Atopic diseases, the new "epidemic of the twenty-first century" and a central health problem of industrial nations, call for the development of innovative primary prevention strategies. The present review provides an overview of current experimental and immunomodulatory procedures and their underlying mechanisms.
asthma; Th1/Th2-cytokines; immunomodulation; mouse model
Although extensively studied in adults, nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity in children, especially in young children, remains poorly defined. Pediatricians, prescribing antipyretics for children, rarely encounter significant problems, but the few epidemiologic studies performed show conflicting results. Although it is clear that some patients with acetylsalicylic acid (ASA)-sensitive asthma have their clinical onset of disease in childhood and bronchoconstriction after ASA challenge is seen in 0 to 22% of asthmatic children so challenged, ibuprofen at antipyretic doses may cause acute respiratory problems only in a very small number of mild to moderate asthmatics. The recently elucidated mechanism of action of acetaminophen may explain some occurrences of adverse reactions in patients with cross-reactive NSAID hypersensitivity on the basis of its inhibitory activity on the newly described enzyme, cyclooxygenase (COX)-3. This nonspecific sensitivity to inhibition of COX is most likely genetically determined and shows a remarkable association with atopic disease even in the very young age group and possibly an increased predilection in specific ethnic groups. This review summarizes state-of-the-art published data on NSAID hypersensitivity in preschool children.
acetaminophen; acetylsalicylic acid (ASA); children; hypersensitivity; ibuprofen; NSAID; preschool
Anticholinergics, or specific antimuscarinic agents, by inhibition of muscarinic receptors cause bronchodilatation, which might correlate with activation of these receptors by the muscarinic agonist methacholine. The aim of this study was to determine whether a positive bronchodilator response to the anticholinergic ipratropium bromide could predict airway hyperresponsiveness in patients with persistent allergic asthma. The study comprised 40 patients with mild and moderate persistent allergic asthma. Diagnosis was established by clinical and functional follow-up (skin-prick test, spirometry, bronchodilator tests with salbutamol and ipratropium bromide, and methacholine challenge testing). The bronchodilator response was positive to both bronchodilator drugs in all patients. After salbutamol inhalation, forced expiratory volume in 1 second (FEV1) increased by 18.39 ± 6.18%, p < .01, whereas after ipratropium bromide, FEV1 increased by 19.14 ± 6.74%, p < .01. The mean value of FEV1 decreased by 25.75 ± 5.16%, p < .01 after methacholine (PC20 FEV1 [provocative concentration of methacholine that results in a 20% fall in FEV1] from 0.026 to 1.914 mg/mL). Using linear regression, between methacholine challenge testing and bronchodilator response to salbutamol, a positive, weak, and stastistically significant correlation for FEV1 was found (p < .05). Correlations between methacholine challenge testing and the bronchodilator response to ipratropium bromide were positive and weak but not statistically significant. The positive bronchodilator response to ipratropium bromide could not predict airway hyperresponsiveness.
airway hyperresponsiveness; allergic asthma; bronchodilator response; ipratropium bromide; methacholine challenge testing; salbutamol
Interleukin-12 (IL-12) was measured in 45 asthmatic children aged 3 to 16 years. The assessments were performed on 20 children during an episode of acute exacerbation and on 25 children during remission. There was no significant difference between the mean IL-12 level during exacerbation (1.63 ± 2.08 pg/mL) and during remission (0.88 ± 0.56 pg/mL) (p = .83). A positive, but insignificant, correlation was found between forced expiratory volume in 1 second and IL-12 (p = .634). IL-12 levels were significantly lower in children with a positive family history of asthma (1.13 ± 1.78 pg/mL) compared with those without (1.31 ± 1.06 pg/mL) (p < .012), supporting the theory that the gene-environment interactions affect the immune responses. IL-12 peripheral blood levels had no detectable impact on the course of established asthma in the study population.
asthma; family history; IL-12
Food-dependent exercise-induced anaphylaxis (FDEIA) is recognized as a distinct category of exercise-induced anaphylaxis (EIA) but is very likely underdiagnosed. This report describes a 41-year-old Indian woman who experienced two separate episodes of anaphylaxis while dancing after she had eaten chickpea-containing foods. The chickpea, a small legume, is a staple ingredient in culinary traditions from around the world, especially in India, the Middle East, and North Africa. Chickpea-containing dishes are also becoming more widespread in the Western world with the growing popularity of South Asian, Middle Eastern, and African cuisines. It is important to consider FDEIA in cases of unexplained anaphylaxis as reactions can occur several hours after ingesting the culprit food(s). Furthermore, no reaction occurs if a sensitized individual eats the culprit food(s) without exercising afterward; therefore, triggering foods can easily be overlooked. Current ideas on the pathophysiology, predisposing factors, workup, and treatment of FDEIA are also summarized here.
anaphylaxis; exercise; food allergy
Picture yourself as a researcher in immunology. To begin your project, you ask a question: Do CD8 T cells require antigen to maintain a memory response? This question is of prime importance to numerous medical fields. In chronologic order, you digest the literature, but unfortunately, you hit a major stumbling block in the 1990s. The crux of the problem is that which so often happens in science: two well-recognized, capable groups emerge with diametrically opposed conclusions, leaving you pondering which set of wellcontrolled data to believe. Fortunately, years later, a surprising group of articles sheds light on this mystery and subtly reconciles these two positions.
antigen; CD8 cells; central memory; effector memory
Anaphylaxis, an acute and potentially lethal multi-system clinical syndrome resulting from the sudden, systemic degranulation of mast cells and basophils, occurs in a variety of clinical scenarios and is almost unavoidable inmedical practice. Healthcare professionalsmust be able to recognize its features, treat an episode promptly and appropriately, and be able to provide recommendations to prevent future episodes. Epinephrine, administered immediately, is the drug of choice for acute anaphylaxis. The discussion provides an overview of one set of evidence-based and consensus parameters for the diagnosis and management of anaphylaxis.
anaphylaxis; epinephrine; management; prevention
Over the past several decades, significant advances have been seen in the diagnosis and treatment of asthma. Recent research has focused on potential phenotypic and genotypic predictors of response to therapy. In this review, we will examine each of the three major therapeutic classes of asthma therapy, focusing on a potential genetic clue to medication response.
asthma; genetic polymorphisms
Specific allergen immunotherapy (SIT) is disease-modifying and efficacious. However, the use of whole allergen preparations is associated with frequent allergic adverse events during treatment. Many novel approaches are being designed to reduce the allergenicity of immunotherapy preparations whilst maintaining immunogenicity. One approach is the use of short synthetic peptides which representing dominant T cell epitopes of the allergen. Short peptides exhibit markedly reduced capacity to cross link IgE and activate mast cells and basophils, due to lack of tertiary structure. Murine pre-clinical studies have established the feasibility of this approach and clinical studies are currently in progress in both allergic and autoimmune diseases.
allergy; epitope; IL-10; immunological tolerance; immunotherapy; peptide; regulatory T cell; T cell
Despite asthma and chronic obstructive pulmonary disease being widely regarded as heterogeneous diseases, a consensus for an accurate system of classification has not been agreed. Recent studies have suggested that the recognition of subphenotypes of airway disease based on the pattern of airway inflammation may be particularly useful in increasing our understanding of the disease. The use of non-invasive markers of airway inflammation has suggested the presence of four distinct phenotypes: eosinophilic, neutrophilic, mixed inflammatory and paucigranulocytic asthma. Recent studies suggest that these subgroups may differ in their etiology, immunopathology and response to treatment. Importantly, novel treatment approaches targeted at specific patterns of airway inflammation are emerging, making an appreciation of subphenotypes particularly relevant. New developments in phenotyping inflammation and other facets of airway disease mean that we are entering an era where careful phenotyping will lead to targeted therapy.
asthma; COPD; eosinophil; inflammation; neutrophil
A 59-year-old man was admitted to the hospital with pulmonary infiltration, fever, erythema, and eosinophilia. Two weeks before admission, he received amoxicillin, acetaminophen, and shoseiryu-to (a Japanese herbal medicine) for a common cold. Bronchoalveolar lavage was performed, and an increased number of eosinophils was recovered. Transbronchial biopsy specimens showed granuloma and interstitial thickening with eosinophils and lymphocytes. Drug-induced eosinophilic pneumonia was suspected, so all drugs were discontinued. The symptoms and infiltration shadow disappeared. A drug-induced lymphocyte stimulation test (DLST) was positive for acetaminophen but not for amoxicillin. In contrast to the DLST, a provocation test revealed that amoxicillin induced the drug allergy. A very striking observation was the coexistence of pulmonary eosinophilia and granulomatous lung infiltrations. In addition, there was a discrepancy between the DLST and provocation test findings. To our knowledge, there is no previous report of drug-induced eosinophilic pneumonia with a granulomatous reaction.
amoxicillin; drug-induced lymphocyte stimulation test; drug-induced pneumonia; granuloma; provocation test
Chymotrypsin- or trypsin V- (a mixture of trypsin and chymotrypsin) digested β-lactoglobulin (BLG) peptides were prepared and were confirmed to have much less immunoglobulin (lg)G and lgE reactivity compared with intact BLG by IgG inhibition enzymelinked immunosorbent assay and IgE dot blotting. The lymphocyte responses to intact BLG and these peptides were examined using peripheral blood mononuclear cells (PBMCs) from 10 patients with cow's milk allergy. The PBMCs from most patients had lower lymphocyte responses to chymotrypsin- and trypsin V-digested BLG peptides than those to intact BLG. However, PBMCs from one and two patients retained significant proliferative responses to both peptides and to only the former peptide, respectively. Interferon-c production stimulated by chymotrypsin-digested peptides was still detectable in all five patients tested. Chymotrypsindigested BLG reduced lgE reactivity but still induced some lymphocyte responses.
Subtle increases in immaturity of immune function in early infancy have been implicated in the rising susceptibility to allergic disease, particularly relative impairment of type 1 interferon (IFN)-γ responses in the neonatal period. Although genetic predisposition is a clear risk factor, the escalating rates of allergic disease in infancy suggest that environmental factors are also implicated. We previously showed that maternal smoking in pregnancy may impair neonatal IFN-γ responses. Our more recent studies now indicate that this common avoidable toxic exposure is also associated with attenuation of innate immune function, with attenuated Toll-like receptor (TLR)-mediated microbial responses (including TLR-2, -3, -4, and -9 responses). Most notably, the effects were more marked if the mothers were also allergic. In this review, we discuss the significance of these observations in the context of the emerging hypothesis that variations in TLR function in early life may be implicated in allergic propensity. There is now growing evidence that many of the key pathways involved in subsequent T-cell programming and regulation (namely, antigen-presenting cells and regulatory T cells) rely heavily on microbe-driven TLR activation for maturation and function. Factors that influence the function and activity of these innate pathways in early life may contribute to the increasing predisposition for allergic disease. Although "cleaner" environments have been implicated, here we explore the possibility that other common environmental exposures (such as maternal smoking) could also play a role.
allergic disease; cord blood; cotinine; cytokines; innate immunity; pregnancy; smoking; Toll-like receptors
Interleukin (IL)-9 is a pleiotropic T helper 2-type cytokine that has been shown to be up-regulated in allergic airway disease, including asthma. IL-9 has been demonstrated to be a potent stimulus for the production and secretion of mucus from airway epithelial cells via induction of a calcium-activated chloride channel, hCLCA1. The objective of this study was to investigate the expression of IL-9 and hCLCA1 following allergen challenge in the nasal mucosa of allergic rhinitis patients. Nasal biopsies were obtained from allergic rhinitis patients out of allergen season both before (baseline) and after local antigen challenge with either ragweed or diluent (control). Immunohistochemistry and in situ hybridization were used to assess IL-9 protein and hCLCA1 messenger ribonucleic acid. Eosinophils and T cells were detected using immunohistochemistry. IL-9 and hCLCA1 were very low at baseline, and expression was significantly up-regulated following ragweed challenge. Whereas the number of eosinophils increased after allergen challenge, T-cell counts did not change significantly. The results of this study demonstrate the relationship between specific allergen challenge and expression of both IL-9 and hCLCA1, suggesting a possible mechanism for the increased production of mucus from airway epithelial cells in allergic rhinitis.
In the large majority of previous studies, patients with a history of acute urticaria induced by nonsteroidal anti-inflammatory drugs (NSAIDs) seeking safe alternative drugs have undergone tolerance tests uniquely with compounds exerting little or no inhibitory effect on the cyclooxygenase 1 enzyme. In light of recently published studies, however, this approach seems inadequate and should be changed. The present article critically reviews the clinical management of patients presenting with a history of urticaria induced by a single NSAID or multiple NSAIDs and suggests a simple, updated diagnostic algorithm that may assist clinicians in correctly classifying their patients.
aspirin; drug allergy; nonsteroidal anti-inflammatory drug; urticaria
Chronic urticaria is a skin disorder characterized by transient pruritic weals that recur from day to day for 6 weeks or more. It has a great impact on patients' quality of life. In spite of this prevalence and morbidity, we are only beginning to understand its physiopathology and we do not have a curative treatment. Moreover, a patient with chronic urticaria may undergo extensive laboratory evaluations seeking a cause only to be frustrated when none is found. In recent years there have been significant advances in our understanding of some of the molecular mechanisms responsible for hive formation. The presence and probable role of IgG autoantibodies directed against epitopes expressed on the alpha-chain of the IgE receptor and to lesser extent, to IgE in a subset of patients is generally acknowledged. These autoantibodies activate complement to release C5a, which augments histamine release, and IL4 and leukotriene C4 are released as well. A perivascular cellular infiltrate results without predominance of either Th1 or Th2 lymphocyte subpopulations. Basophils of all chronic urticaria patients (autoimmune or idiopathic) are hyperresponsive to serum, regardless of source, but poorly responsive to anti IgE. In this review we will summarize the recent contributions to this field and try to provide insights to possible future directions for research on this disease.
autoimmunity; basophils; chronic urticaria; cotinine; IgE receptor; mast cells