Showing papers in "The Journal of Allergy and Clinical Immunology in 2005"
TL;DR: White adipose tissue is no longer considered an inert tissue mainly devoted to energy storage but is emerging as an active participant in regulating physiologic and pathologic processes, including immunity and inflammation.
Abstract: White adipose tissue is no longer considered an inert tissue mainly devoted to energy storage but is emerging as an active participant in regulating physiologic and pathologic processes, including immunity and inflammation. Macrophages are components of adipose tissue and actively participate in its activities. Furthermore, cross-talk between lymphocytes and adipocytes can lead to immune regulation. Adipose tissue produces and releases a variety of proinflammatory and anti-inflammatory factors, including the adipokines leptin, adiponectin, resistin, and visfatin, as well as cytokines and chemokines, such as TNF-α, IL-6, monocyte chemoattractant protein 1, and others. Proinflammatory molecules produced by adipose tissue have been implicated as active participants in the development of insulin resistance and the increased risk of cardiovascular disease associated with obesity. In contrast, reduced leptin levels might predispose to increased susceptibility to infection caused by reduced T-cell responses in malnourished individuals. Altered adipokine levels have been observed in a variety of inflammatory conditions, although their pathogenic role has not been completely clarified.
2,482 citations
TL;DR: The targeting of DC-SIGN by certain probiotic bacteria might explain their beneficial effect in the treatment of a number of inflammatory diseases, including atopic dermatitis and Crohn's disease.
Abstract: Background Lactobacilli are probiotic bacteria that are frequently tested in the management of allergic diseases or gastroenteritis. It is hypothesized that these probiotics have immunoregulatory properties and promote mucosal tolerance, which is in part mediated by regulatory T cells (Treg cells). On the basis of pathogenic or tissue-specific priming, dendritic cells (DC) acquire different T cell–instructive signals and drive the differentiation of naive T H cells into either T H 1, T H 2, or regulatory effector T cells. Objective We studied in what way different species of lactobacilli prime human DCs for their ability to drive Treg cells. Methods Human monocyte-derived DCs were cultured in vitro with lactobacilli of different species. Results Two different species of lactobacilli, Lactobacillus reuteri and Lactobacillus casei , but not Lactobacillus plantarum , prime monocyte-derived DCs to drive the development of Treg cells. These Treg cells produced increased levels of IL-10 and were capable of inhibiting the proliferation of bystander T cells in an IL-10–dependent fashion. Strikingly, both L reuteri and L casei , but not L plantarum , bind the C-type lectin DC-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN). Blocking antibodies to DC-SIGN inhibited the induction of the Treg cells by these probiotic bacteria, stressing that ligation of DC-SIGN can actively prime DCs to induce Treg cells. Conclusions The targeting of DC-SIGN by certain probiotic bacteria might explain their beneficial effect in the treatment of a number of inflammatory diseases, including atopic dermatitis and Crohn's disease.
742 citations
TL;DR: In this population of children at increased risk of developing allergies and asthma, the most significant risk factor for the development of preschool childhood wheezing is the occurrence of symptomatic rhinovirus illnesses during infancy that are clinically and prognostically informative based on their seasonal nature.
Abstract: Background The contribution of viral respiratory infections during infancy to the development of subsequent wheezing and/or allergic diseases in early childhood is not established. Objective To evaluate these relationships prospectively from birth to 3 years of age in 285 children genetically at high risk for developing allergic respiratory diseases. Methods By using nasal lavage, the relationship of timing, severity, and etiology of viral respiratory infections during infancy to wheezing in the 3rd year of life was evaluated. In addition, genetic and environmental factors that could modify risk of infections and wheezing prevalence were analyzed. Results Risk factors for 3rd year wheezing were passive smoke exposure (odds ratio [OR]=2.1), older siblings (OR=2.5), allergic sensitization to foods at age 1 year (OR=2.0), any moderate to severe respiratory illness without wheezing during infancy (OR=3.6), and at least 1 wheezing illness with respiratory syncytial virus (RSV; OR=3.0), rhinovirus (OR=10) and/or non–rhinovirus/RSV pathogens (OR=3.9) during infancy. When viral etiology was considered, 1st-year wheezing illnesses caused by rhinovirus infection were the strongest predictor of subsequent 3rd year wheezing (OR=6.6; P P Conclusion In this population of children at increased risk of developing allergies and asthma, the most significant risk factor for the development of preschool childhood wheezing is the occurrence of symptomatic rhinovirus illnesses during infancy that are clinically and prognostically informative based on their seasonal nature.
700 citations
Icahn School of Medicine at Mount Sinai1, Food and Drug Administration2, American College of Emergency Physicians3, Stanford University4, Johns Hopkins University5, University of Texas Southwestern Medical Center6, American Academy of Pediatrics7, Harvard University8, University of Pennsylvania9, Medical University of South Carolina10, National Institutes of Health11, University of Virginia12, National Health Service13, University of Manitoba14
TL;DR: This dissertation aims to provide a history of medical marijuana use in the United States and Canada over a 40-year period from 1989 to 2002, with a focus on the period up to and including the year ending in 2002.
Abstract: Hugh A. Sampson, MD, Anne Munoz-Furlong, BA, S. Allan Bock, MD, Cara Schmitt, MS, Robert Bass, MD, Badrul A. Chowdhury, MD, Wyatt W. Decker, MD, Terence J. Furlong, MS, Stephen J. Galli, MD, David B. Golden, MD, Rebecca S. Gruchalla, MD, Allen D. Harlor, Jr, MD, David L. Hepner, MD, Marilyn Howarth, MD, Allen P. Kaplan, MD, Jerrold H. Levy, MD, Lawrence M. Lewis, MD, Phillip L. Lieberman, MD, Dean D. Metcalfe, MD, Ramon Murphy, MD, Susan M. Pollart, MD, Richard S. Pumphrey, MD, Lanny J. Rosenwasser, MD, F. Estelle Simons, MD, Joseph P. Wood, MD, and Carlos A. Camargo, Jr, MD New York, NY, Fairfax and Charlottesville, Va, Boulder and Denver, Colo, Baltimore, Rockville, and Bethesda, Md, Rochester, Minn, Stanford, Calif, Dallas, Tex, Eugene, Ore, Boston, Mass, Philadelphia, Pa, Charleston, SC, Atlanta, Ga, St Louis, Mo, Cordova, Tenn, Scottsdale, Ariz, Manchester, United Kingdom, and Winnipeg, Manitoba, Canada
641 citations
TL;DR: Findings are inconclusive but weight-loss studies on the basis of behavioral change and bariatric studies have shown substantial improvements in the clinical status of many obese patients with asthma who lost weight.
Abstract: The prevalences of asthma and obesity have increased substantially in recent decades in many countries, leading to speculation that obese persons might be at increased risk of asthma development In adults cross-sectional, case-control, prospective, and weight-loss studies are in the aggregate consistent with a role for obesity in the pathogenesis of asthma In children 3 of 4 prospective studies also show a significant association between excess weight and asthma incidence Because of the methodologic shortcomings of many studies, these findings are inconclusive, however Population surveys do suggest that persons with asthma are disproportionately obese compared with persons who have never had asthma Weight-loss studies on the basis of behavioral change and bariatric studies have shown substantial improvements in the clinical status of many obese patients with asthma who lost weight Clarifying the nature of the relationship between obesity and asthma incidence and the role of weight management among patients with asthma are both critical areas with important ramifications for the prevention and treatment of asthma
594 citations
TL;DR: The majority of the US population represented in NHANES III was sensitized to 1 or more allergens, and the higher prevalences observed in NHanES III reflect true changes in prevalence or methodological differences between the surveys cannot be determined with certainty.
Abstract: Background Allergy skin tests were administered in the second and third National Health and Nutrition Examination Surveys (NHANES II and III) conducted in the United States from 1976 through 1980 and 1988 through 1994, respectively. Objectives This study estimated positive skin test response rates in NHANES III and identified predictors of one or more positive test responses. Comparisons with NHANES II were also made. Methods In NHANES III, 10 allergens and 2 controls were tested in all subjects aged 6 to 19 years and a random half-sample of subjects aged 20 to 59 years. A wheal-based definition of a positive test response was used. Results In NHANES III, 54.3% of the population had positive test responses to 1 or more allergens. Prevalences were 27.5% for dust mite, 26.9% for perennial rye, 26.2% for short ragweed, 26.1% for German cockroach, 18.1% for Bermuda grass, 17.0% for cat, 15.2% for Russian thistle, 13.2% for white oak, 12.9% for Alternaria alternata , and 8.6% for peanut. Among those with positive test responses, the median number of positive responses was 3.0. Adjusted odds of a positive test response were higher for the following variables: age of 20 to 29 years, male sex, minority race, western region, old homes, and lower serum cotinine levels. For the 6 allergens common to NHANES II and III, prevalences were 2.1 to 5.5 times higher in NHANES III. Conclusions The majority of the US population represented in NHANES III was sensitized to 1 or more allergens. Whether the higher prevalences observed in NHANES III reflect true changes in prevalence or methodological differences between the surveys cannot be determined with certainty.
591 citations
TL;DR: These parameters were developed by the Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma and Immunology, the American College of Allergies, ASTI, and ACAAI as mentioned in this paper.
Abstract: These parameters were developed by the Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma and Immunology; the American College of Allergy, Asthma and Immunology; and the Joint Council of Allergy, Asthma and Immunology. The American Academy of Allergy, Asthma and Immunology (AAAAI) and the American College of Allergy, Asthma and Immunology (ACAAI) have jointly accepted responsibility for establishing "The diagnosis and management of anaphylaxis: an updated practice parameter." This is a complete and comprehensive document at the current time. The medical environment is a changing environment, and not all recommendations will be appropriate for all patients. Because this document incorporated the efforts of many participants, no single individual, including those who served on the Joint Task force, is authorized to provide an official AAAAI or ACAAI interpretation of these practice parameters. Any request for information about or an interpretation of these practice parameters by the AAAAI or ACAAI should be directed to the Executive Offices of the AAAAI, the ACAAI, and the Joint Council of Allergy, Asthma and Immunology. These parameters are not designed for use by pharmaceutical companies in drug promotion. This is a complete and comprehensive document at the current time. The medical environment is a changing environment, and not all recommendations will be appropriate for all patients.
545 citations
TL;DR: Whether responses to ICSs and LTRAs are concordant for individuals or whether asthmatic patients who do not respond to one medication respond to the other is investigated.
Abstract: Background Responses to inhaled corticosteroids (ICSs) and leukotriene receptor antagonists (LTRAs) vary among asthmatic patients. Objective We sought to determine whether responses to ICSs and LTRAs are concordant for individuals or whether asthmatic patients who do not respond to one medication respond to the other. Methods Children 6 to 17 years of age with mild-to-moderate persistent asthma were randomized to one of 2 crossover sequences, including 8 weeks of an ICS, fluticasone propionate (100 μg twice daily), and 8 weeks of an LTRA, montelukast (5-10 mg nightly depending on age), in a multicenter, double-masked, 18-week trial. Response was assessed on the basis of improvement in FEV 1 and assessed for relationships to baseline asthma phenotype-associated biomarkers. Results Defining response as improvement in FEV 1 of 7.5% or greater, 17% of 126 participants responded to both medications, 23% responded to fluticasone alone, 5% responded to montelukast alone, and 55% responded to neither medication. Compared with those who responded to neither medication, favorable response to fluticasone alone was associated with higher levels of exhaled nitric oxide, total eosinophil counts, levels of serum IgE, and levels of serum eosinophil cationic protein and lower levels of methacholine PC 20 and pulmonary function; favorable response to montelukast alone was associated with younger age and shorter disease duration. Greater differential response to fluticasone over montelukast was associated with higher bronchodilator use, bronchodilator response, exhaled nitric oxide levels, and eosinophil cationic protein levels and lower methacholine PC 20 and pulmonary function values. Conclusions Response to fluticasone and montelukast vary considerably. Children with low pulmonary function or high levels of markers associated with allergic inflammation should receive ICS therapy. Other children could receive either ICSs or LTRAs.
537 citations
TL;DR: In this article, a randomized, double-blind, placebo-controlled study of subcutaneous injection immunotherapy was performed in subjects with allergic rhinoconjunctivitis, with or without asthma.
Abstract: Background Allergen-specific immunotherapy uses aqueous extracts of natural source materials as a basis for preparations to downregulate the allergic response. Recombinant DNA technology has enabled the cloning of many allergens, thus facilitating investigations aimed at improving efficacy and safety of immunotherapy. Objective To determine the effectiveness of a mixture of 5 recombinant grass pollen allergens in reducing symptoms and need for symptomatic medication in patients allergic to grass pollen. Methods A randomized, double-blind, placebo-controlled study of subcutaneous injection immunotherapy was performed in subjects with allergic rhinoconjunctivitis, with or without asthma. Primary endpoint was a symptom medication score compiled from separate symptom and medication scores. Secondary endpoints included a rhinitis quality of life questionnaire, conjunctival provocation, and specific antibody responses. Results The symptom medication score showed significant improvements in subjects receiving recombinant allergens as opposed to placebo, with reductions in both symptoms and medication usage. The rhinitis quality of life questionnaire revealed clinically relevant significant improvements in overall assessment and in 5 of 7 separate domains, and conjunctival provocation showed a clear trend in favor of active treatment. All treated subjects developed strong allergen-specific IgG 1 and IgG 4 antibody responses. Some patients were not sensitized to Phl p 5 but nevertheless developed strong IgG antibody responses to that allergen. Conclusion A recombinant allergen vaccine can be a effective and safe treatment to ameliorate symptoms of allergic rhinitis. The clinical benefit is associated with modification of the specific immune response with promotion of IgG 4 and reduction of IgE antibodies consistent with the induction of IL-10–producing regulatory T cells.
460 citations
TL;DR: The anti-inflammatory effects of omalizumab at different sites of allergic inflammation and the clinical benefits of anti-IgE therapy in patients with allergic asthma and allergic rhinitis emphasize the fundamental importance of IgE in allergic inflammation.
Abstract: Anti-IgE therapy with omalizumab reduces serum levels of free IgE and downregulates expression of IgE receptors (FceRI) on mast cells and basophils. In the airways of patients with mild allergic asthma, omalizumab reduces FceRI + and IgE + cells and causes a profound reduction in tissue eosinophilia, together with reductions in submucosal T-cell and B-cell numbers. In patients with seasonal allergic rhinitis, omalizumab inhibits the allergen-induced seasonal increases in circulating and tissue eosinophils. Omalizumab decreases FceRI expression on circulating dendritic cells, which might lead to a reduction in allergen presentation, T H 2 cell activation, and proliferation. As a systemic anti-IgE agent, omalizumab has demonstrated clinical efficacy in patients with moderate and severe allergic asthma and in those with seasonal and perennial allergic rhinitis, as well as in patients with concomitant allergic asthma and allergic rhinitis. The anti-inflammatory effects of omalizumab at different sites of allergic inflammation and the clinical benefits of anti-IgE therapy in patients with allergic asthma and allergic rhinitis emphasize the fundamental importance of IgE in allergic inflammation.
443 citations
TL;DR: There is increasing interest in the possibility that dietary antioxidant and lipid intakes might be important in determining expression of disease during pregnancy and early childhood and that dietary interventions should be targeted at these groups.
Abstract: It has been hypothesized that decreasing antioxidant (fruit and vegetables), increased n-6 polyunsaturated fatty acid (PUFA; (margarine, vegetable oil), and decreased n-3 PUFA (oily fish) intakes have contributed to the recent increases in asthma and atopic disease. Epidemiologic studies in adults and children have reported beneficial associations between dietary antioxidants and lipids and parameters of asthma and atopic disease. The associations with n-6 and n-3 PUFA appear to be very complex and might differ between asthma and atopic dermatitis. Dietary antioxidants are probably exerting antioxidant and nonantioxidant immunomodulatory effects. Dietary lipids exert numerous complex effects on proinflammatory and immunologic pathways. It has also been suggested that atopic dermatitis is associated with an enzyme defect in lipid metabolism. In spite of this, the results of interventional supplementation studies in established disease have been disappointing, and there is now increasing interest in the possibility that dietary antioxidant and lipid intakes might be important in determining expression of disease during pregnancy and early childhood and that dietary interventions should be targeted at these groups. It also seems likely that there is individual variation in the responses of individuals to lipid, and probably antioxidant, supplementation. Further research to determine whether dietary intervention can reduce the risk of asthma and atopic disease is justified.
TL;DR: In this paper, the development of tolerance, control of inflammation, and response to normal mucosal flora are interrelated and linked to specific immune mechanisms, and Leptin is emerging as a cytokine-like immune regulator that has complex effects in both overnutrition and in the inflammatory response in malnutrition.
Abstract: Lack of adequate macronutrients or selected micronutrients, especially zinc, selenium, iron, and the antioxidant vitamins, can lead to clinically significant immune deficiency and infections in children. Undernutrition in critical periods of gestation and neonatal maturation and during weaning impairs the development and differentiation of a normal immune system. Infections are both more frequent and more often become chronic in the malnourished child. Recent identification of genetic mechanisms is revealing critical pathways in the gastrointestinal immune response. New studies show that the development of tolerance, control of inflammation, and response to normal mucosal flora are interrelated and linked to specific immune mechanisms. Nutrients act as antioxidants and as cofactors at the level of cytokine regulation. Protein calorie malnutrition and zinc deficiency activate the hypothalamic-pituitary-adrenal axis. Increased circulating levels of glucocorticoids cause thymic atrophy and affect hematopoiesis. Chronic undernutrition and micronutrient deficiency compromise cytokine response and affect immune cell trafficking. The combination of chronic undernutrition and infection further weakens the immune response, leading to altered immune cell populations and a generalized increase in inflammatory mediators. Obesity caused by excess nutrition or excess storage of fats relative to energy expenditure is a form of malnutrition that is increasingly seen in children. Leptin is emerging as a cytokine-like immune regulator that has complex effects in both overnutrition and in the inflammatory response in malnutrition. Because the immune system is immature at birth, malnutrition in childhood might have long-term effects on health.
TL;DR: Significant increases in tolerance to hazelnut after sublingual immunotherapy as assessed by double-blind, placebo-controlled food challenge, and good tolerance to this treatment are confirmed.
Abstract: Background: Food allergy may be life-threatening, and patients affected need to receive accurate diagnoses and treatment. Hazelnut has often been implicated as responsible for allergic reactions, and trace quantities can induce systemic reactions. Objective: The aim of this study was to evaluate the efficacy and tolerance of sublingual immunotherapy with a standardized hazelnut extract in patients allergic to hazelnut. Methods: This was a randomized, double-blind, placebocontrolled study. Inclusion criteria were a history of hazelnut allergy and positive skin prick test and double-blind placebocontrolled food challenge results. Patients were then randomly assigned into 2 treatment groups (hazelnut immunotherapy or placebo). Efficacy was assessed by double-blind, placebocontrolled food challenge after 8 to 12 weeks of treatment. Blood samples were drawn for measurement of specific IgE, IgG4, and serum cytokines before and after treatment. Results: Twenty-three patients were enrolled and divided into 2 treatment groups. Twenty-two patients reached the planned maximum dose at 4 days. Systemic reactions were observed in only 0.2% of the total doses administered. Mean hazelnut quantity provoking objective symptoms increased from 2.29 g to 11.56 g (P 5 .02; active group) versus 3.49 g to 4.14 g (placebo; NS). Moreover, almost 50% of patients who underwent active treatment reached the highest dose (20 g), but only 9% in the placebo. Laboratory data showed an increase in IgG4 and IL-10 levels after immunotherapy in only the active group. Conclusion: Our data confirm significant increases in tolerance to hazelnut after sublingual immunotherapy as assessed by double-blind, placebo-controlled food challenge, and good tolerance to this treatment. (J Allergy Clin Immunol 2005;116:1073-9.)
TL;DR: An overview of oral tolerance is provided and data related to food hypersensitivity wherever evidence is available is cited.
Abstract: The gastrointestinal tract is the largest immunologic organ in the body. It is constantly bombarded by a myriad of dietary proteins. Despite the extent of protein exposure, very few patients have food allergies because of development of oral tolerance to these antigens. Once proteins contact the intestinal surface, they are sampled by different cells and, depending on their characteristics, result in different responses. Antigens might be taken up by Microfold cells overlying Peyer's patches, dendritic cells, or epithelial cells. Different cells of the immune system participate in oral tolerance induction, with regulatory T cells being the most important. Several factors can influence tolerance induction. Some are antigen related, and others are inherent to the host. Disturbances at different steps in the path to oral tolerance have been described in food hypersensitivity. In this review we provide an overview of oral tolerance and cite data related to food hypersensitivity wherever evidence is available.
TL;DR: In general, studies reveal that infants fed formulas of intact cow's milk or soy protein compared with breast milk have a higher incidence of atopic dermatitis and wheezing illnesses in early childhood.
Abstract: Breast-feeding is the preferred method of infant nutrition for numerous reasons. However, its role in the prevention of allergic disease remains controversial. Reasons for this controversy include methodological differences and flaws in the studies performed to date, the immunologic complexity of breast milk itself and, possibly, genetic differences among patients that would affect whether breast-feeding is protective against the development of allergies or is in fact sensitizing. The preponderance of evidence does suggest, however, that there would be much to lose by not recommending breast-feeding. In general, studies reveal that infants fed formulas of intact cow's milk or soy protein compared with breast milk have a higher incidence of atopic dermatitis and wheezing illnesses in early childhood. Consistent with these findings, exclusive breast-feeding should be encouraged for at least 4 to 6 months in infants at both high and low risk of atopy and irrespective of a history of maternal asthma.
TL;DR: Children who were both sensitive and exposed to cockroach allergen had significantly more asthma symptom days, more caretaker interrupted sleep, and more school days missed than children who were not sensitive or exposed.
Abstract: Background Asthma-associated morbidity is rising, especially in inner city children. Objective We evaluated the allergen sensitivities, allergen exposures, and associated morbidity for participants in the Inner City Asthma Study. We also determined geographic variations of indoor allergen levels. Methods Nine hundred thirty-seven inner city children 5 to 11 years old with moderate to severe asthma underwent allergen skin testing. Bedroom dust samples were evaluated for Der p 1, Der f 1, Bla g 1, Fel d 1, and Can f 1. Results Skin test sensitivities to cockroach (69%), dust mites (62%), and molds (50%) predominated, with marked study site–specific differences. Cockroach sensitivity was highest in the Bronx, New York, and Dallas (81.2%, 78.7%, and 78.5%, respectively), and dust mite sensitivity was highest in Dallas and Seattle (83.7% and 78.0%, respectively). A majority of homes in Chicago, New York, and the Bronx had cockroach allergen levels greater than 2 U/g, and a majority of those in Dallas and Seattle had dust mite allergen levels greater than 2 μg/g. Levels of both of these allergens were influenced by housing type. Cockroach allergen levels were highest in high-rise apartments, whereas dust mite allergen levels were highest in detached homes. Children who were both sensitive and exposed to cockroach allergen had significantly more asthma symptom days, more caretaker interrupted sleep, and more school days missed than children who were not sensitive or exposed. Conclusion Geographic differences in allergen exposure and sensitivity exist among inner city children. Cockroach exposure and sensitivity predominate in the Northeast, whereas dust mite exposure and sensitivity are highest in the South and Northwest. Cockroach allergen appears to have a greater effect on asthma morbidity than dust mite or pet allergen in these children.
TL;DR: An evidence-based summary of the health effects of air pollutants on asthma, focusing on diesel exhaust particles (DEPs) as a model particulate air pollutant is provided, followed by consideration of the mechanisms underlying DEP-induced inflammation.
Abstract: In recent decades, clinicians and scientists have witnessed a significant increase in the prevalence of allergic rhinitis and asthma. The factors underlying this phenomenon are clearly complex; however, this rapid increase in the burden of atopic disease has undeniably occurred in parallel with rapid industrialization and urbanization in many parts of the world. Consequently, more people are exposed to air pollutants than at any point in human history. Worldwide, increases in allergic respiratory disease have mainly been observed in urban communities. Epidemiologic and clinical investigations have suggested a strong link between particulate air pollution and detrimental health effects, including cardiopulmonary morbidity and mortality. The purpose of this review is to provide an evidence-based summary of the health effects of air pollutants on asthma, focusing on diesel exhaust particles (DEPs) as a model particulate air pollutant. An overview of observational and experimental studies linking DEPs and asthma will be provided, followed by consideration of the mechanisms underlying DEP-induced inflammation and a brief discussion of future research and clinical directions.
TL;DR: The human host survives many infectious challenges in the absence of preexisting specific (adaptive) immunity because of the existence of a separate set of protective mechanisms that do not depend on specific antigenic recognition.
Abstract: The human host survives many infectious challenges in the absence of preexisting specific (adaptive) immunity because of the existence of a separate set of protective mechanisms that do not depend on specific antigenic recognition. These antigen-independent mechanisms constitute innate immunity. Antimicrobial peptides are released at epithelial surfaces and disrupt the membranes of many microbial pathogens. Toll-like receptors on epithelial cells and leukocytes recognize a range of microbial molecular patterns and generate intracellular signals for activation of a range of host responses. Cytokines released from leukocytes and other cells exhibit a vast array of regulatory functions in both adaptive and innate immunity. Chemokines released from infected tissues recruit diverse populations of leukocytes that express distinct chemokine receptors. Natural killer cells recognize and bind virus-infected host cells and tumor cells and induce their apoptosis. Complement, through the alternative and mannose-binding lectin pathways, mediates antibody-independent opsonization, phagocyte recruitment, and microbial lysis. Phagocytes migrate from the microcirculation into infected tissue and ingest and kill invading microbes. These innate immune mechanisms and their interactions in defense against infection provide the host with the time needed to mobilize the more slowly developing mechanisms of adaptive immunity, which might protect against subsequent challenges.
TL;DR: Fractional exhaled nitric oxide in healthy children is below 15 to 25 ppb depending on age and self-reported atopy, and higher FE NO was seen in children with self- reported rhinitis/conjunctivitis or hay fever.
Abstract: Background Fractional exhaled nitric oxide (FE NO ) is used in monitoring of asthma. Objectives The aim of this multicenter study was to establish normal values of FE NO and assess feasibility in children with a standardized method and equipment approved for clinical use. Methods FE NO was measured in healthy subjects of 4 to 17 years according to American Thoracic Society guidelines (single breath online, exhalation flow 50 mL/s) with a chemiluminescence analyzer (NIOX Exhaled Nitric Oxide Monitoring System, Aerocrine, Sweden) in 3 European and 2 US centers. Each child performed 3 acceptable nitric oxide measurements within 6 attempts and completed an extended International Study of Asthma and Allergy in Children questionnaire. Results Measurement of FE NO was attempted in 522 children. Four hundred five children completed the study according to the protocol. Geometric mean FE NO in 405 children was 9.7 ppb, and the upper 95% confidence limit was 25.2 ppb. FE NO increased significantly with age, and higher FE NO was seen in children with self-reported rhinitis/conjunctivitis or hay fever. The success rate was age-dependent and improved from 40% in the children 4 years old to almost 100% from the age of 10 years. The repeatability of 3 approved measurements was 1.6 ppb (95% CI, 1.49-1.64 ppb). Conclusion FE NO in healthy children is below 15 to 25 ppb depending on age and self-reported atopy. Measurement of FE NO by NIOX® is simple and safe and has a good repeatability. Feasibility depends on age and may be difficult in the preschool child.
TL;DR: The biologic basis of children's unique vulnerability to highly prevalent outdoor air pollutants is reviewed, with a special focus on ozone, respirable particulate matter, lead, sulfur dioxide, carbon monoxide, and nitrogen oxides.
Abstract: A growing body of research supports the role of outdoor air pollutants in acutely aggravating chronic diseases in children, and suggests that the pollutants may have a role in the development of these diseases. This article reviews the biologic basis of children's unique vulnerability to highly prevalent outdoor air pollutants, with a special focus on ozone, respirable particulate matter (PM 2.5 [ 10 [
TL;DR: It is indicated that serum leptin is increased during allergic reactions in the airways and may play a role in the relationship between obesity and asthma.
Abstract: Background Epidemiologic data indicate that the incidence of asthma is increased in obese patients. Objective Because the serum levels of the satiety hormone and proinflammatory cytokine leptin are increased in obese individuals, we sought to determine whether leptin can augment allergic airway responses. Methods We sensitized and challenged BALB/cJ mice with ovalbumin. Alzet® micro-osmotic pumps were implanted in the mice to deliver a continuous infusion of either saline or leptin (1.75 μg/g/d). Two days later, the mice were challenged with either aerosolized saline or ovalbumin once per day for 3 days. We measured airway responsiveness, performed bronchoalveolar lavage, and obtained blood to measure serum leptin and IgE 24 or 48 hours after the last challenge. Results Leptin infusion increased serum leptin concentrations, which were increased further after ovalbumin sensitization and challenge. Ovalbumin challenge increased bronchoalveolar lavage fluid cells and cytokines, serum IgE, lung cytokine mRNA expression, and responses to inhaled, aerosolized methacholine. It is important to note that the changes in methacholine responsiveness and IgE were augmented in leptin- versus saline-infused mice. Conclusions These results indicate that serum leptin is increased during allergic reactions in the airways and may play a role in the relationship between obesity and asthma.
TL;DR: TRECs are a stable analyte that can identify T-cell lymphopenia in newborn dried blood spots so that infants with SCID can receive early, life-saving treatment.
Abstract: Background Severe combined immunodeficiency (SCID) is a treatable, inherited lack of cellular and humoral immunity caused by diverse mutations in several different genes and leading to death in infancy unless immune reconstitution is provided Currently no population screening exists for SCID, but early diagnosis would improve outcome Objective Because all patients with SCID make few or no T cells, we asked whether the absence of T-cell receptor excision circles (TRECs), DNA episomes in newly formed T cells, could identify SCID regardless of genotype Methods DNA isolated from dried blood spots was assayed by real-time PCR to quantitate TRECs Control PCR was performed on a segment of the β-actin gene After pilot studies with adult and cord blood control subjects, blood from SCID patients was spotted onto filters and tested, followed by screening of actual blood spots from the Maryland Newborn Screening Program Finally, newborn blood spots were recovered and tested from 2 infants after their diagnosis of SCID Results In contrast to filters from the newborn screening program, which had a mean of 1020 TRECs in two 3-mm punches, samples from 23 infants with SCID had Conclusion TRECs are a stable analyte that can identify T-cell lymphopenia in newborn dried blood spots so that infants with SCID can receive early, life-saving treatment
Saint Louis University1, University of California, Los Angeles2, University of Cincinnati3, George Washington University4, University of Pennsylvania5, University of Washington6, University of Pittsburgh7, University of Texas Southwestern Medical Center8, Stanford University9, Cleveland Clinic10, University of Missouri–Kansas City11, Children's Mercy Hospital12, Pennsylvania State University13
TL;DR: These parameters were developed by the Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma and Immunology, and are not designed for use by pharmaceutical companies in drug promotion.
Abstract: These parameters were developed by the Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma and Immunology; the American College of Allergy, Asthma and Immunology; and the Joint Council of Allergy, Asthma and Immunology. The American Academy of Allergy, Asthma and Immunology (AAAAI) and the American College of Allergy, Asthma and Immunology (ACAAI) have jointly accepted responsibility for establishing "The diagnosis and management of sinusitis: a practice parameter update." This is a complete and comprehensive document at the current time. The medical environment is a changing environment, and not all recommendations will be appropriate for all patients. Because this document incorporated the efforts of many participants, no single individual, including those who served on the Joint Task force, is authorized to provide an official AAAAI or ACAAI interpretation of these practice parameters. Any request for information about or an interpretation of these practice parameters by the AAAAI or the ACAAI should be directed to the Executive Offices of the AAAAI, the ACAAI, and the Joint Council of Allergy, Asthma and Immunology. These parameters are not designed for use by pharmaceutical companies in drug promotion.
TL;DR: Although the authors cannot as yet predict the allergenicity of a given food protein, understanding of the molecular properties that might predispose them to becoming allergens is an important first step and will undoubtedly contribute to the integrative allergenic risk assessment process being adopted by regulators.
Abstract: Plant food allergens belong to a rather limited number of protein families and are also characterized by a number of biochemical and physicochemical properties, many of which are also shared by food allergens of animal origin. These include thermal stability and resistance to proteolysis, which are enhanced by an ability to bind ligands, such as metal ions, lipids, or steroids. Other types of lipid interaction, including membranes or other lipid structures, represent another feature that might promote the allergenic properties of certain food proteins. A structural feature clearly related to stability is intramolecular disulfide bonds alongside posttranslational modifications, such as N-glycosylation. Some plant food allergens, such as the cereal seed storage prolamins, are rheomorphic proteins with polypeptide chains that adopt an ensemble of secondary structures resembling unfolded or partially folded proteins. Other plant food allergens are characterized by the presence of repetitive structures, the ability to form oligomers, and the tendency to aggregate. A summary of our current knowledge regarding the molecular properties of food allergens is presented. Although we cannot as yet predict the allergenicity of a given food protein, understanding of the molecular properties that might predispose them to becoming allergens is an important first step and will undoubtedly contribute to the integrative allergenic risk assessment process being adopted by regulators.
TL;DR: The identification of T regulatory cells as key regulators of immunologic processes in peripheral tolerance to allergens has opened an important era in the prevention and treatment of allergic diseases and current strategies for drug development and allergen-specific immunotherapy exploit these observations with the potential to provide cure for allergic diseases.
Abstract: The identification of T regulatory (T Reg ) cells as key regulators of immunologic processes in peripheral tolerance to allergens has opened an important era in the prevention and treatment of allergic diseases. Both naturally occurring CD4 + CD25 + T Reg cells and inducible populations of allergen-specific IL-10–secreting T R 1 cells inhibit allergen-specific effector cells in experimental models. Allergen-specific T Reg cell responses contribute to the control of allergic inflammation in several ways. Skewing of allergen-specific effector T cells to a T Reg phenotype appears to be a crucial event in the development of a healthy immune response to allergens and successful outcome in allergen-specific immunotherapy. The increased levels of IL-10 and TGF-β produced by T Reg cells can potently suppress IgE production while simultaneously increasing the production of the noninflammatory antibody isotypes IgG4 and IgA, respectively. T Reg cells directly or indirectly suppress effector cells of allergic inflammation, such as mast cells, basophils, and eosinophils, and contribute to remodeling in asthma and atopic dermatitis. In addition, mediators of allergic inflammation that trigger cyclic AMP–associated G protein–coupled receptors, such as histamine receptor 2, might play a role in peripheral tolerance mechanisms against allergens. Current strategies for drug development and allergen-specific immunotherapy exploit these observations with the potential to provide cure for allergic diseases.
TL;DR: Respiratory viruses were detected in the majority of children presenting to emergency departments with asthma during the September epidemic of the disease and in a significant minority of children with asthma in the community.
Abstract: Background Predictable peaks of asthma exacerbation requiring hospital treatment, of greatest magnitude in children and of uncertain etiology, occur globally after school returns. Objective We wished to determine whether asthmatic children requiring emergency department treatment for exacerbations after school return in September were more likely to have respiratory viruses present and less likely to have prescriptions for control medications than children with equally severe asthma not requiring emergent treatment. Methods Rates of viral detection and characteristics of asthma management in 57 (of 60) children age 5 to 15 years presenting to emergency departments with asthma in 2 communities in Canada between September 10 and 30, 2001, (cases) were compared with those in 157 age-matched volunteer children with asthma of comparable severity studied simultaneously (controls). Results Human picornaviruses were detected in 52% of cases and 29% of controls ( P =.002) and viruses of any type in 62% of cases and 41% of controls ( P =.011). Cases were less likely to have been prescribed controller medication (inhaled corticosteroid, 49% vs 85%; P P =.04). Conclusion Respiratory viruses were detected in the majority of children presenting to emergency departments with asthma during the September epidemic of the disease and in a significant minority of children with asthma in the community. The latter were more likely to have anti-inflammatory medication prescriptions than children requiring emergent treatment. Such medication may reduce the risk of emergency department treatment for asthma during the September epidemic.
TL;DR: In this article, the structural changes in the airway of well-defined groups of subjects with severe and moderate asthma and to correlate the extent of airway remodeling with disease severity.
Abstract: Background Airway remodeling in asthma comprises a range of structural changes. Several studies have suggested an association between these changes and disease severity. The relationship between the extent of remodeling and lung function is not well defined. Objective We sought to contrast the structural changes in the airways of well-defined groups of subjects with severe and moderate asthma and to correlate the extent of remodeling with disease severity. Methods Endobronchial biopsy specimens were obtained from 15 subjects with severe and 13 subjects with moderate asthma. Epithelial integrity, cell-layer areas, subepithelial fibrosis, and the distance between epithelial and airway smooth muscle (ASM) layers were measured by means of image analysis. Collagen was identified by using Van Giesen stain, and ASM was defined by using smooth muscle α-actin immunostaining. Specific immunostains were performed for the evaluation of RANTES, IL-8, and eotaxin expression as markers of ASM phenotype. Results ASM area was greater in subjects with severe (0.24 ± 0.03 mm 2 ) than in subjects with moderate (0.05 ± 0.01 mm 2 ) asthma ( P P Conclusion Smooth muscle alteration is the key structural change that distinguishes severe from moderate asthma, and phenotypic change in ASM might contribute to the difficulty in obtaining adequate control in some subjects with severe asthma.
TL;DR: The concept of airway remodeling in asthma has been proposed in this paper, which suggests that the alteration of the structure and function of key airway constituents, including airway smooth muscle, epithelium, blood vessels, and mucus glands, might explain the progressive loss of lung function that is observed clinically.
Abstract: Airway inflammation, airflow obstruction, and bronchial hyperresponsiveness are characteristic phenotypic features of asthma. Clinically, airflow obstruction in asthma often is not fully reversible, and many asthmatic subjects experience an accelerated and progressive loss of lung function over time. Histopathologic studies of the asthmatic airway have demonstrated stereotypic changes that might explain the loss of lung function that many patients with asthma experience. The notion of airway remodeling in asthma postulates that the alteration of the structure and function of key airway constituents, including airway smooth muscle, epithelium, blood vessels, and mucus glands, might explain, at least in part, the progressive loss of lung function that is observed clinically. Inflammation driven by CD4 + lymphocytes and mediated by effector cells, particularly the eosinophil, appears to modulate the function of mesenchymal cells, including fibroblasts and myofibroblasts, changing the composition of the airway wall matrix. Changes in the airway epithelium might alter the function of the underlying smooth muscle and the composition of the matrix and could drive inflammation. Alterations in the structure and function of airway smooth muscle change the mechanical properties of the airway wall and might also affect the function of other airway constituents. A variety of experimental models have identified candidate mechanisms and mediators for these observed changes, which are thus potential therapeutic targets. However, clinical studies to date have been disappointing, and it remains to be seen whether targeted therapies will prevent the progressive loss of lung function seen in asthma.
TL;DR: A brief update of the clinical symptoms associated with allergic conjunctivitis, the rationale for disease classification, recent advances in the understanding of the pathogenesis of the diseases, and an update on both preclinical and clinical advances toward refined therapies for these diseases are provided.
Abstract: Allergic conjunctivitis is in actuality a group of diseases affecting the ocular surface and is usually associated with type 1 hypersensitivity reactions. Two acute disorders, seasonal allergic conjunctivitis and perennial allergic conjunctivitis, exist, as do 3 chronic diseases, vernal keratoconjunctivitis, atopic keratoconjunctivitis, and giant papillary conjunctivitis. The ocular surface inflammation (usually mast cell driven) results in itching, tearing, lid and conjunctival edema-redness, and photophobia during the acute phase and can lead to a classic late-phase response (with associated eosinophilia and neutrophilia) in a subset of individuals. As is the case in other allergic diseases, a chronic disease can also develop, accompanied by remodeling of the ocular surface tissues. In severe cases the patient experiences extreme discomfort and sustains damage to the ocular surface. For such cases, there is no highly effective and safe treatment regimen. Topical administration of corticosteroids is used in severe cases but is associated with an increased risk for the development of cataracts and glaucoma. Thus there is a worldwide search for new biotargets for the treatment of these diseases. Here we provide a brief update of the clinical symptoms associated with these diseases, the rationale for disease classification, recent advances in our understanding of the pathogenesis of the diseases, and an update on both preclinical and clinical advances toward refined therapies for these diseases.