こどもの食物アレルギーの予防と治療

The risk of allergic symptoms by accidental ingestion as well as the influence on physical development and consequent reduced quality of life due to elimination diets are challenges associated with food allergies. Children with infantile-onset food allergies are at a high risk of developing subsequent asthma and allergic rhinitis. Therefore, research interest in prevention and early remission of food allergies has recently gained traction. The “dual-allergen-exposure hypothesis” was advocated by Lack in ２００８, and the hypothesis highlights percutaneous sensitization and oral tolerance for pathogenesis of food allergy as promising research strategies. Recently, some studies have focused on the prevention or early tolerance induction of food allergies. In addition, previous research has shown that atopic dermatitis can be prevented by using moisturizer in the neonatal stage of high-risk children. However, there is no evidence to suggest that skin care alone can prevent the onset of food allergies. Meanwhile, aggressive eczema treatment and early consumption of eggs has been shown to have a preventive effect on egg allergy in high-risk infants. However, further research is needed in the area of prevention of food allergy from the viewpoint of oral tolerance, including investigation of different foods, determining the appropriate time of ingestion, the amount of food to be ingested, antigenicity, and frequency of ingestion. Previous works report that even if food allergy does develop, the ingestion of causative food below the allergy-symptom threshold may be useful for early tolerance induction. Oral immunotherapy has also been reported to be effective in children with severe food allergy. Therefore, we hope that future studies will improve our knowledge to overcome problems associated with food allergies, for safe and effective prevention and treatment of food allergy in children

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修士論文要

Pediatric eosinophilic gastroenteritis

Eosinophilic gastrointestinal disorders are chronic inflammatory diseases in which eosinophils highly infiltrate into gastrointestinal tissue, resulting in gastrointestinal dysfunction. Here, we report a case of pediatric eosinophilic gastroenteritis (EGE). A 7-year-old boy with multiple food allergies (cow milk, hen's egg, fish, shellfish, and chicken) was admitted to our hospital because of continuous abdominal pain and vomiting. His soy allergy had been diagnosed to have oral tolerance based on an oral food challenge at the age of 6 years. He was diagnosed with EGE based on biopsy findings showing eosinophilic infiltration (>20 eosinophils per high-power field) into the gastrointestinal mucosa. A diet eliminating soy, wheat, beef, pork, rice, and sesame in addition to the food that had already been eliminated and oral corticosteroids improved his symptoms and peripheral eosinophilia. A relapse of both abdominal pain and peripheral eosinophilia after the reintroduction of soy or pork identified them as foods causative of EGE. This report highlights the utility of elimination diets in improving EGE symptoms and the subsequent reintroduction of offending foods in identifying causative foods. Furthermore, EGE onset should be considered when introducing potentially allergic food in the management of food allergy

Sensitization to secretoglobin and lipocalins in a group of young children with risk of developing respiratory allergy

Background: Multiple sensitizations in early age have been reported to be a risk for development of asthma. This study evaluates the emergence and evolution of IgE to aeroallergens among a cohort of children with physician-diagnosed atopic dermatitis and/or showing food allergy symptoms and to examine the relation to asthma development. Methods: Three-hundred and four children (median age 13.4 months at entry) with food allergy symptoms and/or atopic dermatitis without asthma at inclusion were analysed for IgE antibodies against food-, indoor- and outdoor-allergens and pet allergen components and correlated to the individuals’ outcome on asthma inception. Results: At 2 years of follow-up, physician-diagnosed asthma was 19.7% (n = 49) and asthma diagnosed any time was 24% (n = 67). History of persistent cough and asthma of father, combination of milk- and wheat-allergy symptoms and dual sensitization to house dust mite and Japanese cedar were independent risk factors for asthma. Sensitization to dog was the most prevalent inhalant allergen at entry. Asthma children had a higher proportion of sensitization to dog, cat and horse allergens at entry compared with non-asthma children. Being sensitized to both food, house dust mite and pet allergens was strongly associated with asthma (p = 0.0006). Component resolved diagnosis for dog and cat allergens showed that IgE antibodies to Can f 1 and Fel d 1 was common even at very young age. Conclusions: Early sensitization to inhalant allergens increases the risk of developing asthma as well as having milk and wheat allergy symptoms. Sensitization to dog, was common at an early age despite dog ownership. Sensitization to secretoglobin and lipocalins and less to serum albumins explained the pet sensitization

A unique B2 B cell subset in the intestine

Over 80% of the body's activated B cells are located in mucosal sites, including the intestine. The intestine contains IgM+ B cells, but these cells have not been characterized phenotypically or in terms of their developmental origins. We describe a previously unidentified and unique subset of immunoglobulin M+ B cells that present with an AA4.1−CD21−CD23− major histocompatibility complex class IIbright surface phenotype and are characterized by a low frequency of somatic hypermutation and the potential ability to produce interleukin-12p70. This B cell subset resides within the normal mucosa of the large intestine and expands in response to inflammation. Some of these intestinal B cells originate from the AA4.1+ immature B2 cell pool in the steady state and are also recruited from the recirculating naive B cell pool in the context of intestinal inflammation. They develop in an antigen-independent and BAFF-dependent manner in the absence of T cell help. Expansion of these cells can be induced in the absence of the spleen and gut-associated lymphoid tissues. These results describe the existence of an alternative pathway of B cell maturation in the periphery that gives rise to a tissue-specific B cell subset

Is oral food challenge useful to avoid complete elimination in Japanese patients diagnosed with or suspected of having IgE-dependent hen's egg allergy? A systematic review

Background: IgE-mediated egg allergy is a common food allergy worldwide. Patients with egg allergy are known to easily achieve tolerance compared to other allergens such as nuts. Oral food challenge (OFC) is often performed on patients diagnosed with or suspected of having IgE-mediated food allergy, but whether hen's egg OFC is useful in IgE-dependent egg allergy patients to avoid complete elimination remains unknown. Methods: We identified articles in which OFCs were performed in Japanese patients diagnosed with or suspected of having IgE-mediated egg allergy. We evaluated whether the OFCs were useful to avoid the complete elimination of eggs by assessing the following: (1) the number of patients who could avoid complete elimination; (2) the number of patients who experienced serious adverse events (SAEs); or (3) adverse events (AEs); (4) improvement in quality of life (QOL); and (5) immunological changes. Results: Fifty-nine articles were selected in the study; all the references were case series or case studies in which OFC was compared to pre-challenge conditions. The overall negative ratio against egg OFC was 62.7%, but an additional 71.9% of OFC-positive patients could take eggs when expanded to partial elimination. Of the 4182 cases, 1146 showed AEs in the OFC, and two cases reached an SAE. Two reports showed an improvement in QOL and immunological changes, although the evidence was weak. Conclusions: OFCs against eggs may be useful to avoid complete elimination, but medical professionals should proceed with the test safely and carefully

Anaphylactic shock due to latex allergy

Natural rubber latex (NRL) allergy is one of the most important causes of severe anaphylaxis during medical intervention. We report a pediatric case of latex allergy with multiple surgical histories. A 12-year-old girl developed anaphylactic shock during the pyeloplasty for ureteropelvic junction restenosis. Latex gloves or medications used during the surgery were suspected to be the cause of anaphylactic shock. We diagnosed her latex allergy on the basis of the results that serum latex-specific IgE, skin prick tests of extract from NRL gloves and recombinant Hev b 6.02 solution were positive. Basophil activation test of NRL gloves was also positive, supporting the diagnosis of immediate allergic reactions caused by NRL. It was speculated that a history of multiple surgeries in infancy became a trigger of sensitization to latex in this patient. Reoperation after the diagnosis of NRL allergy was carried out in a latex-free environment and completed without any allergic symptoms. It would be necessary to perform the pre-screening of latex allergy to prevent the onset of latex allergy especially in the patients with multiple surgical histories

Functionally confirmed compound heterozygous ADAM17 missense loss-of-function variants cause neonatal inflammatory skin and bowel disease 1

A disintegrin and metalloprotease 17 (ADAM17) is the major sheddase that processes more than 80 substrates, including tumour necrosis factor-α (TNFα). The homozygous genetic deficiency of ADAM17 causing a complete loss of ADAM17 expression was reported to be linked to neonatal inflammatory skin and bowel disease 1 (NISBD1). Here we report for the first time, a family with NISBD1 caused by functionally confirmed compound heterozygous missense variants of ADAM17, namely c.1699T>C (p.Cys567Arg) and c.1799G>A (p.Cys600Tyr). Both variants were detected in two siblings with clinical features of NISBD1, such as erythroderma with exudate in whole body, recurrent skin infection and sepsis and prolonged diarrhoea. In a cell-based assay using Adam10/17 double-knockout mouse embryonic fibroblasts (Adam10/17−/− mEFs) exogenously expressing each of these mutants, phorbol 12-myristate 13-acetate-stimulated shedding was strongly reduced compared with wild-type ADAM17. Thus, in vitro functional assays demonstrated that both missense variants cause the loss-of-function of ADAM17, resulting in the development of NISBD1. Our study further expands the spectrum of genetic pathology underlying ADAM17 in NISBD1 and establishes functional assay systems for its missense variants

乳児期早期における鶏卵、牛乳アレルゲン特異的免疫グロブリンのクラススイッチを伴うアイソタイプ形成経過と、湿疹による低親和性、高親和性の抗原特異的IgE抗体の形成

Introduction: Allergen‐specific immunoglobulin isotype formation associated with immunoglobulin class‐switching during the lactation period is the immunological background for food allergy in infants. We analyzed the serial changes in the production of feeding type‐related egg‐ and milk‐specific immunoglobulin isotypes from birth to 6 months of age with or without eczema in 84 infants. Methods: Allergen‐specific immunoglobulin G1 (IgG1), IgG2, IgG3, IgG4, IgA, and IgE levels of hen’s egg and bovine milk were measured in cord blood and blood samples from infants at 2, 4, and 6 months of age by the densely carboxylated protein microarray. Results: Formula and mixed feeding were associated with a rapid increase in cow’s milk allergen‐specific immunoglobulins and feeding type‐related significant differences in casein‐specific immunoglobulin levels were detected. Breast and mixed feeding were associated with slow but significant increase in ovalbumin‐specific IgG1 and IgE levels, but not other immunoglobulins. We found two different immunoglobulin isotype formation at 6 months of age with low‐ or high‐affinity IgE against ovalbumin. One isotype formation pattern had relatively high ovalbumin‐specific IgG1 levels, detectable IgG2, and low‐affinity IgE, while the other had low ovalbumin‐specific IgG1 levels, undetectable IgG2, and high levels of high‐affinity IgE. The incidence of eczema was significantly higher in the latter pattern (84.6%), compared with the remaining infants (42.2%). Conclusions: Feeding practice‐related allergen sensitization and immunoglobulin isotype formation were identified during the lactation period. The development of eczema during the lactation period could potentially modify the immunoglobulin isotype formation with high levels of high‐affinity IgE