Allergy-associated Diseases Research Articles

Prenatal antibiotic exposure increases the risk of infant atopic dermatitis: data from a Greek cohort.

Background. The human microbiome is important due to the impact it has on host immunologic development and allergy-associated diseases. This study aimed to investigate the impact of prenatal exposure to antibiotics on the incidence of atopic dermatitis (AD) in children at 18 months of age. Methods. Mothers were interviewed at baseline, in the maternity ward and by phone questionnaire after 18 months. Demographic data, mode of delivery, yoghurt consumption, antibiotic and other drug use during pregnancy, atopic history, diagnosis of AD and history of infections in the offspring were noted. Results. 385 mothers were interviewed at baseline. 231 (60%) mothers with 236 children responded at follow up. Cesarean section was reported in 116 (50.2%) deliveries while antibiotic use during pregnancy in 55/231 (23.8%) women. 43/236 (18.22%) infants were diagnosed with AD. Intravenous antibiotic use was associated with a 7.7 increased risk of AD diagnosis in the offspring (95%CI 1.23-48.27, p = 0.029). An increased odd for AD was recorded for mothers 30-40 years of age (OR 4.50, 95%CI 1.08-18.7, p = 0.039). No significant association between cesarean section and AD (p = 0.70) was recorded. In multivariate analysis, reported food allergy (OR 8.03, 95%CI 2.30-27.97, p = 0.001) and otitis media episodes in children (OR 3.76, 95%CI 1.60-8.83, p = 0.002) were significantly associated with AD diagnosis. Conclusions. An increased risk of AD was recorded only when antibiotics were given prenatally by intravenous route and in women between 30-40 years of age. Children with food allergy had an increased risk for AD. The relatively high percentage of cesarean sections was not a risk factor for AD.

Secretory Leukocyte Protease Inhibitor Is Present in Circulating and Tissue-Recruited Human Eosinophils and Regulates Their Migratory Function.

Eosinophils and secretory leukocyte protease inhibitor (SLPI) are both associated with Th2 immune responses and allergic diseases, but whether the fact that they are both implicated in these conditions is pathophysiologically related remains unknown. Here we demonstrate that human eosinophils derived from normal individuals are one of the major sources of SLPI among circulating leukocytes. SLPI was found to be stored in the crystalline core of eosinophil granules, and its dislocation/rearrangement in the crystalline core likely resulted in changes in immunostaining for SLPI in these cells. High levels of SLPI were also detected in blood eosinophils from patients with allergy-associated diseases marked by eosinophilia. These include individuals with eosinophilic granulomatosis with polyangiitis (EGPA) and atopic dermatitis (AD), who were also found to have elevated SLPI levels in their plasma. In addition to the circulating eosinophils, diseased skin of AD patients also contained SLPI-positive eosinophils. Exogenous, recombinant SLPI increased numbers of migratory eosinophils and supported their chemotactic response to CCL11, one of the key chemokines that regulate eosinophil migratory cues. Together, these findings suggest a role for SLPI in controlling Th2 pathophysiologic processes via its impact on and/or from eosinophils.

Helminth Induced Immunoregulation and Novel Therapeutic Avenue of Allergy.

Allergic diseases are increasing at an alarming rate worldwide, particularly in developed countries. In contrast, there is a decrease in the prevalence of helminthic infections and other neglected diseases. The hygiene hypothesis elaborates parasitic infection, and allergy-associated diseases have an inverse relationship. Acute helminthic infection and allergic reaction stimulate Type 2 helper cells (Th2) immune response with up-regulation of cytokines IL-4-, IL-5-, and IL-13-mediated IgE and mast cell production, as well as eosinophilia. However, people who chronically suffer from helminthic infections are demarcated through polarized Th2 resulting in alternative macrophage activation and T regulatory response. This regulatory system reduces allergy incidence in individuals that are chronically diseased through helminth. As a result, the excretory-secretory (ES) substance derived from parasites and extracellular vesicular components can be used as a novel therapeutic modality of allergy. Therefore, the aim of this review meticulously explored the link between helminth infection and allergy, and utilization of the helminth secretome for therapeutic immunomodulation.

Is microbiome a target for the management of allergy associated diseases in children?

Is microbiome a target for the management of allergy associated diseases in children?

Recent advances in the management of allergy associated diseases in children.

The allergy symptoms could arise from variable organ systems and have fluctuating nature in severity as well as symptoms. Moreover, these symptoms could be related to multiple pathological states like common cold, chronic obstipation, diarrhea, etc. On the other hand, food allergy diagnosis that usually spread by IgE-mediated inhalant also poses a great challenge in front of the scientific fraternity. So far, many advances in the field of allergy diagnosis, as well as therapeutics, have been made. These advances include skin prick testing (SPT), serum specific IgE (sIgE) level test, component resolved diagnosis (CRD) test, etc. The present review article would be focused on important pathological states associated with allergy observed commonly in children. Moreover, the latest developments about timely management and accurate diagnosis are also discussed.

Modulation of allergic responses by mitochondrial STAT3 inhibitors.

Recently, we have shown that mast cell mitochondrial STAT3 could serve as a new target for the regulation of the allergic response as it plays an essential role in immunologically mediated degranulation of mast cells. In the present work, we explored how two recently developed mitochondrial STAT3 inhibitors (Mitocur-1 and Mitocur-3) modulate the allergic response. Experiments were performed both invitro in cultured human/mouse mast cells and with rat basophilic leukemia (RBL) cells and also invivo in mice. The effect of mitochondrial STAT3 inhibition on mast cell function was determined via checking degranulation and several cytokines secretion levels. Here, we show that treatment of rodent and human cultured mast cells with low concentrations of mitochondrial STAT3 inhibitors had no effect on STAT3 target gene expression. However, these inhibitors caused a significant reduction in mast cell exocytosis and cytokine release, due to a decrease in OXPHOS activity and STAT3 serine 727 phosphorylation. It was also observed in an OVA mouse model of allergic asthma that one of the inhibitors used significantly reduced eosinophilia and neutrophilia compared to the control mice group. Furthermore, it was observed that treatment with this inhibitor resulted in a significant reduction in blood histamine levels in mice after IgE-Ag challenge. The present data strongly suggest that the development of mitochondrial STAT3 inhibitors could serve as a potential treatment for allergy-associated diseases.

Novel Genetic Variants Associated with Child Refractory Esophageal Stricture with Food Allergy by Exome Sequencing.

Background: Refractory esophageal stricture (RES) may be attributed to food allergy. Its etiology and pathogenesis are not fully understood. Identification of novel genetic variants associated with this disease by exome sequencing (exome-seq) may provide new mechanistic insights and new therapeutic targets. Methods: To identify new and novel disease-associating variants, whole-exome sequencing was performed on an Illumina NGS platform in three children with RES as well as food allergy. Results: A total of 91,024 variants were identified. By filtering out ‘normal variants’ against those of the 1000 Genomes Project, we identified 12,741 remaining variants which are potentially associated with RES plus food allergy. Among these variants, there are 11,539 single nucleotide polymorphisms (SNPs), 627 deletions, 551 insertions and 24 mixture variants. These variants are located in 1370 genes. They are enriched in biological processes or pathways such as cell adhesion, digestion, receptor metabolic process, bile acid transport and the neurological system. By the PubMatrix analysis, 50 out of the top 100 genes, which contain most variants, have not been previously associated with any of the 17 allergy-associated diseases. These 50 genes represent newly identified allergy-associated genes. Those variants of 627 deletions and 551 insertions have also not been reported before in RES with food allergy. Conclusions: Exome-seq is potentially a powerful tool to identify potential new biomarkers for RES with food allergy. This study has identified a number of novel genetic variants, opening new avenues of research in RES plus food allergy. Additional validation in larger and different patient populations and further exploration of the underlying molecular mechanisms are warranted.

Atypical Eosinophilic Esophagitis

The classic endoscopic findings of eosinophillic esophagitis (EoE) are linear furrowing, concentric esophageal rings, diminished vascular pattern, white surface exudates and linear tears. Occasionally, in severe cases of EoE, a small caliber esophagus and strictures can be seen. These findings are not pathognomonic but collectively suggest the diagnosis of EoE. In this case report, we present a rare endoscopic finding of an esophageal polyp secondary to eosinophillic esophagitis. A 36-year-old Italian woman presented with burning chest discomfort, difficulty swallowing and regurgitation of food for the past year. She reports a history an esophageal tumor diagnosed 19 years earlier, treated with multiple sessions of laser ablation therapy. Due to progressively worsening symptoms she underwent an upper endoscopy and was found to have a single, 3cm semi-pedunculated polyp in the distal esophagus. Multiple biopsies were taken and pathology revealed esophageal mucosa with a focal marked increase in intraepitheal eosinophils. The patient was referred for Endoscopic Ultrasound (EUS) with Endoscopic Mucosal Resection (EMR). Upon further questioning she admitted to having a history of asthma and seasonal allergies, raising suspicion for EoE. She was given a trial of prednisone and proton pump inhibitor. Two weeks later EUS evaluation revealed a single, small 5mm polyp in the distal esophagus. Pathology revealed fragments of a squamous papilloma with acute inflammation. The patient was diagnosed with an atypical endoscopic manifestation of eosinophillic esophagitis. Eosinophilic esophagitis is an allergy-associated disease increasingly recognized in industrialized countries. The prevalence is estimated to reach up to 50 patients per 100,000 people in some regions1. It is unclear whether the increase in prevalence is secondary to a rise in incidence or better understanding of the disease. EoE has been described with classic endoscopic findings such as linear furrowing, concentric esophageal rings, diminished vascular pattern, white surface exudates and linear tears. In this case we recognize a unique endoscopic finding of an esophageal polyp in a young woman secondary to EoE. In review of the literature, this rare finding has primarily been described in the pediatric population. This case should heighten awareness of an association between eosinophilic esophagitis and esophageal polyps.

Breast-feeding does not protect against allergic sensitization in early childhood and allergy-associated disease at age 7 years

Extended breast-feeding is recommended for newborn children at risk of allergy-associated diseases, but the evidence of a protective effect on sensitization and these diseases remains elusive. The aim of this study was to investigate the effects of the duration of exclusive breast-feeding on the development of sensitization in preschool children. Information on breast-feeding was gathered by interviews involving 335 children aged 1, 6, and 12 months from the Copenhagen Prospective Study on Asthma in Childhood2000 birth cohort born to mothers with a history of asthma. Skin prick test responses and specific IgE levels against 12 common inhalant and 10 food allergens were assessed longitudinally at ages ½ year, 1½ years, 4 years, and 6 years. Eczema, wheeze/asthma, and allergic rhinitis were diagnosed at the Copenhagen Prospective Studies on Asthma in Childhood clinic at 7 years of age, strictly adhering to predefined algorithms. Associations between duration of exclusive breast-feeding and outcomes were analyzed by logistic regression. We found no significant association between duration of exclusive breast-feeding and development of sensitization in the first 6 years of life (odds ratio [OR]: ½ year, 1.10 [95% CI, 0.90-1.36]; 1½ years, 1.15 [95% CI, 0.97-1.36]; 4 years, 1.08 [95% CI, 0.93-1.25]; and 6 years, 0.96 [95% CI, 0.84-1.10]) or with current eczema, wheeze/asthma, and allergic rhinitis at age 7 years (OR, 1.07 [95% CI, 0.92-1.24]; OR, 0.97 [95% CI, 0.82-1.14]; and OR, 1.02 [95% CI, 0.84-1.23], respectively). Adjusting for reverse causation by excluding children with eczema, wheeze, or a positive skin prick test response before ending exclusive breast-feeding did not alter the results. Exclusive breast-feeding does not affect sensitization in early childhood or associated diseases at 7 years of age in at-risk children.

Allergy in Extremis

Allergy-associated diseases have a multitude of confirmed or suspected etiologies and associations affecting organs and organ systems. The hyper-reactivity of the immune system in which the eosinophils are prominent plays a central role in organ-specific and systemic effects in these diseases. Patients may be plagued with nonspecific, episodic, or progressive signs and symptoms. Patients may also exhibit signs and symptoms that mimic more common conditions. Recognition of certain patterns of clinical signs and symptoms may lead to definitive clinical diagnosis and effective treatment, particularly of less common but potentially lethal disease entities. The lack of clinical recognition of these patterns, whether due to "red herring" historical information, lack of sign/symptom specificity, clinical presentation at early stage, or unfamiliarity with the constellation of disease presentation, may delay or preclude diagnosis and treatment. The forensic pathologist must also have an awareness of varied clinical presentations of diseases because these can provide us with direction toward the ultimate determination of cause and manner of death.The importance and contribution of the practice of forensic pathology are highlighted in the instance of sudden and unexpected death, whereby the previously unrecognized or unconfirmed disease entity that leads to the death is revealed via analysis of scene information, autopsy performance, and review of medical history and history of the most recent illness. Through this comprehensive approach, a greater understanding of the extent and potential lethality of disease with reiteration of the importance of early clinical diagnosis and treatment is reinforced. This benefits the medical community involved in diagnosis and treatment, clinicians and pathologists alike, with the ultimate goal of reduction of morbidity and mortality.Reported is a case of sudden unexpected death with historical, gross, and microscopic findings consistent with a multisystem, inflammatory, allergic disease entity.

282: TSLP-elicited basophil responses mediate the pathogenesis of eosinophilic esophagitis

Eosinophilic esophagitis (EoE) is a food allergy-associated disease characterized by esophageal eosinophilia and associated inflammation. EoE has become increasingly common in industrialized countries. However, current management strategies, such as treatment with swallowed steroids and dietary restrictions, are nonspecific or negatively impact the quality of life of EoE patients. In addition, use of more specific therapies that target immunoglobulin E (IgE) and interleukin (IL)-5 have been largely unsuccessful in ameliorating EoE. Thus, there is an urgent need to identify novel, specific immunological pathways that underlie the pathogenesis of EoE that could be targeted to treat this disease. Recently, a genome-wide association study identified that EoE is associated with a gain-of-function polymorphism in the gene that encodes thymic stromal lymphopoietin (TSLP). TSLP is an IL-7 family member cytokine that promotes allergic inflammation by eliciting T helper type 2 cytokine responses, IgE production, and the expansion of a distinct population of basophils. However, whether TSLP directly promotes allergic inflammation in the esophagus and the mechanisms by which TSLP might contribute to the pathogenesis of EoE remain unknown. Here, we describe a new murine model of experimental EoE-like disease that was used to investigate the role of TSLP in allergic inflammation of the esophagus. Murine experimental EoE-like disease developed independently of IgE but was dependent on TSLP-elicited basophils. Critically, therapeutic antibody-mediated neutralization of TSLP or depletion of basophil populations ameliorated established EoE-like disease in mice. Finally, elevated TSLP levels and exaggerated basophil responses were observed in esophageal biopsies from EoE patients, and a gain-of-function polymorphism in TSLP correlated with increased basophil responses in patients with EoE. Together, these data indicate that TSLP-elicited basophil responses may play a key role in mediating the pathogenesis of EoE, suggesting that targeting the TSLP-basophil axis could represent a new and promising therapeutic target in the treatment of EoE.

Studies on Early Allergic Sensitization in the Lithuanian Birth Cohort

Cohort studies are of great importance in defining the mechanism responsible for the development of allergy-associated diseases, such as atopic dermatitis, allergic asthma, and allergic rhinoconjunctivitis. Although these disorders share genetic and environmental risk factors, it is still under debate whether they are linked or develop sequentially along an atopic pathway. The current study was aimed to determine the pattern of allergy sensitization in the Lithuanian birth cohort “Alergemol” (n = 1558) established as a part of the multicenter European birth cohort “EuroPrevall”. Early sensitization to food allergens in the “Alergemol” birth cohort was analysed. The analysis revealed 1.3% and 2.8% of symptomatic-sensitized subjects at 6 and 12 months of age, respectively. The sensitization pattern in response to different allergens in the group of infants with food allergy symptoms was studied using allergological methods in vivo and in vitro. The impact of maternal and environmental risk factors on the early development of food allergy in at 6 and 12 months of age was evaluated. Our data showed that maternal diet, diseases, the use of antibiotics, and tobacco smoke during pregnancy had no significant impact on the early sensitization to food allergens. However, infants of atopic mothers were significantly more often sensitized to egg as compared to the infants of nonatopic mothers.

C-Fos as a regulator of degranulation and cytokine production in FcepsilonRI-activated mast cells.

The AP-1 complex is composed of c-Jun and c-Fos and is a key component in the regulation of proinflammatory genes. Mast cells play a significant role in the initiation of many inflammatory responses, such as allergy and allergy-associated diseases. In the present work, we characterized the role of c-Fos in mast cell function by investigating IL-3-dependent cell proliferation, degranulation capability, and cytokine expression in c-Fos-deficient mice. In c-Fos-deficient mast cells, we found that FcepsilonRI-mediated degranulation was significantly inhibited, which correlates with the reduced expression of SWAP-70, VAMP-7, and Synaptotagmin I genes, which are involved directly in the degranulation process. These findings show that c-Fos plays an important role in FcepsilonRI-mediated regulation of mast cell function.

Latex allergy in the workplace.

While less than 1% of the general population is sensitized to latex, the U.S. Occupational Safety and Health Administration estimates that 8-12% of health-care workers are sensitized. The major source of workplace exposure is powdered natural rubber latex (NRL) gloves. NRL is harvested from HEVEA: brasiliensis trees and ammoniated to prevent coagulation resulting in the hydrolysis of the latex proteins. Prior to use in manufacturing, the latex is formulated by the addition of multiple chemicals. Thus, human exposure is to a mixture of residual chemicals and hydrolyzed latex peptides. Clinical manifestations include irritant contact dermatitis, allergic contact dermatitis (type IV), and type I immediate hypersensitivity response. Type I (IgE-mediated) NRL allergy includes contact urticaria, systemic urticaria, angioedema, rhinitis, conjunctivitis, bronchospasm, and anaphylaxis. Taking an accurate history, including questions on atopic status, food allergy, and possible reactions to latex devices makes diagnosis of type-I latex allergy possible. To confirm a diagnosis, either in vivo skin prick testing (SPT) or in vitro assays for latex-specific IgE are performed. While the SPT is regarded as a primary confirmatory test for IgE-mediated disease, the absence of a U.S. Food and Drug Administration-licensed HEVEA: brasiliensis latex extract has restricted its use in diagnosis. Serological tests have, therefore, become critically important as alternative diagnostic tests. Three manufacturers currently have FDA clearance for in vitro tests, to detect NRL-specific IgE. The commercially available assays may disagree on the antibody status of an individual serum, which may be due to the assay's detecting anti-NRL IgEs to different allergenic NRL proteins. Sensitized individuals produce specific IgE antibody to at least 10 potent HEVEA: allergens, Hev b 1-Hev b 10, each of which differs in its structure, size, and net charge. The relative content and ratios of Hevs in the final allergen preparation most probably could effect diagnostic accuracy. The Hev proteins have been cloned and expressed as recombinant proteins. Sequencing demonstrates both unique epitopes and sequences commonly found in other plant proteins. Sequence homology helps to explain the cross reactivity to a variety of foods experienced by latex allergic individuals. The development of recombinant allergens provides reagents that should improve the diagnostic accuracy of tests for latex allergy. Although clinical and exposure data have been gathered on the factors affecting response in latex-allergic individuals, less is known regarding the development of sensitization. Coupled with in vitro dermal penetration studies, murine models have been established to investigate the route of exposure in the development of latex sensitization. Time-course and dose-response studies have shown subcutaneous, intratracheal, or topical administrations of non-ammoniated latex proteins to induce IgE production. Both in vitro penetration and in vivo studies highlight the importance of skin condition in the development of latex allergy, with enhanced penetration and earlier onset of IgE production seen with experimentally abraded skin. The diagnosis of latex allergy is complicated by these variables, which in turn hinder the development of intervention strategies. Further epidemiological assessment is needed to more explicitly define the scope, trends, and demographics of latex allergy. Diagnostic accuracy can be improved through greater knowledge of proteins involved in the development of latex allergy, and better documentation of the presently available diagnostic tests. In vivo and in vitro models can elucidate mechanisms of sensitization and provide an understanding of the role of the exposure route in latex allergy-associated diseases. Together, these efforts can lead to intervention strategies for reducing latex allergy in the workplace.