smooth muscle involves the CXCL10/CXCR3 axis, and several mast cell mediators have profound effects on airway smooth muscle function. The autacoids are established as potent bronchoconstrictors, whereas the proteases tryptase and chymase are being demonstrated to have a range of actions consistent with key roles in inflammation, tissue remodeling, and bronchial hyperresponsiveness. IL-4 and IL-13, known mast cell products, also induce bronchial hyperresponsiveness in the mouse independent of the inflammatory response and enhance the magnitude of agonist-induced intracellular Ca2+ responses in cultured human airway smooth muscle. There are therefore many pathways by which the close approximation of mast cells with airway smooth muscle cells might lead to disordered airway smooth muscle function. Mast cells also infiltrate the airway mucous glands in subjects with asthma, showing features of degranulation, and a positive correlation with the degree of mucus obstructing the airway lumen, suggesting that mast cells play an important role in regulating mucous gland secretion. The development of potent and specific inhibitors of mast cell secretion, which remain active when administered long-term to asthmatic airways, should offer a novel approach to the treatment of asthma.

Update on glucocorticoid action and resistance

Abstract: Extensive development of inhaled and oral glucocorticoids has resulted in highly potent molecules that have been optimized to target activity to the lung and minimize systemic exposure. These have proved highly effective for most asthmatic subjects, but despite these developments, there are a number of subjects with asthma who fail to respond to even high doses of inhaled or even oral glucocorticoids. Advances in delineating the fundamental mechanisms of glucocorticoid pharmacology, especially the concepts of transactivation and transrepression and cofactor recruitment, have resulted in better understanding of the molecular mechanisms whereby glucocorticoids suppress inflammation. The existence of multiple mechanisms underlying glucocorticoid insensitivity raises the possibility that this might indeed reflect different diseases with a common phenotype, and studies examining the efficacy of potential new agents should be targeted toward subgroups of patients with severe corticosteroid-resistant asthma who clearly require effective new drugs and other approaches to improved asthma control.

New perspectives on epidermal barrier dysfunction in atopic dermatitis: Gene–environment interactions

Abstract: Atopic dermatitis (AD) is a multifactorial, chronic inflammatory skin disorder in which genetic mutations and cutaneous hyperreactivity to environmental stimuli play a causative role. Genetic mutations alone might not be enough to cause clinical manifestations of AD, and this review will propose a new perspective on the importance of epidermal barrier dysfunction in genetically predisposed individuals, predisposing them to the harmful effects of environmental agents. The skin barrier is known to be damaged in patients with AD, both in acute eczematous lesions and also in clinically unaffected skin. Skin barrier function can be impaired first by a genetic predisposition to produce increased levels of stratum corneum chymotryptic enzyme. This protease enzyme causes premature breakdown of corneodesmosomes, leading to impairment of the epidermal barrier. The addition of environmental interactions, such as washing with soap and detergents, or long-term application of topical corticosteroids can further increase production of stratum corneum chymotryptic enzyme and impair epidermal barrier function. The epidermal barrier can also be damaged by exogenous proteases from house dust mites and Staphylococcus aureus. One or more of these factors in combination might lead to a defective barrier, thereby increasing the risk of allergen penetration and succeeding inflammatory reaction, thus contributing to exacerbations of this disease.

Prenatal farm exposure is related to the expression of receptors of the innate immunity and to atopic sensitization in school-age children.

Abstract: Background There is increasing evidence that environmental exposures determining childhood illnesses operate early in life. Prenatal exposure to a farming environment through the mother might also play an important role. Objective We sought to investigate the role of maternal exposures to environments rich in microbial compounds for the development of atopic sensitization, asthma, and corresponding alterations in the innate immune system in offspring. Methods In the children of the cross-sectional Prevention of Allergy Risk Factors for Sensitization in Children Related to Farming and Anthroposophic Life Style study, asthma and atopy were assessed by means of standardized questionnaires (n = 8263) and serum IgE measurements (n = 2086). In a subsample (n = 322) gene expression of Toll-like receptors (TLR2 and TLR4) and CD14 was assessed. Maternal exposures were defined through questionnaire information. Results Both atopic sensitization (adjusted odds ratio, 0.58; 95% CI, 0.39-0.86) and the gene expression of receptors of innate immunity were strongly determined by maternal exposure to stables during pregnancy, whereas current exposures had much weaker or no effects. A dose-response relation was found between the extent of upregulation of these genes and the number of different farm animal species the mother had encountered in her pregnancy. Each additional farm animal species increased the expression of TLR2, TLR4, and CD14 by a factor of 1.16 (95% CI, 1.07-1.26), 1.12 (95% CI, 1.04-1.2), and 1.10 (95% CI, 1.03-1.23), respectively. Conclusion Maternal exposure to an environment rich in microbial compounds might protect against the development of atopic sensitization and lead to upregulation of receptors of the innate immune system. The underlying mechanisms potentially operating through the intrauterine milieu or epigenetic inheritance await further elucidation. Clinical implications When assessing risk factors of allergies in an infant's medical history, attention must also be paid to environmental exposures affecting the mother.

Sublingual immunotherapy with once-daily grass allergen tablets: A randomized controlled trial in seasonal allergic rhinoconjunctivitis

Abstract: Background Specific immunotherapy is the only treatment modality that has the potential to alter the natural course of allergic diseases. Sublingual immunotherapy has been developed to facilitate access to this form of treatment and to minimize serious adverse events. Objective To investigate the efficacy and safety of sublingual grass allergen tablets in seasonal allergic rhinoconjunctivitis. Methods A multinational, multicenter, randomized, placebo-controlled trial conducted during 2002 and 2003. Fifty-five centers in 8 countries included 855 participants age 18 to 65 years who gave a history of grass pollen–induced allergic rhinoconjunctivitis and had a positive skin prick test and elevated serum allergen-specific IgE to Phleum pratense. Participants were randomized to 2500, 25,000, or 75,000 SQ-T grass allergen tablets (GRAZAX; ALK-Abello, Horsholm, Denmark) or placebo for sublingual administration once daily. Mean duration of treatment was 18 weeks. Results Average rhinoconjunctivitis scores during the season showed moderate reductions of symptoms (16%) and medication use (28%) for the grass allergen tablet 75,000 SQ-T ( P = .0710; P = .0470) compared with placebo. Significantly better rhinoconjunctivitis quality of life scores ( P = .006) and an increased number of well days ( P = .041) were also observed. Efficacy was increased in the subgroup of patients who completed the recommended preseasonal treatment of at least 8 weeks before the grass pollen season (symptoms, 21%, P = .0020; and medication use, 29%, P = .0120). No safety concerns were observed. Conclusion This study confirms dose-dependent efficacy of the grass allergen tablet. Although further studies are required, the greater tolerability of the tablet may permit immunotherapy to be available to a much broader group of patients with impaired quality of life caused by grass pollen allergy. Clinical implications For patients with grass pollen allergy, sublingual immunotherapy is well tolerated and can reduce symptoms and improve quality of life.

Cytokines and chemokines orchestrate atopic skin inflammation

Abstract: Atopic dermatitis (AD) is a common pruritic and chronically relapsing inflammatory skin disease. The pathophysiology of AD includes disturbed skin barrier functions, frequent allergic responses against allergens, defects in the antimicrobial immune defense, and a genetic predisposition. In this review we summarize advances in our understanding of the complex interdependent network of members of the rapidly growing protein superfamilies of cytokines and chemokines that lead to the development of AD.

Molecular regulation of mast cell activation

Abstract: The mast cell is a central player in allergy and asthma. Activation of these cells induces the release of preformed inflammatory mediators localized in specialized granules and the de novo synthesis and secretion of cytokines, chemokines, and eicosanoids. The balance of engaging inhibitory and activatory cell-surface receptors on mast cells determines whether the cell becomes active on encountering a challenge. However, recent evidence suggests that, once activated, a mast cell's response is further regulated by the balance of both positive and negative intracellular molecular events that extend well beyond the traditional role of kinases and phosphatases. These functional responses are also carefully governed by other protein and lipid mediators that determine the rate and extent of the response. Molecules that have adaptor functions, modulate lipids, and provide synergistic signals add to the regulatory complexity. Considerable information has been obtained from the study of the high-affinity receptor for IgE (FcɛRI), and thus it is the major focus of this review. The unifying theme is that the regulatory steps mentioned herein are required for promoting effective responses while protecting against unwanted inflammatory responses.

Mechanisms of airway hyperresponsiveness

Abstract: Airway hyperresponsiveness (AHR) to direct (histamine and methacholine) and indirect (exercise, cold air, hyperventilation, AMP) challenges is a universal and defining feature of asthma. One component of AHR is transient or inducible and occurs after allergen exposure, for example, and improves occasionally rapidly after inhaled corticosteroids or environmental control. This transient airway hyperresponsiveness is more marked to the indirect stimuli. There are convincing data linking this component of AHR to airway inflammation; however, the precise mechanisms linking airway inflammation and hyperresponsiveness of the airway smooth muscle are not clear. The other component of AHR is more persistent and is relatively refractory to environmental control and inhaled corticosteroids. This is likely secondary to structural airway changes, which are collectively referred to as airway remodeling, and which are a result of the chronic (rather than the acute) effects of airway inflammation. This persistent AHR is best reflected by airway hyperresponsiveness to direct stimuli such as methacholine. The mechanisms are also uncertain, but reduced airway caliber, increased airway wall thickness, increased airway smooth muscle mass, and perhaps contractility likely all play a role.

Efficacy and safety of sublingual immunotherapy with grass allergen tablets for seasonal allergic rhinoconjunctivitis

Abstract: Background Allergen immunotherapy (desensitization) by injection is effective for seasonal allergic rhinitis and has been shown to induce long-term disease remission. The sublingual route also has potential, although definitive evidence from large randomized controlled trials has been lacking. Objective The aim was to confirm the efficacy of a rapidly dissolving grass allergen tablet (GRAZAX, ALK-Abello, Horsholm, Denmark) compared with placebo in patients with seasonal rhinoconjunctivitis. Methods A longitudinal, double-blind, placebo-controlled, parallel-group study that included 51 centers from 8 countries. Subjects were randomized (1:1) to receive a grass allergen tablet or placebo once daily. A total of 634 subjects with a history of grass pollen–induced rhinoconjunctivitis for at least 2 years and confirmation of IgE sensitivity (positive skin prick test and serum-specific IgE) were included in the study. Subjects commenced treatment at least 16 weeks before the grass pollen season, and treatment was continued throughout the entire season. Results The primary efficacy analysis showed a reduction of 30% in rhinoconjunctivitis symptom score ( P P Conclusion Sublingual immunotherapy with grass allergen tablets was effective in grass pollen–induced rhinoconjunctivitis. The tablet was well tolerated with minor local side effects. Clinical implications The grass allergen tablet represents a safe alternative to injection immunotherapy suitable for home use.

Anti–IL-5 (mepolizumab) therapy for eosinophilic esophagitis

Abstract: Background Eosinophilic esophagitis (EE) is characterized by high numbers of eosinophils in the esophagus and epithelial hyperplasia, and is being increasingly recognized. IL-5 promotes eosinophil trafficking to the esophagus, and positively regulates eosinophil growth, activation, survival, and tissue recruitment. Objective We hypothesized that the humanized monoclonal IgG 1 antibody against human IL-5 (mepolizumab) may be useful in the control of EE. Methods An open-label phase I/II safety and efficacy study of anti–IL-5 in 4 adult patients with EE and longstanding dysphagia and esophageal strictures was conducted. Patients received 3 infusions of anti–IL-5 (750 mg intravenously monthly) without change in their current therapy. The levels of plasma IL-5, peripheral blood eosinophils, and CCR3 + cells in blood, quality of life measurements, and histological analysis of esophageal biopsies were determined before and 1 month after treatment. Results Peripheral blood eosinophilia and percent of CCR3 + cells decreased by 6.4-fold and 7.9-fold ( P P P P = .03). Therapy was generally well tolerated, and responsiveness to anti–IL-5 therapy did not correlate with plasma IL-5 levels. Conclusion Anti–IL-5 therapy is associated with marked decreases in peripheral blood and esophageal eosinophilia (including the number of CCR3 + blood cells) in patients with EE and improved clinical outcomes. Clinical implications Anti–IL-5 is a promising therapeutic intervention for EE.

IL-31 is associated with cutaneous lymphocyte antigen-positive skin homing T cells in patients with atopic dermatitis.

Abstract: Background IL-31 is a newly discovered T-cell cytokine that, when overexpressed in mice, results in pruritus and skin dermatitis resembling human atopic dermatitis (AD). Objective We sought to investigate the expression of IL-31 and IL-31 receptor A (IL-31RA) in skin biopsy specimens and peripheral blood cells from patients with AD and healthy individuals. Methods Expression of IL-31 and IL-31RA was evaluated in skin biopsy specimens from patients with AD and healthy individuals by means of immunohistochemistry and RT-PCR. IL-31 protein production by skin-homing cutaneous lymphocyte antigen (CLA)–positive T cells was also assessed. Results IL-31RA protein was expressed by keratinocytes and infiltrating macrophages in skin biopsy specimens from patients with AD. Comparisons between skin from patients with AD and healthy skin showed IL-31RA expression at higher levels on epidermal keratinocytes in AD samples. Infiltrating cells, more numerous in skin from patients with AD compared with that of healthy individuals, expressed IL31 mRNA. Histomorphometric analysis of these cells indicated they were of the lymphocytic lineage, with the majority of cells staining positive for CLA and CD3. IL31 mRNA and protein expression is largely restricted to CD45RO + (memory) CLA + T cells in peripheral blood of patients with AD and healthy volunteers. Moreover, circulating CLA + T cells from patients with AD, but not from patients with psoriasis, are capable of producing higher levels of IL-31 compared with CLA + T cells from healthy individuals. However, the average levels of IL-31 were not significantly different between patients with AD and healthy individuals. Conclusion We provide evidence that IL-31 expression is associated with CLA + T cells and might contribute to the development of AD-induced skin inflammation and pruritus.

Nasal IL-5 levels determine the response to anti-IL-5 treatment in patients with nasal polyps.

Abstract: Background Chronic rhinosinusitis with nasal polyps is characterized by an eosinophilic inflammation and high IL-5 levels. Objectives Antagonizing the effect of IL-5 is a potential new treatment strategy in patients with nasal polyps. Methods In a double-blind, placebo-controlled, randomized, 2-center safety and pharmacokinetic study, 24 subjects with bilateral nasal polyps were randomized to receive a single intravenous infusion of reslizumab, a humanized anti-human IL-5 mAb, at 3 mg/kg or 1 mg/kg or placebo. We evaluated the safety and pharmacokinetics of reslizumab, and biologic activity was assessed by means of endoscopic evaluation of polyp size, symptoms, peripheral eosinophil counts, peripheral and local IL-5 levels, eotaxin levels, and eosinophil cationic protein levels. Results We demonstrated that a single injection of reslizumab up to 3 mg/kg is safe and well tolerated. Blood eosinophil numbers and concentrations of eosinophil cationic protein were reduced up to 8 weeks after treatment in serum and nasal secretions. Individual nasal polyp scores improved only in half of the treated patients for 4 weeks. Responders had increased IL-5 concentrations in nasal secretions at baseline compared with nonresponders, and logistic regression analysis revealed that increased nasal IL-5 levels (>40 pg/mL) predict the response to anti-IL-5 treatment. Conclusion A single injection of anti–IL-5 reduces the size of nasal polyps for 4 weeks in half of the patients, and nasal IL-5 levels predict the response to anti–IL-5 treatment. Clinical implications Intravenous administration of a humanized anti-human IL-5 mAb is safe and reduces the size of nasal polyps in half of the patients.

Enhanced expression levels of IL-31 correlate with IL-4 and IL-13 in atopic and allergic contact dermatitis

Abstract: Background IL-31 is produced by activated T lymphocytes, preferentially by T H 2 cells. Transgenic mice overexpressing IL-31 have a phenotype resembling allergic dermatitis in human subjects. Objective We sought to evaluate the potential importance of IL-31 in the pathogenesis of human T cell–mediated skin diseases. Methods We analyzed total RNA taken from 149 skin biopsy specimens from patients with atopic dermatitis (AD), allergic contact dermatitis (ACD), or psoriasis in comparison with specimens taken from patients with healthy skin (n = 13) by using quantitative real-time PCR for the expression of T H 1/T H 2 cytokines. Results We found statistically increased mRNA levels of IL-31 in biopsy specimens taken from patients with AD, irrespective of the severity of the disease and serum IgE levels. Moreover, IL-31 mRNA levels were strongly increased in many biopsy specimens taken from patients with ACD. However, no increased transcription of IL-31 could be detected in biopsy specimens taken from psoriatic plaques. A comparison of mRNA levels of IL-31 with T H 1 or T H 2 cytokines demonstrates a correlation of the expression of IL-31 with IL-4 and IL-13 but not with IFN-γ. No significant increase of IL-31 receptor mRNA could be detected in any disease, whereas the second receptor subunit of IL-31, the oncostatin M receptor, seems to be enhanced transcribed in patients with psoriasis. Conclusion IL-31 expression is not only increased in patients with AD but also in those with ACD, 2 pruritic skin disorders. In both types of eczema, expression of IL-31 is associated with the expression of the T H 2 cytokines IL-4 and IL-13. Clinical implications IL-31 might contribute not only to the development of AD but also to ACD-provoked skin inflammation.

The many faces of the hygiene hypothesis.

Abstract: About 15 years have gone by since Strachan first proposed the idea that infections and unhygienic contact might confer protection against the development of allergic illnesses. The so-called hygiene hypothesis has ever since undergone numerous more or less subtle modifications by various researchers in the fields of epidemiology, clinical science, and immunology. Three major tracts have developed exploring the role of overt viral and bacterial infections, the significance of environmental exposure to microbial compounds, and the effect of both on underlying responses of the innate and adaptive immunity. To date, a truly unifying concept has not yet emerged, but various pieces of a complex interplay between immune responses of the host, characteristics of the invading microorganism, the level and variety of the environmental exposure, and the interactions between a genetic background and a range of exposures becomes apparent. These influences are discussed as determinants for a number of complex allergic illnesses in this review, while we attempt to pay attention to the importance of different phenotypes, namely of the asthma syndrome. Even if today practical implications cannot directly be deduced from these findings, there is great potential for the development of novel preventive and therapeutic strategies in the future.

Sublingual immunotherapy: a comprehensive review.

Abstract: Sublingual immunotherapy (SLIT) has been used with increasing frequency in Europe and is viewed with increasing interest by allergists in the United States. To address this interest, a Joint Task Force of the American College of Allergy, Asthma and Immunology and the American Academy of Allergy, Asthma and Immunology's Immunotherapy and Allergy Diagnostic Committees reviewed the available literature on SLIT and prepared this report. The task force concluded that despite clear evidence that SLIT is an effective treatment, many questions remained unanswered, including effective dose, treatment schedules, and overall duration of treatment. Until these have been determined, an assessment of the cost/benefit ratio of the treatment cannot be made. SLIT does appear to be associated with few serious side effects, but it has not been administered in high-risk asthmatic patients, nor in the studies reviewed has it been administered as a mixture of non–cross-reacting allergens. Furthermore, there is currently no allergy extract approved for this use in the United States, nor is there a Current Procedural Terminology code for billing purposes. All of these factors should be given careful consideration by anyone contemplating initiating SLIT treatment for their allergic patients.

The medical effects of mold exposure

Abstract: Exposure to molds can cause human disease through several well-defined mechanisms. In addition, many new mold-related illnesses have been hypothesized in recent years that remain largely or completely unproved. Concerns about mold exposure and its effects are so common that all health care providers, particularly allergists and immunologists, are frequently faced with issues regarding these real and asserted mold-related illnesses. The purpose of this position paper is to provide a state-of-the-art review of the role that molds are known to play in human disease, including asthma, allergic rhinitis, allergic bronchopulmonary aspergillosis, sinusitis, and hypersensitivity pneumonitis. In addition, other purported mold-related illnesses and the data that currently exist to support them are carefully reviewed, as are the currently available approaches for the evaluation of both patients and the environment.

Filaggrin loss-of-function mutations predispose to phenotypes involved in the atopic march.

Abstract: Background Childhood eczema often precedes the development of asthma and allergic rhinitis in the so-called atopic march . Recently, 2 loss-of-function mutations in the gene encoding the epidermal barrier protein filaggrin were reported to be predisposing factors for eczema and concomitant asthma, suggesting a possible role in disease transition. Objective We aimed to assess the importance of filaggrin loss-of-function mutations in the susceptibility to eczema and associated clinical phenotypes. Methods The filaggrin mutations were genotyped and tested for association with allergic disorders in 2 large European populations including 1092 children with eczema. Results Highly significant association of the filaggrin null mutations with eczema and concomitant asthma was replicated. Moreover, we found that these mutations predispose to asthma, allergic rhinitis, and allergic sensitization only in the presence of eczema. We show that the presence of 2 filaggrin null alleles is an independent risk factor for asthma in children with eczema, and that the 2 investigated mutations account for about 11% of eczema cases in the German population. Conclusion These results lend strong support to the role of filaggrin in the pathogenesis of eczema and in the subsequent progression along the atopic march. The fact that previous expression of eczema is a prerequisite for the manifestation of allergic airways disease and specific sensitization highlights the importance of the epidermal barrier in the pathogenesis of these disorders. Clinical implications Our results suggest that the maintenance and repair of the epidermal barrier in infants with eczema may prevent the subsequent development of allergic airways disease.

The Wiskott-Aldrich syndrome.

Abstract: The Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder with variable clinical phenotypes that correlate with the type of mutations in the WAS protein (WASP) gene. WASP, a key regulator of actin polymerization in hematopoietic cells, has 5 well-defined domains that are involved in signaling, cell locomotion, and immune synapse formation. WASP facilitates the nuclear translocation of nuclear factor κB and was shown to play an important role in lymphoid development and in the maturation and function of myeloid monocytic cells. Mutations of WASP are located throughout the gene and either inhibit or dysregulate normal WASP function. Analysis of a large patient population demonstrates a phenotype-genotype correlation: classic WAS occurs when WASP is absent, X-linked thrombocytopenia when mutated WASP is expressed, and X-linked neutropenia when missense mutations occur in the Cdc42-binding site. The progress made in dissecting the function of WASP has provided new diagnostic possibilities and has propelled our therapeutic strategies from conservative symptomatic treatment to curative hematopoietic stem cell transplantation and toward gene therapy.

Efficacy and safety of specific immunotherapy with SQ allergen extract in treatment-resistant seasonal allergic rhinoconjunctivitis

Abstract: Background Specific immunotherapy is widely used to treat allergic rhinitis, but few large-scale clinical trials have been performed. Objective We sought to assess the efficacy and safety of specific immunotherapy with 2 doses of Alutard grass pollen in patients with moderately severe seasonal allergic rhinitis inadequately controlled with standard drug therapy. Methods We performed a double-blind, randomized, placebo-controlled study of 410 subjects (203 randomized to 100,000 standardized quality units [SQ-U] maintenance, 104 to 10,000 SQ-U, and 103 to placebo). Three hundred forty-seven (85%) completed treatment. Groups were well matched for demographics and symptoms. Results Across the whole pollen season, mean symptom and medication scores were 29% and 32% lower, respectively, in the 100,000–SQ-U group compared with those in the placebo group (both P P P = .16). Quality-of-life measures confirmed the superiority of both doses to placebo. Local and delayed side effects were common but generally mild. Clinically significant early and delayed systemic side effects were confined to the 100,000–SQ-U group, but no life-threatening reactions occurred. Conclusions One season of immunotherapy with Alutard grass pollen reduced symptoms and medication use and improved the quality of life of subjects with moderately severe hay fever. The 100,000–SQ-U regimen was more effective, but the 10,000–SQ-U regimen caused fewer side effects.

Molecular mechanisms of β2-adrenergic receptor function, response, and regulation

Abstract: The human β 2 -adrenoceptor is a member of the 7-transmembrane family of receptors, encoded by a gene on chromosome 5, and widely distributed in the respiratory tract. Intracellular signaling after β 2 -adrenoceptor activation is largely affected through cyclic adenosine monophosphate and protein kinase A. Differences in the mechanism of interaction of short- and long-acting β 2 -agonists and the β 2 -receptor are reflected in the kinetics of airway smooth muscle relaxation and the onset and duration of bronchodilation in asthmatic patients. β-Adrenoceptor desensitization associated with prolonged β 2 -agonist activation differs depending on the cell type and is reflected in different profiles of clinical tolerance to chronic β 2 -agonist therapy. A number of genetic polymorphisms of the β 2 -receptor have been described that appear to alter the behavior of the receptor, including the response to β 2 -agonists. The synergy between the β 2 -receptor and the glucocorticoid receptor functions has implications for the combined use of β 2 -agonists and corticosteroids in the treatment of respiratory disease.

Apple allergy across Europe: how allergen sensitization profiles determine the clinical expression of allergies to plant foods.

Abstract: Background Allergy to a plant food can either result from direct sensitization to that food or from primary sensitization to pollen, latex, or another food. Objective We sought to investigate the primary sensitizers in apple allergy across Europe, the individual allergens involved, and whether these differences determine the clinical presentation. Methods Patients (n = 389) with positive case histories and skin prick test responses to fresh apple were selected in the Netherlands, Austria, Italy, and Spain. Skin prick tests and RASTs to a panel of pollens and plant foods were performed, as well as RASTs to Bet v 1 and the apple allergens Mal d 1, 2, 3, and 4. Results In the Netherlands, Austria, and Italy apple allergy is mild (>90% isolated oral symptoms) and related to birch pollinosis and sensitization to Bet v 1 and its apple homologue, Mal d 1, which has an odds ratio of local reactions of 2.85 (95% CI, 1.47-5.55). In Spain apple allergy is severe (>35% systemic reactions) and related to peach allergy and sensitization to Mal d 3 (nonspecific lipid transfer protein), which has an odds ratio of systemic reactions of 7.76 (95% CI, 3.87-15.56). Conclusion The analysis of individual apple allergens in a clinical context has provided insight into the sensitization pathway and into the intrinsic risk an allergen bears to induce mild or severe food allergy. Clinical implications Information on the sensitization pathway is essential to develop preventive strategies in food allergy. The application of individual food allergens with a known intrinsic risk will improve the prognostic value of diagnostic tests.

Approaches to the treatment of hypereosinophilic syndromes: a workshop summary report.

Abstract: Hypereosinophilic syndromes are a heterogeneous group of uncommon disorders characterized by the presence of marked peripheral blood eosinophilia, tissue eosinophilia, or both, resulting in a wide variety of clinical manifestations. Although corticosteroids are the first-line therapy for many of these disorders, approaches to the treatment of patients who do not tolerate or are unresponsive to corticosteroids are poorly standardized. A multidisciplinary group of 37 clinicians and scientists participated in a workshop held in May 2005 in Bern, Switzerland to discuss current and future approaches to therapy for 3 eosinophil-mediated disorders: hypereosinophilic syndrome, Churg-Strauss syndrome, and eosinophil-associated gastrointestinal disease. The goal of the workshop was to summarize available data regarding treatment of these disorders to identify the most promising therapies and approaches for further study. There was consensus among all of the participants that the identification of markers of disease progression to assess treatment responses is a research priority for all 3 disorders. Furthermore, the need for newer therapeutic strategies and novel drugs, as well as multicenter trials to assess all treatment modalities, was emphasized.

Clinical and pathologic perspectives on aspirin sensitivity and asthma

Abstract: Aspirin and other nonsteroidal anti-inflammatory drugs that inhibit COX-1 induce unique nonallergic reactions, consisting of attacks of rhinitis and asthma. These hypersensitivity reactions occur in a subset of asthmatic subjects, thus identifying them as having this exclusive clinical presentation. We refer to these patients as having aspirin-exacerbated respiratory disease, a disease process that produces devastating eosinophilic inflammation of both the upper and lower respiratory tracts. This review focuses on a description of patients with aspirin-exacerbated respiratory disease, methods available to diagnose their condition, the unique ability of all nonsteroidal anti-inflammatory drugs that inhibit COX-1 to cross-react with aspirin, an update on pathogenesis, and current thoughts about treatment.