Allergology International
Online ISSN : 1440-1592
Print ISSN : 1323-8930
ISSN-L : 1323-8930
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Showing 1-22 articles out of 22 articles from the selected issue
Editorial
Invited Review Articles
Review Series: Valuable Lessons from Analyses of Common Signs and Symptoms in Rare Diseases
  • Yoshiyuki Minegishi
    2021 Volume 70 Issue 4 Pages 407-414
    Published: 2021
    Released: October 13, 2021
    JOURNAL FREE ACCESS

    Clinically and pathologically, the patients with hyper-IgE syndrome present similar skin manifestations to common atopic dermatitis. The original hyper-IgE syndrome is characterized by diminished inflammatory response, in combination with Staphylococcus aureus skin abscess and pneumonia followed by pneumatocele formation. These immunological manifestations are frequently associated with skeletal and connective tissue abnormalities. We previously identified that major causal variants of the hyper-IgE syndrome are dominant negative variants in the STAT3.

    In addition to the identification of new causative variants for the disorders similar to the original hyper-IgE syndrome, causative variants for new types of hyper-IgE syndrome centered only on atopy, high serum IgE levels, and susceptibility to infection, but not associated with diminished inflammatory response, pneumatocele formation, and connective tissue manifestations, have been identified. Recent discovery identified a novel zinc finger protein that regulates STAT3 transcription. Investigation of IL6ST variants disclosed that IL6ST/IL6R cytokine receptor plays a crucial role for the signal transduction upstream of STAT3 in the pathogenesis of the original hyper-IgE syndrome. Even if the same IL6ST variants are used for the signal transduction of IL-6 family cytokines, the signaling defect is more severe in IL-6/IL-11 and milder in LIF. The fact that the non-immune manifestations of the gain-of-function mutations of TGFBR1 and TGFBR2 are similar to the those of dominant negative mutations of STAT3 provide a clue to elucidate molecular mechanisms of non-immune manifestations of hyper-IgE syndrome. Research on this hereditary atopic syndrome is being actively conducted to elucidate the molecular mechanisms and to develop new therapeutic approaches.

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  • Keisuke Okamoto, Tomohiro Morio
    2021 Volume 70 Issue 4 Pages 415-420
    Published: 2021
    Released: October 13, 2021
    JOURNAL FREE ACCESS

    Monogenic diseases of the immune system, also known as inborn errors of immunity (IEIs), are caused by single-gene mutations and result in immune deficiency and dysregulation. More than 400 monogenic diseases have been described to date, and this number is rapidly expanding. The increasing availability of next-generation sequencing is now facilitating the diagnosis of IEIs. It is known that IEIs can predispose a person to not only infectious diseases but also cancer and immune disorders, such as inflammatory, autoimmune, and atopic diseases. IEIs with eosinophilia and atopic diseases can occur in several disorders. IEIs with eosinophilia have provided insights into human immunity and the pathogenesis of allergic diseases. Eosinophilia is not a rare finding in clinical practice, and it often poses problems in terms of etiologic research and differential diagnoses. Secondary eosinophilia is the most common form. The main underlying conditions are infectious diseases such as parasitic infections, allergic disorders, drug reactions, and of course IEIs. In clinical settings, the recognition of IEIs in the context of an allergic phenotype with eosinophilia is critical for prompt diagnosis and appropriate treatment aimed at modulating pathophysiological mechanisms and improving clinical symptoms.

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  • Kiyofumi Yamanishi, Yasutomo Imai
    2021 Volume 70 Issue 4 Pages 421-429
    Published: 2021
    Released: October 13, 2021
    JOURNAL FREE ACCESS

    Unlike other barrier epithelia of internal organs, the stratified squamous epithelium of the skin is always exposed to the external environment. However, the robust barrier structure and function of the skin are highly resistant against external insults so as to not easily allow foreign invasions. Upon sensing danger signals, the innate immunity system is promptly activated. This process is mediated by alarmins, which are released passively from damaged cells. Nuclear alarmins or stressorins are actively released from intact cells in response to various cellular stresses. Alarmins/stressorins are deeply involved in the disease processes of chronic skin disorders of an unknown cause, such as rosacea, psoriasis, and atopic dermatitis. Furthermore, alarmins/stressorins are also induced in the congenital skin disorders of ichthyosis and keratoderma due to defective keratinization. Studies on alarmin activation and its downstream pathways may help develop novel therapeutic agents for intractable skin disorders.

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  • Masaki Yamada, Yuriko Ishikawa, Ken-Ichi Imadome
    2021 Volume 70 Issue 4 Pages 430-438
    Published: 2021
    Released: October 13, 2021
    JOURNAL FREE ACCESS
    Hypersensitivity to mosquito bites (HMB) is a rare disease characterized by transient intense skin reaction and systemic inflammation. Clinical presentation of HMB resembles other mosquito allergic responses, and it can also be difficult to clinically distinguish HMB from other severe allergic reactions. However, a distinctive pathophysiology underlies HMB.
    HMB belongs to a category of Epstein-Barr virus (EBV)-associated natural killer (NK) cell lymphoproliferative disorders (LPD). Hence, HMB may progress to systemic diseases, such as hemophagocytic lymphohistiocytosis, chronic active EBV disease, and EBV-associated malignancies.
    A triad of elevated serum IgE, NK lymphocytosis, and detection of EBV DNA in peripheral blood is commonly observed, and identification of EBV-infected NK cells usually facilitates the diagnosis. However, the effective treatment is limited, and its precise etiology remains unknown.
    Local CD4+ T cell proliferation triggered by mosquito bites appears to help induce EBV reactivation and EBV-infected NK-cell proliferation. These immunological interactions may explain the transient HMB signs and symptoms and the disease progression toward malignant LPD.
    Further research to elucidate the mechanism of HMB is warranted for better diagnosis and treatment of HMB and other forms of EBV-associated LPD.
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Original Articles
  • Tetsuro Fujino, Hideki Hasunuma, Masumi Okuda, Midori Saito, Takeshi U ...
    2021 Volume 70 Issue 4 Pages 439-444
    Published: 2021
    Released: October 13, 2021
    JOURNAL FREE ACCESS

    Background: Wheezing is a common symptom in infants, which may occasionally develop into asthma. There are many factors related to infant wheezing, including anatomical features, viral infections, and passive smoking. There are only a few reports on the association between renovation and pregnancy worldwide, and reports on this association are inadequate in Japan. This study aimed to examine the association between house renovation and new construction during pregnancy and wheezing in infants during the first year of life using data from the Japan Environment and Children's Study (JECS).

    Methods: Data of pregnant women registered in JECS were collected using self-administered questionnaires during the second/third trimester and 1 month after delivery. Childbirth records were completed by the doctors. Similarly, wheezing in infants was evaluated using self-administered questionnaires 1 year after birth. Logistic regression analysis was used to determine the primary outcome.

    Results: In total, 75,731 infants, excluding those with unknown gender, who were not singleton infants, and who relocated during pregnancy and the first month of life, were examined in this study. Renovation during pregnancy increased the prevalence of wheezing (odds ratio [OR]: 1.33, 95% confidence interval [CI]: 1.20-1.48) and recurrent wheezing (OR: 1.22, 95% CI: 1.00-1.48) in the first year of life. The relationship between new construction during pregnancy and wheezing in infants was insignificant (OR: 0.98, 95% CI: 0.90-1.06).

    Conclusions: Renovation during pregnancy may be a risk factor for wheezing in infants, and should be avoided.

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  • Takuya Wada, Yuichi Adachi, Shokei Murakami, Yasunori Ito, Toshiko Ita ...
    2021 Volume 70 Issue 4 Pages 445-451
    Published: 2021
    Released: October 13, 2021
    JOURNAL FREE ACCESS

    Background: Evidence regarding independent effects of maternal smoking in different time frames of pregnancy and maternal exposure to secondhand smoke on the development of wheeze/asthma in her offspring is limited. We aimed to investigate the effect of maternal exposure to tobacco smoke on wheeze/asthma development at 1 year of age in her offspring using data from the nationwide birth cohort study in Japan.

    Methods: Pregnant women who lived in the 15 designated regional centers throughout Japan were recruited. We obtained information about maternal smoking or secondhand smoke status and wheeze/asthma development in the offspring from a self-administered questionnaire.

    Results: We analyzed 90,210 singleton births. Current maternal smoking during pregnancy increased the risks of wheeze/asthma in the offspring compared with no maternal smoking (wheeze: 1-10 cigarettes/day: adjusted odds ratio (aOR) 1.436, 95% CI 1.270-1.624; ≧11 cigarettes/day: aOR 1.669, 95% CI 1.341-2.078; asthma: 1-10 cigarettes/day: aOR 1.389, 95% CI 1.087-1.774; ≧11 cigarettes/day: aOR 1.565, 95% CI 1.045-2.344). Daily maternal exposure to secondhand smoke during pregnancy also increased the risks of wheeze/asthma in her offspring compared with no secondhand smoke exposure (wheeze: aOR 1.166, 95% CI 1.083-1.256; asthma: aOR 1.258, 95% CI 1.075-1.473). The combination of current maternal smoking during pregnancy and maternal history of allergy increased the risks of wheeze/asthma in her offspring (wheeze: aOR 2.007, 95% CI 1.739-2.317; asthma: aOR 1.995, 95% CI 1.528-2.605).

    Conclusions: We found that current maternal smoking and maternal secondhand smoke exposure during pregnancy increased the risks of wheeze and asthma in her offspring.

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  • Katsumasa Kitamura, Tomoya Ito, Komei Ito
    2021 Volume 70 Issue 4 Pages 452-457
    Published: 2021
    Released: October 13, 2021
    JOURNAL FREE ACCESS
    Supplementary material
    Background: Since few studies have analyzed time trends in pediatric anaphylaxis, including triggers and adrenaline usage, this study aimed to reveal these issues in a comprehensive analysis of pediatric anaphylaxis cases.
    Methods: The Aichi Medical Association performed a comprehensive survey of pediatric anaphylaxis cases aged under 15 years from 87 secondary and 25 tertiary emergency care hospitals in Aichi Prefecture (population 7.5 million), Japan.
    Results: Between April 2016 and March 2020, 3423 cases of anaphylaxis were identified. Food items were the most frequent trigger (73%), followed by exercise after food ingestion (4.3%), and drugs (2.2%). Egg (19%) and milk (17%) specifically were the most frequent among food triggers, while the largest proportional increase was observed in tree nuts from 6.0% in 2017 to 15% in 2019. Overall, 1647 (48%) cases were admitted to the hospital, of which 26 (0.8%) were admitted to the intensive care unit. Drug-induced anaphylaxis was associated with the highest admission rate (71%). Of the 2493 food-induced anaphylaxis cases, 1107 (44%) were treated with adrenaline. Among them, 343 cases included previously prescribed adrenaline auto-injectors (AAI), with 225 (66%) usages prior to hospital arrival. There was no significant difference in the admission rate between the cases in which AAIs were used and those with adrenaline administered in the hospital (68% and 72%, respectively).
    Conclusions: The proportion of tree nuts in food-induced anaphylaxis increased significantly. Although prehospital AAI use has become widespread, it was not associated with lower admission rate compared to in-hospital adrenaline usage.
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  • Mai Matsumoto, Motoi Takenaka, Kiyoshi Aoyagi, Yoshihito Tomita, Kazuh ...
    2021 Volume 70 Issue 4 Pages 458-462
    Published: 2021
    Released: October 13, 2021
    JOURNAL FREE ACCESS
    Supplementary material

    Background: Oral allergy syndrome (OAS) is an IgE-mediated food allergy. Ingestion of causative antigens leads to the development of local symptoms such as numbness of the oral mucosa in most cases and anaphylaxis in a few cases. The prevalence of OAS including in healthy people has not been investigated. Thus, we conducted a questionnaire survey of Japanese university students.

    Methods: We conducted a cross-sectional study of 2688 first-year students using a questionnaire survey in marksheet format and examined the epidemiological characteristics of OAS.

    Results: Only 2.7% of students were aware of the term “oral allergy syndrome”. A total of 143 (5.3%) students had OAS. There were significant associations between OAS and other allergic diseases including allergic rhinitis (AR) (OR: 3.8, 95% CI: 2.7–5.5), atopic dermatitis (AD) (OR: 4.6, 95%CI: 3.3–6.6), and bronchial asthma (BA) (OR: 3.0, 95%CI: 2.0–4.5). The onset age of OAS showed bimodal peaks at 0 and 10 years, and the latter peak coincided with the peak onset age of AR.

    Conclusions: Awareness of OAS was low in our study, which will make it difficult to treat properly and prevent its development. This survey confirmed the association between OAS and other allergic diseases, especially AR, which suggests that OAS is involved in the allergic march. A novel finding was that sensitization to antigens for OAS occurred around the same time as sensitization to antigens for AR. These results will help medical professionals diagnose OAS and develop lifestyle guidelines to prevent OAS-related symptoms such as anaphylaxis.

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  • Sina M. Erhard, Johanna Bellach, Songül Yürek, Sebastian Tschirner, Va ...
    2021 Volume 70 Issue 4 Pages 463-470
    Published: 2021
    Released: October 13, 2021
    JOURNAL FREE ACCESS
    Supplementary material
    Background: Primary hazelnut allergy is a common cause of anaphylaxis in children, as compared to birch-pollen associated hazelnut allergy. Population-based data on hazelnut and concomitant birch-pollen allergy in children are lacking. We aimed to investigate the prevalence of primary and pollen-associated hazelnut allergy and sensitization profiles in school-aged children in Berlin, Germany.
    Methods: 1570 newborn children were recruited in Berlin in 2005-2009. The school-age follow-up (2014-2017) was based on a standardized web-based parental questionnaire and clinical evaluation by a physician including skin prick tests, allergen specific immunoglobulin E serum tests and placebo-controlled double-blind oral food challenges, if indicated.
    Results: 1004 children (63.9% response) participated in the school-age follow-up assessment (52.1% male). For 1.9% (n = 19, 95%-confidence interval 1.1%-2.9%) of children their parents reported hazelnut-allergic symptoms, for half of these to roasted hazelnut indicating primary hazelnut allergy. Symptoms of birch-pollen allergy were reported for 11.6% (n = 116 95%-CI 9.7%-13.7%) of the children. Both birch-pollen allergy and hazelnut allergy associated symptoms affected 0.6% (n = 6, 95%-CI 0.2%-1.3%) of children. Assessment of allergic sensitization was performed in 261 participants and showed that almost 20% of these children were sensitized to hazelnut, being the most frequent of all assessed food allergens, or birch-pollen, the majority to both.
    Conclusions: Based on parental reports hazelnut-allergic symptoms were far less common than sensitization to hazelnut. This needs to be considered by physicians to avoid unnecessary changes in diet due to sensitization profiles only, especially when there is a co-sensitization to hazelnut and birch-pollen.
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  • Satoshi Morioke, Shunsuke Takahagi, Reo Kawano, Atsushi Fukunaga, Susu ...
    2021 Volume 70 Issue 4 Pages 471-479
    Published: 2021
    Released: October 13, 2021
    JOURNAL FREE ACCESS
    Supplementary material

    Background: Recurrent angioedema (RecAE) has a substantial impact on patients’ daily lives. However, there have been no disease-specific patient-reported outcomes (PROs) available in Japan to measure disease activity and health-related QoL impairment in such patients.

    Methods: Japanese versions of the Angioedema Activity Score (AAS) and the Angioedema Quality of Life Questionnaire (AE-QoL) were examined for their validity and reliability. By using these questionnaires, the relationship between disease activity and QoL impairment among the Japanese population of RecAE were analyzed in real-world setting.

    Results: The Japanese AAS and AE-QoL domains showed good internal consistency of 0.967 and > 0.835. For known group validity, AAS28 and AE-QoL total scores were higher in more severe patients than those with milder disease and QoL impairment, respectively. AAS28 showed strong correlation with indexes of disease activity, while the AE-QoL total score correlated with Dermatology Life Quality Index (DLQI). Sufficient reproductivity of the AAS and AE-QoL was shown by their intraclass correlation coefficients of 0.890 and 0.700. The Japanese population is characterized by the total score of AAS28, 34.3 ± 38.8 (mean ± SD); and AE-QoL, 38.7 ± 25.2. Each domain score of AE-QoL was 32.4 ± 29.7 in “Functioning”, 35.0 ± 27.8 in “Fatigue/mood”, 50.7 ± 30.6 in “Fears/shame”, or 24.7 ± 29.8 in “Food”. Changes in AAS28 and AE-QoL positively correlated to Patient global assessment of disease activity and DLQI, respectively.

    Conclusions: The Japanese AAS and AE-QoL are valid and reliable instruments for Japanese patients with RecAE, and active disease affecting QoL. They help assess disease activity and QoL of RecAE in routine patient care and clinical trials.

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  • Nobuyuki Nishimori, Shota Toyoshima, Tomomi Sasaki-Sakamoto, Koremasa ...
    2021 Volume 70 Issue 4 Pages 480-488
    Published: 2021
    Released: October 13, 2021
    JOURNAL FREE ACCESS
    Supplementary material

    Background: We previously reported upregulation of expression of Mas-related G protein-coupled receptor X2 (MRGPRX2) on mast cells (MCs) in the skin of patients with severe chronic spontaneous urticaria (CSU). Serum levels of substance P (SP) were reportedly significantly elevated, in correlation with the severity of CSU. Hemokinin-1 (HK-1) reportedly induced histamine release from LAD2 cells via MRGPRX2. We aimed to investigate HK-1's role in CSU.

    Methods: The concentrations of HK-1 and SP were measured using ELISAs. Skin- and synovium-derived cultured MCs were generated by culturing dispersed skin and synovial cells, respectively, with stem cell factor. MRGPRX2 expression in the MCs was reduced using a lentiviral shRNA silencing technique.

    Results: Anti-SP Ab used in the SP ELISA showed 100% cross-reactivity to HK-1, but anti-HK-1 Ab showed 0% cross-reactivity to SP. The serum level of HK-1 was significantly lower in patients with CSU (n = 151) than in non-atopic healthy control (NC) subjects (n = 114). The EC50 of histamine release from MCs induced by HK-1 (5056 nM) was 12-fold higher than by SP (426 nM). Brief pretreatment of MCs with HK-1 at concentrations of 3.0-10 μM significantly reduced histamine release by 0.1 μM SP. However, brief incubation of MCs with HK-1 did not elicit rapid MRGPRX2 internalization.

    Conclusions: In NC subjects, high HK-1 concentrations may desensitize MGRPRX2-mediated MC activation, thereby preventing MC degranulation by SP.

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