Yes / In this commentary, we focus on allergy as a facilitating factor in the pathogenesis of alopecia areata (AA). From previous studies on AA, it is well known that subsets of patients can have one or more of; seasonal relapse, comorbid atopic rhinitis, asthma and dermatitis, lesion infiltrating eosinophils and plasma cells, high levels of total IgE, specific IgE for house dust mites (HDMs), and/or disrupted skin barrier function by the evaluation of filaggrin. Allergy and AA share a similar genetic background; both contributing to an immune reaction imbalance. Furthermore, adjunctive treatment with antihistamines, or desensitization for HDM, can reduce the severity of alopecia in atopic AA patients. Therefore, allergies may contribute to the onset and relapse of AA. Identification of an allergic or atopic immune component in AA patient subsets may indicate adjunctive treatment intervention measures against allergies should be taken which may improve the success of conventional AA treatment.

Asthma is the most common chronic respiratory disease affecting young children and adults all over the world. An estimated 34.1 million Americans have reported asthma in their lifetime and the disease costs ~US $56 billion dollars to treat each year. Current treatment is based on a paradigm of asthma as a non-infectious atopic condition whose root cause is inflammation. Chronically administered anti-inflammatory medications, primarily inhaled corticosteroids (ICS), ameliorate asthma symptoms in many patients. However, up to 50% of asthmatics, characterized by neutrophil infiltration, IL-17 secretion and increased risk of fatality are refractory to ICS treatment. Chlamydia pneumoniae, a ubiquitous, obligate intracellular pathogen with an innate propensity to persist and cause chronic infections, along with Mycoplasma pneumoniae have been implicated in the development of chronic, refractory asthma. C. pneumoniae infections are common in infants and young children, often coinciding with the development of early onset asthma in the population. These facts lead the Webley lab to evaluate the carriage of Chlamydia in pediatric respiratory disease patients and the work confirmed that respiratory infections caused by Chlamydia is a significant risk factor in asthma development and live Chlamydia was isolated from the lungs of children with chronic asthma. However, the exact mechanism underlying chlamydial involvement in the disease remained unknown and we believed that a better understanding could shed important light on expanded treatment options and mechanisms of this infectious asthma phenotype. The work presented here provides new insight into how (1) early life chlamydial infection can lead to asthma initiation and exacerbation (2) respiratory chlamydial infection induces cellular and chemical immune responses that support asthmatic inflammation (3) other respiratory pathogens (eg. Mycoplasma) can drive similar immunological responses resulting in significant lung pathology.

Atopic asthma is a complex disease process that has a significant social, personal and economic burden across all ages. Leukotriene-receptors are involved in the cascade of inflammation that may result in symptoms of atopy and asthma. Two leukotriene receptors have been identified in the lung. The cysteinyl leukotriene receptor 1 and cysteinyl leukotriene receptor 2 genes (i.e., CYSLTR1 and CYSLTR2) have been sequenced, and a number of single nucleotide polymorphisms (SNPs) within these genes have been identified.The purpose of this study was to: (1) Determine the relationship between CYSLTR1 genotypes, CYSLTR2 genotype, atopy, elevated IgE level, and eosinophilia, (2) Determine the relationship between CYSLTR1 genotypes, CYSLTR2 genotype, asthma, and atopic asthma, and (3) Determine the degree of interaction between CYSLTR2 genetic variation and gender in atopic asthma.Nested within two sub-studies of the Tucson Epidemiological Study of Airway Obstructive Disease (TESAOD) study, a prospective longitudinal cohort, 853 individuals were entered into this study. Study criteria included Non-Hispanic white adults, who consented to genetic testing in the two sub-studies. Tagging SNPs of the CYSLTR1 and CYSLTR2 genes were genotyped. Serum IgE status and eosinophilia were obtained from existing dataset. Questionnaires collected in the parent study were used to obtain demographic and clinical data.SNP rs321006 in the CYSLTR1 gene was associated with atopy among Non-Hispanic white women. Assuming a recessive model, among female Non-Hispanic white adults, the odds of having rs321073 CC genotype was 5.82 times higher among those with atopic asthma than those without atopic asthma. No gene by gender interaction was found between SNP of interest in CYSLTR2 and atopic asthma. Genetic association of SNPs rs321006 with atopy and rs321073 with atopic asthma are novel findings to date.Implications for nurses, clinicians, and scientists include better understanding of associations of these genetic variations with asthma, atopy, and atopic asthma that can generate further inquiry into other mechanisms of atopic asthma. These novel genetic associations with atopy and atopic asthma may have the potential for personalized medicine that might afford patients with appropriate treatment based on their genotype.

No description available.

共著者あり。共著者名:Hizawa Nobuyuki, Yamaguchi Etsuro, Jinushi Eisei, Nishimura Masaharu. / Hokkaido University (北海道大学) / 博士 / 医学

Atopic asthma is characterized by excessive T helper 2 (Th2)-like immunity to allergens in the bronchial mucosa. The Th2-cytokine interleukin (IL)-4 induces IgE production, while the Th2-cytokine IL-5 promotes eosinophilic inflammation in the airways of asthmatics. Most asthmatics are atopic, but a subgroup is non-atopic. We hypothesize that allergen-induced Th2, particularly IL-5, responses can be observed in peripheral blood in both atopic and non-atopic asthmatic children but not in healthy control children. The aim of the present study was to determine IL-4, IL-5, IL-9, IL-10, IL-13 and IFN-γ secretion induced from peripheral blood mononuclear cells (PBMC) by a broad panel of inhalant allergens (timothy, cat, birch, dog and house dust mite) in asthmatic children with and without sensitization. The study included 13 atopic asthmatic, 5 non-atopic asthmatic, and 12 non-atopic non-asthmatic children. PBMC were stimulated with allergens and cytokine production was measured with enzyme-linked immunosorbent assay (ELISA). Higher levels of cat and dog antigen-induced IL-5 release were more commonly observed in both atopic and non-atopic asthmatics than in controls. Children with atopic, but not non-atopic, asthma produced higher levels of allergen-induced IL-4 and IL-9 than controls. Non-atopic asthmatics produced more IL-10 than atopic asthmatics after cat stimulation. High levels of eosinophilia-associated IL-5 responses are induced by cat and dog allergen in both atopic and non-atopic asthmatic children. The Th2 cytokines IL-4 and IL-9 were associated only with atopic asthma, probably due to their IgE-inducing properties.

Allergic disease encompasses multiple complex syndromes including hayfever, food allergies, eczema and asthma. Atopy is the genetic predisposition towards an IgE-driven immune response in reaction to environmental stimuli, and often serves as a predictor for the development of allergies in the future. While disease etiology is not yet fully understood, many factors including genetics and the environment play a role in the development of allergic disease. Reliable methods for predicting atopic disease development are crucial in emerging therapeutic approaches, which aim to decrease allergic disease severity and clinical progression through early detection and preventative measures. While DCs are emerging as key players in the development of allergic disease, they are challenging to study in vivo due to their low numbers, and ex vivo methods remain relatively unstudied. In this project, receptor expression profiles of atopic-at-risk infants compared to not-atrisk infants were examined in DCs found in cord-blood at birth and CD34+-derived DCs cultured ex vivo. Atopic-at-risks exhibited a higher percentage of ex vivo pDCs expressing TSLPR when compared to not-at-risks. Additionally, an increase of FcεRI expression in atopic-at-risks was found approaching significance in in vivo mDCs. Furthermore, DC differentiation in culture from hematopoietic progenitors and the differences between in vivo and ex vivo DCs were studied. Results indicated a consistent 10-fold increase in the DC population after a 12-day culture compared to cord blood DC numbers. Additionally, a distinct DC population emerged as early as Day 3 with a substantial increase in the percentage of mDCs relative to pDCs. A trend of increased TSLP, CD80, CD86 receptor expression and decreased TLR-5, ST2, FcεRI receptor expression after culture in both mDCs and pDCs was also noted. / Thesis / Master of Science (MSc) / Allergic disease development typically begins in infancy, progressing classically in a series of stages from early life through adulthood. Currently, there is a lack of reliable predictive tests for the development of atopic sensitization and disease. This has slowed efforts to intercept and prevent allergy development at its earliest stages. Dendritic cells (DCs) link innate and adaptive immunity and are thought to be key players in the development of allergic disease. However, the low numbers of DCs in blood make them challenging to study. Methods such as inducing the differentiation of DCs from progenitors are often utilized to obtain a sufficient number of cells. This project investigates whether receptor expression of cord blood-derived DCs grown ex vivo are comparable to the profiles of in vivo DCs at birth. Furthermore, the expression of key receptors on DCs grown in vivo/ex vivo are compared in atopic at-risk, not-at-risk infants.

<p>Background: The reasons why some individuals become IgE-sensitised and allergic are largely unknown, though genetic- and early life environmental factors seem to be of importance.</p><p>Objective: The overall aim of this thesis was to investigate the relationship between IgE-sensitisation and allergic disease, viral infections, genetic markers and early life cytokines.</p><p>Results: IgE-sensitised children were found to have reduced numbers of IL-12 producing cord blood mononuclear cells (CBMC), whereas children diagnosed with eczema were found to have reduced numbers of IFN-γ producing CBMC. When dividing the children into early onset of IgE-sensitisation and late onset of IgE-sensitisation we found that the children with an early onset had low numbers of PHA-induced IL-4, IL-12 and IFN-γ secreting CBMC. At the age of two there was a general exacerbation of cytokine responses in the IgE-sensitised children, and the results were similar for the children with early onset IgE-sensitisation. Children with a late onset IgE-sensitisation were more similar to the non-sensitised children, but with a specific increase in the response to cat allergen (IL-4 and IFN-γ). The mothers of IgE-sensitised children, were just as their children, found to have an exaggerated cytokine response as compared to mothers of non-sensitised children. Maternal responses correlated well to the responses seen in the child, though the samples were taken two years after delivery.</p><p>Cytomegalovirus (CMV) infection in early life was associated to reduced numbers of IL-4, and increased numbers of IFN-γ producing cells at the age of two. No association between CMV seropositivity and IgE-sensitisation was seen. Epstein-Barr virus (EBV) infection, on the other hand, was inversely correlated with IgE –sensitisation, whereas no statistically significant association to cytokine production could be seen.</p><p>We also showed that the IL12B 1188 C-allele was associated to having a positive skin prick test at the age of two. The rare alleles of the three SNPs investigated (IL12B 1188C, IL12RB1132C and IRF1 1688A) were all associated to low IL-12 production at birth.</p><p>Conclusions: Our results indicate that allergic diseases are complex traits, and that both the genetic and the cytokine background differ between the different allergic diseases. We can also conclude that the time of onset seem to play a role when investigating IgE-sensitisation, and that perhaps early and late onset IgE-sensitisation have partly different causes. CMV and EBV infection early in life are associated to a protective cytokine profile and to protection from IgE-sensitisation, respectively, again indicating the heterogeneity and the complexity of allergic diseases.</p>

Mast cells are potent effectors of the inflammatory response, playing an important role in atopy, bacterial immunity, and animal models of arthritis, multiple sclerosis, and heart disease. Hence controlling mast cell numbers and responsiveness is essential for preventing inflammatory disease. This work demonstrated that the cytokine TGF-β1 is a potent inducer of mast cell apoptosis, a finding that was consistent for cultured mouse bone marrow-derived mast cells, peritoneal mast cells, and human mast cells. Cell death appeared to be the result of TGF-mediated repression of IL-3 receptor expression and function, leading to mitochondria1 damage and activation of an apoptotic cascade acting via p53 and caspases. While IL-3 receptor expression was reduced within one day of TGF-βl stimulation, apoptosis required at least 3 days to occur. This delay in onset is postulated to allow for protective mast cell effector functions, protecting the host from infection while preventing the establishment of chronic inflammation. These studies support the theory that TGF- β1 is an inhibitor of mast cell survival. Because of the widespread expression of TGF-β1, this cytokine may be an ideal candidate for control of mast cell homeostasis.

Background: The reasons why some individuals become IgE-sensitised and allergic are largely unknown, though genetic- and early life environmental factors seem to be of importance. Objective: The overall aim of this thesis was to investigate the relationship between IgE-sensitisation and allergic disease, viral infections, genetic markers and early life cytokines. Results: IgE-sensitised children were found to have reduced numbers of IL-12 producing cord blood mononuclear cells (CBMC), whereas children diagnosed with eczema were found to have reduced numbers of IFN-γ producing CBMC. When dividing the children into early onset of IgE-sensitisation and late onset of IgE-sensitisation we found that the children with an early onset had low numbers of PHA-induced IL-4, IL-12 and IFN-γ secreting CBMC. At the age of two there was a general exacerbation of cytokine responses in the IgE-sensitised children, and the results were similar for the children with early onset IgE-sensitisation. Children with a late onset IgE-sensitisation were more similar to the non-sensitised children, but with a specific increase in the response to cat allergen (IL-4 and IFN-γ). The mothers of IgE-sensitised children, were just as their children, found to have an exaggerated cytokine response as compared to mothers of non-sensitised children. Maternal responses correlated well to the responses seen in the child, though the samples were taken two years after delivery. Cytomegalovirus (CMV) infection in early life was associated to reduced numbers of IL-4, and increased numbers of IFN-γ producing cells at the age of two. No association between CMV seropositivity and IgE-sensitisation was seen. Epstein-Barr virus (EBV) infection, on the other hand, was inversely correlated with IgE –sensitisation, whereas no statistically significant association to cytokine production could be seen. We also showed that the IL12B 1188 C-allele was associated to having a positive skin prick test at the age of two. The rare alleles of the three SNPs investigated (IL12B 1188C, IL12RB1132C and IRF1 1688A) were all associated to low IL-12 production at birth. Conclusions: Our results indicate that allergic diseases are complex traits, and that both the genetic and the cytokine background differ between the different allergic diseases. We can also conclude that the time of onset seem to play a role when investigating IgE-sensitisation, and that perhaps early and late onset IgE-sensitisation have partly different causes. CMV and EBV infection early in life are associated to a protective cytokine profile and to protection from IgE-sensitisation, respectively, again indicating the heterogeneity and the complexity of allergic diseases.