Showing papers in "The Journal of Allergy and Clinical Immunology in 2000"

Mechanisms of eosinophil-associated inflammation.

Abstract: Increasing evidence supports a critical role for the eosinophil in disease. Here, the mechanisms underlying eosinophil-associated inflammation are reviewed including eosinophil constituents, eosinophil maturation and release from the bone marrow, and eosinophil tissue recruitment and activation. Eosinophil effector functions in bronchial asthma are summarized with particular attention to pulmonary M2 muscarinic receptors and bronchial hyperreactivity. Recent findings supporting roles for IL-5, the eosinophil, and its ribonucleases in viral immunity are presented. Overall, this information supports an expanded view of eosinophil participation in health and disease.

Atopic dermatitis: New insights and opportunities for therapeutic intervention

Abstract: Atopic dermatitis (AD) is a chronic inflammatory skin disease that frequently predates the development of allergic rhinitis or asthma. It is an important skin condition with significant costs and morbidity to patients and their families; the disease affects more than 10% of children. Recent studies have demonstrated the complex interrelationship of genetic, environmental, skin barrier, pharmacologic, psychologic, and immunologic factors that contribute to the development and severity of AD. The current review will examine the cellular and molecular mechanisms that contribute to AD as well as the immunologic triggers involved in its pathogenesis. These insights provide new opportunities for therapeutic intervention in this common skin condition. (J Allergy Clin Immunol 2000;105:860-76.)

Structural biology of allergens

Abstract: One of the major challenges of molecular allergy is to predict the allergenic potential of a protein, particularly in novel foods. Two aspects have to be distinguished: immunogenicity and cross-reactivity. Immunogenicity reflects the potential of a protein to induce IgE antibodies, whereas cross-reactivity is the reactivity of (usually preexisting) IgE antibodies with the target protein. In addition to these two issues, the relation between IgE-binding potential and clinical symptoms is of interest. This is influenced by physical properties (eg, stability and size) and immunologic properties (affinity and epitope valence). Discussions on immunogenicity and cross-reactivity of allergens rely on the establishment of structural similarities and differences among allergens and between allergens and nonallergens. For comparisons between the 3-dimensional protein folds, the representation as 2-dimensional proximity plots provides a convenient visual aid. Analysis of approximately 40 allergenic proteins (or parts of these proteins), of which the protein folds are either known or can be predicted on the basis of homology, indicates that most of these can be classified into 4 structural families: (1) antiparallel beta-strands: the immunoglobulin-fold family (grass group 2, mite group 2), serine proteases (mite group 3, 6, and 9), and soybean-type trypsin inhibitor (Ole e 1, grass group 11); (2) antiparallel beta-sheets intimately associated with one or more alpha-helices: tree group 1, lipocalin, profilin, aspartate protease (cockroach group 2); (3) (alpha+beta) structures, in which the alpha- and beta-structural elements are not intimately associated: mite group 1, lysozyme/lactalbumin, vespid group 5; and (4) alpha-helical: nonspecific lipid transfer protein, seed 2S protein, insect hemoglobin, fish parvalbumin, pollen calmodulin, mellitin from bee venom, Fel d 1 chain 1, serum albumin. Allergens with parallel beta-strands (in combination with an alpha-helix linking the two strands, a motif commonly found in, for example, nucleotide-binding proteins) seem to be underrepresented. The conclusion is that allergens have no characteristic structural features other than that they need to be able to reach (and stimulate) immune cells and mast cells. Within this constraint, any antigen may be allergenic, particularly if it avoids activation of T(H)2-suppressive mechanisms (CD8 cells and T(H)1 cells).

The natural history of peanut allergy.

Abstract: Background: It has traditionally been assumed that peanut allergy is rarely outgrown. Objective: The goal of this study was to determine the number of children with peanut allergy who become tolerant of peanut. Methods: Patients aged 4 to 20 years with a diagnosis of peanut allergy were evaluated by questionnaire, skin testing, and a quantitative antibody fluorescent-enzyme immunoassay. Patients who had been reaction free in the past year and had a peanut IgE (PN-IgE) level less than 20 kilounits of antibody per liter (kU A /L) were offered an open or double-blind, placebo-controlled peanut challenge. Results: A total of 223 patients were evaluated, and of those, 85 (PN-IgE A /L [median 1.42 kU A /L]) participated in an oral peanut challenge. Forty-eight (21.5%) patients had negative challenge results and were believed to have outgrown their peanut allergy (aged 4-17.5 years [median 6 years]; PN-IgE A /L [median 0.69 kU A /L]). Thirty-seven failed the challenge (aged 4-13 years [median 6.5 years]; RAST A /L [median 2.06 kU A /L]). Forty-one patients with PN-IgE levels less than 20 kU A /L declined to undergo challenge, and 97 were not eligible for challenge because their PN-IgE levels were greater than 20 kU A /L or they had had a recent reaction. Sixty-seven percent of patients with PN-IgE levels less than 2 kU A /L and 61% with levels less than 5 kU A /L had negative challenge results. Of those who underwent challenge, PN-IgE levels for those who passed versus those who failed were different at the time of challenge ( P = .009), but not at the time of diagnosis ( P = .25). Conclusion: This study demonstrates that peanut allergy is outgrown in about 21.5% of patients. Patients with low PN-IgE levels should be offered a peanut challenge in a medical setting to demonstrate whether they can now tolerate peanuts. (J Allergy Clin Immunol 2001;107:367-74.)

Molecular and biochemical classification of plant-derived food allergens.

Abstract: Molecular biology and biochemical techniques have significantly advanced the knowledge of allergens derived from plant foods. Surprisingly, many of the known plant food allergens are homologous to pathogenesis-related proteins (PRs), proteins that are induced by pathogens, wounding, or certain environmental stresses. PRs have been classified into 14 families. Examples of allergens homologous to PRs include chitinases (PR-3 family) from avocado, banana, and chestnut; antifungal proteins such as the thaumatin-like proteins (PR-5) from cherry and apple; proteins homologous to the major birch pollen allergen Bet v 1 (PR-10) from vegetables and fruits; and lipid transfer proteins (PR-14) from fruits and cereals. Allergens other than PR homologs can be allotted to other well-known protein families such as inhibitors of α-amylases and trypsin from cereal seeds, profilins from fruits and vegetables, seed storage proteins from nuts and mustard seeds, and proteases from fruits. As more clinical data and structural information on allergenic molecules becomes available, we may finally be able to answer what characteristics of a molecule are responsible for its allergenicity. (J Allergy Clin Immunol 2000;106:27-36.)

Epithelial-mesenchymal interactions in the pathogenesis of asthma.

Abstract: During lung development, repair, and inflammation, local production of cytokines (eg, transforming growth factor-β) and growth factors (eg, epidermal growth factor) by epithelial and mesenchymal cells mediate bidirectional growth control effectively creating an epithelial-mesenchymal trophic unit. In asthma the bronchial epithelium is highly abnormal, with structural changes involving separation of columnar cells from their basal attachments and functional changes including increased expression and release of proinflammatory cytokines, growth factors, and mediator-generating enzymes. Beneath this damaged structure there is an increase in the number of subepithelial myofibroblasts that deposit interstitial collagens causing thickening and increased density of the subepithelial basement membrane. Our recent studies suggest that the extent of epithelial damage in asthma may be the result of impaired epidermal growth factor receptor–mediated repair. In view of the close spatial relationship between the damaged epithelium and the underlying myofibroblasts, we propose that impaired epithelial repair cooperates with the TH2 environment to shift the set point for communication within the trophic unit. This leads to myofibroblast activation, excessive matrix deposition, and production of mediators that propagate and amplify the remodeling responses throughout the airway wall. (J Allergy Clin Immunol 2000;105:193-204.)

The mechanism of exercise-induced asthma is ...

Abstract: Exercise-induced asthma (EIA) refers to the transient narrowing of the airways that follows vigorous exercise. The mechanism whereby EIA occurs is thought to relate to the consequences of heating and humidifying large volumes of air during exercise. In 1978 airway cooling was identified as an important stimulus for EIA; however, severe EIA also occurred when hot dry air was inspired, and there was no abnormal cooling of the airways. In 1986 the thermal hypothesis proposed that cooling of the airways needed to be followed by rapid rewarming and that these two events caused a vasoconstriction and a reactive hyperemia of the bronchial microcirculation, together with edema of the airway wall, causing the airways to narrow after exercise. The osmotic, or airway-drying, hypothesis developed from 1982-1992 because neither airway cooling nor rewarming appeared to be necessary for EIA to occur. As water is evaporated from the airway surface liquid, it becomes hyperosmolar and provides an osmotic stimulus for water to move from any cell nearby, resulting in cell volume loss. It is proposed that the regulatory volume increase, after cell shrinkage, is the key event resulting in release of inflammatory mediators that cause airway smooth muscle to contract and the airways of asthmatic subjects to narrow. This event may or may not be associated with airway edema. The osmotic and thermal theories come together by considering that inspiration of cold air not only cools the airways but also increases the numbers of airway generations becoming dehydrated in the humidifying process.

Prevalence and etiology of asthma

Abstract: An increased understanding of the causes of asthma is coming from the international comparisons of asthma prevalence, particularly those from the European Community Respiratory Health Survey of asthma prevalence in adults and the International Study of Asthma and Allergies in Childhood. From these and other studies of asthma prevalence, it is possible to draw some tentative conclusions as to the patterns of asthma prevalence worldwide. There are five striking patterns: first, asthma prevalence is increasing worldwide; second, asthma is generally more common in Western countries and less common in developing countries; third, asthma is more prevalent in English-speaking countries; fourth, asthma prevalence is increasing in developing countries as they become more Westernized or communities become urbanized; and fifth, the prevalence of other allergic disorders may also be increasing worldwide. These five key features of the international patterns of asthma prevalence raise major questions about the role of "established" risk factors for the development of asthma. As a result, recent research has expanded to include the study of novel factors that may "program" the initial susceptibility to sensitization or contribute to the development of asthma independent of atopic sensitization. These include various exposures in utero, which are reflected in various perinatal factors measured at birth, and exposures (or lack of exposures) in the early years of life that may make the infant more susceptible to the subsequent development of asthma. These issues are now the focus of an intensive research effort worldwide, and the next few years are likely to see exciting advances in our understanding of the causes of asthma. (J Allergy Clin Immunol 2000;105:S466-72.)

The effects of roasting on the allergenic properties of peanut proteins.

Abstract: Background: Because of the widespread use of peanut products, peanut allergenicity is a major health concern in the United States. The effect or effects of thermal processing (roasting) on the allergenic properties of peanut proteins have rarely been addressed. Objective: We sought to assess the biochemical effects of roasting on the allergenic properties of peanut proteins. Methods: Competitive inhibition ELISA was used to compare the IgE-binding properties of roasted and raw peanut extracts. A well-characterized in vitro model was used to test whether the Maillard reaction contributes to the allergenic properties of peanut proteins. The allergic properties were measured by using ELISA, digestion by gastric secretions, and stability of the proteins to heat and degradation. Results: Here we report that roasted peanuts from two different sources bound IgE from patients with peanut allergy at approximately 90-fold higher levels than the raw peanuts from the same peanut cultivars. The purified major allergens Ara h 1 and Ara h 2 were subjected to the Maillard reaction in vitro and compared with corresponding unreacted samples for allergenic properties. Ara h 1 and Ara h 2 bound higher levels of IgE and were more resistant to heat and digestion by gastrointestinal enzymes once they had undergone the Maillard reaction. Conclusions: The data presented here indicate that thermal processing may play an important role in enhancing the allergenic properties of peanuts and that the protein modifications made by the Maillard reaction contribute to this effect. (J Allergy Clin Immunol 2000;106:763-8.)

The role of lymphocytes in allergic disease.

Abstract: In the last few years strong evidence has accumulated to suggest that allergen-reactive type-2 T helper (T(H)2) cells play an important role in the induction and maintenance of the allergic inflammatory cascade. First, cytokines and chemokines produced by T(H)2 cells (GM-CSF, IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, macrophage-derived chemokine) and those produced by other cell types in response to T(H)2 cytokines or as a reaction to T(H)2-related tissue damage (eotaxin, transforming growth factor-beta, IL-11) account for most pathophysiologic aspects of allergic disorders (production of IgE antibodies; recruitment or activation of mast cells, basophils, and eosinophils; mucus hypersecretion; subepithelial fibrosis; and tissue remodeling). The T(H)2 hypothesis may also explain the complex genetic background responsible for allergic disorders. Several genes are involved in the development and regulation of T(H)2 cells and may provide the reason why the prevalence of atopic allergy is increasing in Western countries. Indeed, a dramatic change has occurred in the last several decades in the "microbial" environment of children, thus probably altering the balance between T(H)1 and T(H)2 responses to "innocuous" antigens (allergens) in favor of T(H)2 responses. Finally, the T(H)2 hypothesis offers exciting opportunities for the development of novel immunotherapeutic strategies targeted to address allergen-specific T(H)2 cells or T(H)2-derived effector molecules in atopic individuals.

A cluster of seven tightly linked polymorphisms in the IL-13 gene is associated with total serum IgE levels in three populations of white children

Abstract: Background: Increased levels of total serum IgE are a strong risk factor for the development of asthma. IgE is also involved in host defenses against parasites and fungi. Linkage of total serum IgE with markers located close to the 3 Mb cluster of cytokine genes in chromosome 5q31 has been reported. IL-4 or IL-13 are regarded as essential for IgE synthesis. Objective: We tested whether polymorphisms in the IL-13 gene might explain the linkage between chromosome 5q31 and total serum IgE levels. Methods: We used denaturing HPLC to detect polymorphisms in overlapping PCR fragments of the IL-13 gene including promoter and 3′ untranslated regions. After sequencing was performed to identify the locations of the polymorphisms, PCR and primer-induced restriction site assays were used to genotype subjects in 3 unselected populations. Results: We report here 7 polymorphisms (6 novel) in IL-13. Four of these polymorphisms are tightly linked to a variant in the terminal portion of the coding region of the gene that results in a predicted amino acid change in residue 130 (Arg130Gln). The Gln form is strongly associated ( P = .000002) with increased serum IgE levels in 3 different populations comprising a total of 1399 children. Two additional polymorphisms in the promoter region of IL-13 are more loosely linked to Arg130Gln and are also less significantly associated with total serum IgE levels. Conclusion: These data suggest that the Arg130Gln polymorphism in IL-13, or others in close linkage with it, is associated with the development of the elevated serum IgE phenotype. (J Allergy Clin Immunol 2000;105:506-13.)

Epidemiologic evidence for asthma and rhinitis comorbidity

Abstract: Asthma and rhinitis are often comorbid conditions, and the overall characteristics of the diseases and the treatment options for the disorders are similar. Several recent epidemiologic studies in the general population have provided evidence to strongly associate the development of asthma with a previous history of either allergic or perennial rhinitis. Additional links between asthma and rhinitis include a description of increased aspirin intolerance in both disorders and the observation that most subjects with occupational asthma experience rhinitis. Further, the likelihood of the development of asthma is much higher in individuals with both perennial and seasonal rhinitis than for individuals with either condition alone. Asthma and rhinitis were found to be comorbidities regardless of atopic state, and perennial rhinitis has been associated with an increase in nonspecific bronchial hyperresponsiveness. Several studies have identified rhinitis as a risk factor for asthma, with the prevalence of allergic rhinitis in asthmatic patients being 80% to 90%. These studies and others demonstrate that the coexistence of asthma and allergic rhinitis is frequent, that allergic rhinitis usually precedes asthma, and that allergic rhinitis is a risk factor for asthma. Finally, studies that have examined the age of onset of atopy as a confounding factor for the development of asthma and allergic rhinitis have suggested that early age atopy may be an important predictive factor for respiratory symptoms that continue into late childhood. In conclusion, rhinitis and asthma are strongly associated, and rhinitis has been identified as a risk factor for asthma.

A murine model of peanut anaphylaxis: T- and B-cell responses to a major peanut allergen mimic human responses

Abstract: Background: Peanut allergy affects 0.6% of the US population. At the present time, allergen avoidance is the only therapeutic option. Animal models of food-induced anaphylaxis would facilitate attempts to design novel immunotherapeutic strategies for the treatment of peanut allergy. Objective: The purpose of this study was to develop a murine model of IgE-mediated peanut hypersensitivity that closely mimics human peanut allergy. Methods: C3H/HeJ mice sensitized orally with freshly ground whole peanut and cholera toxin as adjuvant were challenged orally 3 and 5 weeks later with crude peanut extract. Anaphylactic reactions were determined. T- and B-cell responses to Ara h 1 and Ara h 2, the major peanut allergens, were characterized by evaluating splenocyte proliferative responses and IgE antibody concentrations. Furthermore, IgE antibodies in the sera of patients with peanut allergy and mice were compared for antibody binding to Ara h 2 isoforms and allergenic epitopes. Results: Peanut-specific IgE was induced by oral peanut sensitization, and hypersensitivity reactions were provoked by feeding peanut to sensitized mice. The symptoms were similar to those seen in human subjects. Ara h 1– and Ara h 2–specific antibodies were present in the sera of mice with peanut allergy. Furthermore, these Ara h 2–specific IgE antibodies bound the same Ara h 2 isoforms and major allergenic epitopes as antibodies in the sera of human subjects with peanut allergy. Splenocytes from mice with peanut allergy exhibited proliferative responses to Ara h 1 and Ara h 2. Conclusion: This murine model of peanut allergy mimics the clinical and immunologic characteristics of peanut allergy in human subjects and should be a useful tool for developing immunotherapeutic approaches for the treatment of peanut allergy. (J Allergy Clin Immunol 2000;106:150-8.)

Conjugation of immunostimulatory DNA to the short ragweed allergen Amb a 1 enhances its immunogenicity and reduces its allergenicity

Abstract: Background: Allergen immunotherapy is inconvenient and associated with the risk of anaphylaxis. Efforts to improve the safety of immunotherapy by means of chemical modification of allergens have not been successful because it greatly reduced their antigenicity. Recently, immunostimulatory DNA sequences (ISS or CpG motifs) have been shown to act as strong TH1 response‐inducing adjuvants. Objective: We sought to determine whether conjugation of ISS to the major short ragweed allergen Amb a 1 results in enhanced immunotherapeutic potential in mice and decreased allergenicity in human subjects. Methods: A 22-mer ISS oligodeoxynucleotide (ISS-ODN) was coupled to Amb a 1 and used for immunization of mice, rabbits, and monkeys. Results: In mice the Amb a 1-ISS conjugate induced a T H1 response (IFN-γ secretion), whereas Amb a 1 induced a TH2 response (IL-5 secretion). The T H1 response was not observed with an Amb a 1-non-ISS conjugate. Coinjection of Amb a 1 with ISS-ODN was much less effective in inducing a T H1 response. In mice primed for a T H2 response, injection with Amb a 1-ISS conjugate induced a de novo TH1 response and suppressed IgE antibody formation after challenge with Amb a 1. Amb a 1-ISS conjugate induced high-titer anti-Amb a 1 IgG antibodies in rabbits and cynomolgus monkeys, whereas Amb a 1 alone or Amb a 1 coinjected with ISS-ODN did not induce a detectable response. Amb a 1-ISS conjugate was less allergenic than Amb a 1 alone, as shown by a 30-fold lower histamine release from human basophils of patients with ragweed allergy, whereas mixing ISS-ODN with Amb a 1 did not reduce histamine release. Conclusion: Amb a 1-ISS conjugate has an enhanced TH1biased immunogenicity and reduced allergenicity. It may offer a more effective and safer approach for allergen immunotherapy than currently available methods. (J Allergy Clin Immunol 2000;106:124-34.)

Trends in the cost of illness for asthma in the United States, 1985-1994.

Abstract: Background: During the past decade, there have been notable changes in asthma prevalence, morbidity, and mortality. In this same time period, there have also been important national efforts to increase asthma awareness and improve asthma care. Objective: The purpose of this study was to examine the changes in US cost of illness for asthma during the 10-year period from 1985-1994. Methods: The study was a two-period (1985 and 1994), cross-sectional, cost-of-illness analysis. Cost estimates were based on US population and health care survey data available from the National Center for Health Statistics. Results: The total US costs of asthma for 1994 were $10.7 billion. On the basis of 1985 estimates adjusted to 1994 dollars, total asthma costs increased by 54.1% and direct medical expenditures increased by 20.4% during the 10-year period. In 1985, hospital inpatient care represented the largest component cost of direct medical expenditures (44.6%). Hospital inpatient costs decreased to 29.5% of direct medical expenditures in 1994, primarily because of shorter lengths of stay, as opposed to a decrease in the total number of admissions. In 1994, medications represented the largest component cost of direct medical expenditures (40.1%, up from 30.0% in 1985). The largest component increase in indirect costs was due to loss of work. On the basis of adjusted dollars, estimated costs per affected person with asthma declined by 3.4% (decrease of 15.5% for children and an increase of 2.9% for persons 18 years and older) during this time period. Conclusion: Although the US costs of asthma increased during the 1985-1994 time period, estimated costs per person with asthma demonstrated a modest decline. These findings may represent a combination of reductions in hospital lengths of stay and increasing prevalence of persons with low consumption of asthma-related health care resources. In examining the component costs, it is unclear whether these changes can be attributed to the many local, regional, and national efforts aimed at controlling untoward asthma outcomes during the 1985-1994 time period. (J Allergy Clin Immunol 2000;106:493-9.)

The diverse potential effector and immunoregulatory roles of mast cells in allergic disease

Abstract: Mast cells are of hematopoietic origin but typically complete their maturation in peripheral connective tissues, especially those near epithelial surfaces. Mast cells express receptors that bind IgE antibodies with high affinity (FcepsilonRI), and aggregation of these FcepsilonRI by the reaction of cell-bound IgE with specific antigens induces mast cells to secrete a broad spectrum of biologically active preformed or lipid mediators, as well as many cytokines. Mast cells are widely thought to be essential for the expression of acute allergic reactions, but the importance of mast cells in late-phase reactions and chronic allergic inflammation has remained controversial. Although it is clear that many cell types may be involved in the expression of late-phase reactions and chronic allergic inflammation, studies in genetically mast cell-deficient and congenic normal mice indicate that mast cells may be critical for the full expression of certain features of late-phase reactions and may also contribute importantly to clinically relevant aspects of chronic allergic inflammation. Moreover, the pattern of cytokines that can be produced by mast cell populations, and the enhancement of such cytokine production in mast cells that have undergone IgE-dependent up-regulation of their surface expression of FcepsilonRI, suggests that mast cells may contribute to allergic diseases (and host defense) by acting as immunoregulatory cells, as well as by providing effector cell function.

The environmental predictors of allergic disease.

Abstract: The prevalence of allergic diseases has been on the rise for the last 200 years, when hay fever, an easy and obvious-to-recognize illness, was virtually unknown in Europe and North America. Genetic factors are unlikely to explain these rapid increases. Among the potential environmental factors, exposure to ambient air pollution has been intensely debated. Besides passive smoking, which has convincingly been shown to increase the risk for asthma and bronchial hyperresponsiveness among exposed children, the evidence to suggest that outdoor pollution to sulfur dioxide, particulate matter, diesel exhaust, and ozone is causally related with the inception of allergic diseases is poor. Rather, factors associated with the lifestyle of populations or families, such as socioeconomic status, allergen exposure, sibship size, early childhood infections, dietary habits, and growing up in anthroposophic families or a farming environment, may prove to be of greater relevance. The future challenge is to tackle the complex interplay between environmental factors and genetic determinants that will eventually contribute to a better understanding and to better prevention strategies for such multifactorial conditions as asthma and allergies.

IL-4/IL-13 signaling beyond JAK/STAT.

Abstract: In the past several years, extensive studies on the mechanisms underlying IL-4 and IL-13 signaling have enabled us to gain insight into how these cytokines regulate immune responses. Because both IL-4 and IL-13 use the IL-4Ralpha as a receptor component, these cytokines activate many common signaling pathways. Both of these cytokines use Janus kinases (JAKs) to initiate signaling and activate signal transducer and activator of transcription-6 (STAT6), which is a transcription factor required for many of their biologic functions. In addition to JAK/STAT, these cytokines also activate a variety of other signaling molecules that are important in regulating IL-4-induced proliferation and protection from apoptosis. Suppressor of cytokine signaling-1 (SOCS-1) is a molecule that can inhibit the activation of IL-4 signaling through the inhibition of JAKs. The Fes tyrosine kinase is activated by IL-4 and appears to be important in regulating IL-4-induced proliferation through the phosphorylation of insulin receptor substrate (IRS) molecules. IRS molecules are essential for IL-4-induced proliferation through their ability to recruit phosphoinositol-3 kinase to the activated IL-4 receptor kinase. In addition, IL-4 can activate a number of phosphatases including SH2-containing inositol phosphatase (SHIP), SHP-1, and SHP-2. Finally, B-cell lymphoma gene-6 (BCL-6) appears to regulate a subset of IL-4-induced genes. Thus the biologic responses induced by IL-4/IL-13 require a complex interaction of signaling pathways and regulators.

Protease-dependent activation of epithelial cells by fungal allergens leads to morphologic changes and cytokine production.

Abstract: Background: Proteases in extracts of Aspergillus fumigatus cause epithelial cell desquamation and release of proinflammatory cytokines. Objective: We sought to assess protease activity in Alternaria alternata , Cladosporium herbarum , and Aspergillus fumigatus extracts and study the ability of these extracts to cause desquamation and release of proinflammatory cytokines from epithelial cells. Methods: Protease activities of the fungal extracts were quantified. Changes with respect to cell morphology, cell desquamation, and cytokine production (IL-6 and IL-8) were measured in the absence and presence of the fungal extracts in an airway-derived epithelial cell line (A549) and primary epithelial nasal cells. Results: Fungal proteases differentially induced morphologic changes, cell desquamation, and production of IL-6 and IL-8 in a dose- and time-dependent fashion. Alternaria alternata extracts induced cell shrinking and cell desquamation and strongly enhanced the production of IL-6 and IL-8 at higher concentrations. Aspergillus fumigatus extracts caused cell shrinking, cell desquamation, and production of IL-6 and IL-8, even at low concentrations. The Aspergillus fumigatus –derived extract grown on collagen medium induced a strong dose-dependent decline in cytokine production at higher concentrations. Cladosporium herbarum extracts did not induce morphologic changes or cell desquamation but enhanced IL-6 and IL-8 productions at higher concentrations. The dependence of these effects on intact protease activity was shown by their abrogation by protease inhibitors. Conclusion: Proteases present in fungal extracts interact with epithelial cells, leading to morphologic changes, cell desquamation, and induction of proinflammatory cytokines. It is proposed that these fungal proteases may activate epithelial cells through a protease-activated receptor type 2–driven mechanism. (J Allergy Clin Immunol 2000;105:1185-93.)

738 Abnormal clones of T cells producing interleukin-5 in idiopathic eosinophilia

Abstract: Background The cause of persistent eosinophilia and the hypereosinophilic syndrome is unknown. Recent work suggests that in some patients with the hypereosinophilic syndrome, a clone of abnormal T cells produces large amounts of interleukin-5, a cytokine required for the growth and differentiation of eosinophils. We examined T-cell surface markers, rearranged T-cell–receptor genes, and in vitro production of cytokines by T cells from patients with idiopathic eosinophilia. Methods The expression of surface molecules on T cells was measured by flow cytometry. Cytokine expression was measured by enzyme-linked immunosorbent assay, flow cytometry, and immunohistochemical analysis. To identify dominant (clonal) rearrangements of the T-cell receptor within the lymphocyte population, Southern blot analysis (β chain) and the polymerase chain reaction (γ chain) were performed according to standard protocols. Results Among 60 patients with idiopathic eosinophilia, 16 had circulating T cells with an aberrant immunoph...

Recombinant humanized mAb-E25, an anti-IgE mAb, in birch pollen-induced seasonal allergic rhinitis.

Abstract: Background: Allergic rhinitis is a common condition often requiring treatment Objective: We evaluated whether recombinant humanized (rhu)mAb-E25, a recombinant humanized construct of a murine antibody that binds to circulating IgE, could control symptoms and reduce intake of concomitant medication in seasonal allergic rhinitis (SAR) induced by birch pollen if given subcutaneously in a dose schedule predicted to reduce serum free IgE levels below 25 ng/mL Methods: We randomly assigned 251 adult subjects with a history of SAR and a positive skin test response to birch pollen to receive 300 mg of rhumAb-E25 or placebo given 2 or 3 times during the season, depending on baseline IgE levels The primary efficacy variable was the subject's average daily nasal symptom severity score (sneezing, itching, runny, and stuffy nose) from diary data collected over the double-blind treatment period Secondary efficacy variables included the average number of rescue antihistamine tablets per day, the proportion of days with any SAR medication use, and rhinoconjunctivitis-specific quality of life (QOL) Results: Significant between-treatment differences in favor of rhumAb-E25 were observed in average daily nasal symptom severity scores, the average number of tablets of rescue antihistamines per day, the proportion of days with any SAR medication use, and all domains of QOL Serum-free IgE levels were markedly lower in rhumAb-E25-treated subjects and were associated with clinical effectiveness Recombinant humanized mAb-E25 was well tolerated No anti-rhumAb-E25 antibodies were detected Conclusion: Compared with placebo, rhumAb-E25 was safe and effective in controlling birch pollen-induced SAR symptoms, with less concomitant medication use and improved QOL This study shows the therapeutic potential of anti-IgE antibody in SAR

Evidence for a disease-promoting effect of Staphylococcus aureus–derived exotoxins in atopic dermatitis

Abstract: Background: The skin of patients with atopic dermatitis (AD) exhibits a striking susceptibility to colonization with Staphylococcus aureus Some strains of S aureus secrete exotoxins with T-cell superantigen activity (toxigenic strains), and abnormal T-cell functions are known to play a critical role in AD Objective: Our purpose was to examine the impact of superantigen production by skin-colonizing S aureus on disease severity Methods: In a cross-sectional study of 74 children with AD, the presence and density of toxigenic and nontoxigenic strains of S aureus was correlated with disease severity In a subgroup of patients the T-cell receptor Vβ repertoire of peripheral blood and lesional T cells was investigated and correlated with individual superantigen activity of skin-colonizing S aureus Results: Fifty-three percent of children with AD were colonized with toxigenic strains of S aureus producing staphylococcal enterotoxin C, staphylococcal enterotoxin A, toxic shock syndrome toxin-1, staphylococcal enterotoxin B, and staphylococcal enterotoxin D in decreasing frequency Children colonized with toxigenic S aureus strains had higher disease severity compared with the nontoxigenic and S aureus –negative groups Patients colonized with toxigenic S aureus exhibited shifts in the intradermal T-cell receptor Vβ repertoire that correspond to the respective superantigen-responsive T-cell subsets Conclusion: The data demonstrate that S aureus –released exotoxins can modulate disease severity and dermal T-cell infiltration (J Allergy Clin Immunol 2000;105:814-9)

Concomitant montelukast and loratadine as treatment for seasonal allergic rhinitis: A randomized, placebo-controlled clinical trial

Abstract: Background: Nasal challenge studies have suggested histamine and cysteinyl leukotrienes are important proinflammatory mediators in allergic rhinitis. This study was designed to determine the efficacy of montelukast, a cysteinyl leukotriene receptor antagonist, administered alone or concomitantly with loratadine, an H 1 -receptor antagonist, in seasonal allergic rhinitis. Objective: The purpose of this study was to determine the effect of concomitant use of montelukast and loratadine in the treatment of seasonal allergic rhinitis. Methods: In this multicenter (N = 12) double-blind, randomized, parallel-group, placebo-controlled 2-week trial, 460 men and women, aged 15 to 75 years, with spring seasonal allergic rhinitis were randomly allocated to receive 1 of the following 5 treatments: montelukast 10 or 20 mg, loratadine 10 mg, montelukast 10 mg with loratadine 10 mg, or placebo, once daily in the evening. The primary end point was daytime nasal symptoms score (average of congestion, rhinorrhea, itching, and sneezing). Other end points were eye symptoms, nighttime symptoms, individual daytime nasal symptoms, global evaluations (patient's and physician's), and rhinoconjunctivitis quality-of-life scores. Results: Concomitant montelukast with loratadine improved the primary end point significantly ( P Conclusions: Concomitant montelukast with loratadine provided effective treatment for seasonal allergic rhinitis and associated eye symptoms with a safety profile comparable with placebo. (J Allergy Clin Immunol 2000;105:917-22.)

Genetics of peanut allergy: a twin study.

Abstract: Background: The role of genetics in the etiology of peanut allergy is unknown. For complex genetic traits, twin studies can provide information on the relative contribution of genetic factors to a disease, as the relative confounding effects of environmental factors are markedly decreased. Objective: This study was performed to search for evidence that genetic factors influence peanut allergy by comparing the concordance rate for this allergy among monozygotic and dizygotic twins. Methods: Twin pairs with at least one member with peanut allergy were ascertained through the Food Allergy Network by advertisements in the organization’s newsletters and Web site. Individuals with peanut allergy or parental surrogates were interviewed by telephone. A full atopic history was obtained, and peanut allergy and zygosity were determined using previously validated questionnaires. Heritability of peanut allergy was determined using univariate genetic model fitting by maximum likelihood with the Mx statistical modeling software package. Results: Seventy-five twin pairs were recruited. Seventeen pairs were excluded because of unconvincing peanut allergy histories (9 pairs, including 4 of uncertain zygosity) or because one twin had reportedly never ingested peanut (8 pairs). The median age of the 58 remaining twin pairs was 5 years (range 1 to 58 years). Seventy individuals had peanut allergy. In addition to convincing histories of peanut allergy, 52 (74%) had been tested (skin prick testing with or without radioallergosorbent assay) and all had positive reactions to peanut. Twentynine of the 70 had experienced >1 reaction to peanut; 29 of 70 had multisystem reactions. Among the monozygotic pairs (n = 14), 9 were concordant for peanut allergy (pairwise concordance, 64.3%) and among dizygotic pairs (n = 44), 3 were concordant for peanut allergy (pairwise concordance, 6.8%; χ2 = 21.38, P < .0001). Heritability of peanut allergy was estimated at 81.6% (95% confidence interval 41.6% to 99.7%) with model fitting using a population prevalence of peanut allergy of 0.4%. Conclusions: The significantly higher concordance rate of peanut allergy among monozygotic twins suggests strongly that there is a significant genetic influence on peanut allergy. (J Allergy Clin Immunol 2000;106:53-6.)

IL-9 and its receptor in allergic and nonallergic lung disease: increased expression in asthma.

Abstract: Background: Bronchial asthma is a chronic inflammatory disease associated with genetic components. Recently IL-9 has been reported as a candidate gene for asthma and to be associated with bronchial hyperresponsiveness and elevated levels of total serum IgE. Objective: To investigate the contribution of IL-9 to the pathogenesis of asthma, we examined the expression of IL-9 and its receptor (IL-9R) in bronchial tissue from subjects with atopic asthma (n = 10), chronic bronchitis (n = 11), and sarcoidosis (n = 9) and from atopic (n = 7) and nonatopic (n = 10) healthy control subjects. Methods: Bronchial biopsy specimens were examined for the presence of IL-9 and IL-9R protein and messenger RNA (mRNA) by immunocytochemistry and in situ hybridization, respectively. To phenotype the cells expressing IL-9 in asthmatic tissue, combined in situ hybridization and immunocytochemistry was also performed. Results: There was a highly significant difference (P .05), IL-9R immunoreactivity was significantly higher in asthmatic compared with control subjects. Furthermore, IL-9 mRNA expression levels were also significantly correlated with FEV1 (P < .05) and the airway responsiveness to methacholine producing a 20% fall in FEV1 (P < .01). The cells expressing IL-9 mRNA in asthmatic tissue were CD3+ lymphocytes (68%), major basic protein+ eosinophils (16%), and elastase+ neutrophils (8%). Conclusion: The results of this study demonstrate the potential of IL-9 to be a marker for atopic asthma and furthermore suggest an important role for this cytokine in the pathophysiologic mechanisms of this disease. (J Allergy Clin Immunol 2000;105:108-15.)

Clinical, biochemical, and genetic characterization of a novel estrogen-dependent inherited form of angioedema.

Abstract: Background: Two genetic forms of hereditary angioedema (HAE) are currently recognized. Both are transmitted in an autosomal dominant manner and are characterized by recurrent episodes of localized angioedema. Involvement of the gut leads to episodes of severe abdominal pain, and laryngeal involvement can lead to airway obstruction and even death. One type results from heterozygosity for a nonexpressed C1 inhibitor allele, and the other results from heterozygosity for a nonfunctional C1 inhibitor allele. Objective: This report identifies a third type of HAE, with a unique estrogen-dependent phenotype. Methods: Detailed medical histories were obtained from family members, and a pedigree was constructed to ascertain the mode of inheritance. Determination of serum complement factors, C1 inhibitor protein, C1 inhibitor function, coagulation factor XII, plasma prekallikrein, high molecular weight kininogen, and selected DNA sequences were performed in affected members by using standard assays. Results: Episodes of angioedema were clinically indistinguishable from those associated with previously described forms of HAE; however, these occurred only during pregnancy or the use of exogenous estrogens. Patients were otherwise asymptomatic, except for one patient who had acetyl salicylic acid/nonsteroidal anti-inflammatory drug–related angioedema later in life. History was available for members spanning 4 generations, and affected individuals were identified in 3 generations. Of 46 family members, phenotype could be determined in 13 members. Seven were affected, and 6 were not. One male of undetermined phenotype was an obligate carrier. The unique estrogen-dependent nature of the phenotype means that the status of several members in the third and fourth generation remains unknown. The disorder appears to be transmitted in an autosomal dominant fashion, although other modes of inheritance cannot be excluded entirely. C1 inhibitor protein, C1 inhibitor function, C2, C4, C1q, coagulation factor XII, prekallikrein, and high molecular kininogen were normal in 3 affected family members during asymptomatic periods. DNA sequencing revealed no abnormality in 3 patients in the coding region of the gene encoding C1 inhibitor or in the 5' flanking regions of the genes encoding C1 inhibitor and factor XII. Conclusions: This family appears to have a novel form of inherited angioedema that does not result from C1 inhibitor deficiency or dysfunction. The phenotype is uniquely estrogen dependent. Implications for diagnosis and treatment are discussed. Further studies are required to define the exact nature of the genetic abnormality involved. (J Allergy Clin Immunol 2000;106:546-50.)

Glucocorticoid resistance in asthma is associated with elevated in vivo expression of the glucocorticoid receptor β-isoform

Abstract: Background: Glucocorticoid-resistant bronchial asthma is characterized by failure of corticosteroids to suppress key asthma-relevant, cell–mediated inflammatory responses in the airways. Objective: The mechanism of this phenomenon is not clear but may involve aberrant expression of the β-isoform of the glucocorticoid receptor. Methods: We have measured expression of the α- and β-glucocorticoid receptor isoforms in tuberculin-driven cutaneous cell–mediated inflammatory lesions in people with asthma who are glucocorticoid sensitive and resistant after 9 days of therapy with oral prednisolone (40 mg/day) or matching placebo in a random order, crossover design. Results: After placebo therapy, the mean numbers of cells expressing glucocorticoid receptor α immunoreactivity in the lesions evoked in glucocorticoid-sensitive and -resistant patients with asthma were statistically equivalent. The numbers of cells expressing glucocorticoid receptor β were significantly elevated in the patients who were glucocorticoid resistant, resulting in an 8-fold higher ratio of expression of glucocorticoid receptor α/glucocorticoid receptor β in the patients who were glucocorticoid sensitive. Glucocorticoid receptor α/glucocorticoid receptors β were colocalized to the same cells. Oral prednisolone therapy was associated with a significant decrease in the numbers of cells expressing glucocorticoid receptor α but not glucocorticoid receptor β in the subjects who were glucocorticoid sensitive. No significant change was found in the numbers of cells expressing glucocorticoid receptor α and glucocorticoid receptor β in the patients who were glucocorticoid resistant. Prednisolone therapy reduced the ratio of glucocorticoid receptor α/glucocorticoid receptor β expression for the patients who were glucocorticoid sensitive to a level seen in the patients who were glucocorticoid resistant before therapy. Conclusion: Because glucocorticoid receptor β inhibits α-glucocorticoid receptor–mediated transactivation of target genes, the increased expression of glucocorticoid receptor β in inflammatory cells might be a critical mechanism for conferring glucocorticoid resistance. (J Allergy Clin Immunol 2000;105:943-50.)

Allergic and immunologic disorders of the eye. Part II : Ocular allergy

Abstract: Allergy affects more than 15% of the world population, and some studies have shown that up 30% of the US population has some form of allergy. Most of these patients have various target organs for their allergies, and most have ocular involvement. The ocular component may be the most prominent and sometimes disabling feature of their allergy. Some are affected for only a few weeks to months, whereas others have symptoms that last throughout the year. The seasonal forms may present to clinical allergists, whereas the more chronic forms may present to ophthalmologists. Thus, in the second of this 2-part review series (Part I: Ocular Immunology appeared in the November issue of the Journal), an overview is provided of the spectrum of ocular allergy that ranges from acute seasonal allergic conjunctivitis to chronic variants of atopic keratoconjunctivitis. With a better understanding of the immunologic mechanisms, we now can develop better treatment approaches and design further research in intervention of allergic eye diseases.

Recombinant allergens for diagnosis and therapy of allergic disease

Abstract: Many of the problems associated with using natural allergenic products for allergy diagnosis and treatment can be overcome with use of genetically engineered recombinant allergens. Over the past 10 years, the most important allergens from mites, pollens, animal dander, insects, and foods have been cloned, sequenced, and expressed. In many cases the three-dimensional allergen structure has been determined and B-cell and T-cell epitopes have been mapped. These studies show that allergens have diverse biologic functions (they may be enzymes, enzyme inhibitors, lipocalins, or structural proteins) and that as a rule the allergen function is unrelated to its ability to cause IgE antibody responses. High-level expression systems have been developed to produce recombinant allergens in bacteria, yeast, or insect cells. Recombinant allergens show comparable IgE antibody binding to their natural counterparts (where available) and show excellent reactivity on skin testing and in in vitro diagnostic tests. Cocktails of recombinant allergens can be formulated with predetermined and uniform allergen levels, which could replace natural allergens and result in the development of innovative, patient-based tests for allergy diagnosis. Recombinant allergens also offer the exciting possibility of developing new forms of allergen immunotherapy, including the use of hypoallergens, allergens coupled to IgE suppressive adjuvants, and peptide-based therapies. The production of recombinant allergens as defined molecular entities makes it feasible to consider the possibility of developing prophylactic allergen vaccines. The introduction of recombinant allergens in research and in clinical trials should lead to significant improvements in allergy diagnosis and treatment.

Histamine and tryptase levels in patients with acute allergic reactions: An emergency department-based study.

Abstract: Background: Emergency department visits for acute allergic reactions are common. Although the diagnosis and classification of these allergic reactions is primarily empiric, it is not always clear whether certain signs and symptoms constitute systemic mediator release syndromes, such as anaphylaxis, and thus may warrant more aggressive therapy or follow-up. Objective: We sought to determine associations between various clinical signs and symptoms with both plasma histamine levels and serum tryptase levels in adult patients presenting to an emergency department with acute allergic syndromes. The clinical correlates of raised β-tryptase levels were also investigated. Methods: Ninety-seven adult emergency department patients were prospectively studied by using a questionnaire, physical examination, and serum-plasma sampling. Plasma histamine and serum total and β-tryptase levels were determined. Clinical groupings were compared for mediator levels by using simple and multivariate analysis. Results: Elevated levels of plasma histamine (>10 nmol/L) and serum total tryptase (>15 ng/mL) were observed in 42 and 20 patients, respectively. Detectable β-tryptase (≥1 ng/mL) was observed in 23 patients, including 15 of the patients with elevated total tryptase levels. Suspected food allergy incidences and the duration of reaction were similar in patients with increased histamine levels and in patients with increased tryptase levels. Increased total tryptase levels, histamine levels, or both were observed in some patients who did not have airway, cardiovascular, or abdominal signs. Histamine levels correlated better with clinical signs than tryptase levels. Histamine elevations (>10 nmol/L) were observed more frequently in patients characterized by the following clinical signs in univariate analysis: the presence of urticaria, more extensive erythema, abnormal abdominal findings, and wheezing. Total tryptase increases were observed more frequently only in patients with urticaria. Histamine levels correlated with initial heart rates. In multivariate analysis the extent of urticaria was the best single predictor of plasma histamine levels and of either an elevated histamine or tryptase level. Detectable β-tryptase levels were observed in some patients who had neither elevated total tryptase nor elevated histamine levels. Unlike patients without detectable β-tryptase levels, patients who had detectable β-tryptase levels had a significant correlation between total tryptase and histamine levels ( P Conclusions: Raised histamine and, less commonly, raised tryptase levels are observed in almost 50% of patients presenting to emergency departments with acute allergic reactions. Some cases associated with systemic mediator release do not have classical features of severe anaphylaxis, such as hypotension or tachycardia. The lack of total tryptase elevations in many patients with elevated plasma histamine levels suggests basophil involvement. The clinical utility of β-tryptase determinations in the evaluation of acute allergic reactions needs further study. (J Allergy Clin Immunol 2000;106:65-71.)