Ikuya Tsuge

The transcription factor EPAS1 links DOCK8 deficiency to atopic skin inflammation via IL-31 induction

Mutations of DOCK8 in humans cause a combined immunodeficiency characterized by atopic dermatitis with high serum IgE levels. However, the molecular link between DOCK8 deficiency and atopic skin inflammation is unknown. Here we show that CD4+ T cells from DOCK8-deficient mice produce large amounts of IL-31, a major pruritogen associated with atopic dermatitis. IL-31 induction critically depends on the transcription factor EPAS1, and its conditional deletion in CD4+ T cells abrogates skin disease development in DOCK8-deficient mice. Although EPAS1 is known to form a complex with aryl hydrocarbon receptor nuclear translocator (ARNT) and control hypoxic responses, EPAS1-mediated Il31 promoter activation is independent of ARNT, but in collaboration with SP1. On the other hand, we find that DOCK8 is an adaptor and negative regulator of nuclear translocation of EPAS1. Thus, EPAS1 links DOCK8 deficiency to atopic skin inflammation via IL-31 induction in CD4+ T cells.

Japanese Cedar Pollen-Based Subcutaneous Immunotherapy Decreases Tomato Fruit-Specific Basophil Activation

Background: Some patients with Japanese cedar pollen (JCP)-induced allergic rhinitis develop pollen-food allergy syndrome (PFAS) as a reaction to tomato fruit. Pollen allergen-specific subcutaneous immunotherapy (SCIT) is reportedly beneficial for some associated food allergies; however, the reported changes in food allergen-specific immunoglobulin (Ig)E and IgG4 levels are inconsistent. Here, we investigated immunologic reactivity to tomato fruit after JCP-based SCIT. Methods: Twenty-three children (aged 6-17 years) with JCP-induced allergic rhinitis and sensitized to tomato (serum tomato fruit-specific IgE level >0.34 UA/ml) received JCP-based SCIT. Basophil activation by tomato and JCP extracts and serum-specific IgE and IgG4 levels against these allergens were determined before and after 4 or 5 months of maintenance SCIT. Basophil activation was assessed by monitoring CD203c upregulation on flow cytometry. Results: JCP-based SCIT significantly reduced the basophil activation caused by tomato fruit (p = 0.03) and JCP (p < 0.001) extracts. JCP-specific IgG4 levels markedly increased after SCIT (p < 0.001), whereas tomato fruit-specific IgG4 levels did not. After SCIT, no significant changes were observed in specific IgE levels for tomato fruit (p = 0.11) or JCP (p = 0.19). Conclusions: Tomato fruit-specific basophil activation decreases after JCP-based SCIT, suggesting that it is efficacious in relieving and preventing the symptoms of PFAS in patients with JCP-induced allergic rhinitis.

Acute eosinophilic pneumonia occurring in a dedicator of cytokinesis 8 (DOCK8) deficient patient

Dedicator of cytokinesis 8 (DOCK8) deficiency is an autosomal recessive type of combined immunodeficiency with elevated IgE. In this report, we describe a Japanese girl of non‐consanguineous family suffering from acute eosinophilic pneumonia (AEP) as a presenting feature of DOCK8 deficiency. Although AEP was self‐limiting, consecutively experienced recurrent respiratory infections, severe atopic dermatitis, and vulnerability to viral infections, prompted us to evaluate the possibility of DOCK8 deficiency. Immunological assessments demonstrated decreased IgM, increased IgE, T lymphocytepenia, especially in CD4 T cells, decreased PHA blastogenesis, and decreased CD27+CD19+ memory B cells. Western blotting revealed the absence of DOCK8 protein. Investigation of genomic DNA by multiplex ligation‐dependent probe amplification (MLPA) revealed a heterozygous large deletion of 77 kb spanning from intron 5 to exon 22. DOCK8 cDNA sequencing revealed a nonsense mutation at position 740 (E740X). As far as we know, this is the first Japanese case of DOCK8 deficiency. Pediatr Pulmonol. 2014; 49:E52–E55.

Food sensitization in Japanese infants is associated with a common Filaggrin variant

1 51 F 320 Y 35 20 9 1 10 5 4 2 0.43 0.29 2 78 M 300 N 37 21 13 5 12 11 4 4 2.29 0.14 3 67 M 560 Y 56 47 11 12 8 6 4 2 1.86 0.86 4 55 F 102 N 10 3 6 2 24 20 8 8 1.14 0.43 5 51 F 120 N 38 30 11 5 7 2 4 2 0.57 0.29 6 55 M 590 N 42 18 9 5 19 12 8 5 3.14 0.86 Mean (SD) 60 (11) e 332 (209) e 36 (15) 23 (15) 10 (2) 5 (4) 13.3 (6.7) 9.3 (6.4) 5.3 (2.1) 3.8 (2.4) 1.6 (1.1) 0.5 (0.3) P value e e e e .005 .017 .007 .030 .034

Hen's Egg Allergy

Egg allergy is one of the most frequent food allergies in infants and young children. The prevalence of egg allergy is estimated to be between 1.8 and 2% in children younger than 5 years of age. The reactions are mainly mediated by IgE and partially by non-IgE or are a mix of both types. Egg white contains more than 20 different proteins and glycoproteins. Ovomucoid (Gal d 1), ovalbumin (Gal d 2), conalbumin (ovotransferrin) (Gal d 3) and lysozyme (Gal d 4) have been identified as major allergens in hens egg. Alpha-livetin (Gal d 5) is thought to be a main egg yolk allergen responsible for bird-egg syndrome. The diagnosis of egg allergy is based on history taking, antigen-specific IgE measurements, such as the skin prick test, in vitro antigen-specific blood IgE tests and histamine release tests, and oral food challenges. The measurements of specific IgE to ovomucoid and its linear epitopes are more useful in the diagnosis of heated egg allergy and in the prediction of prognosis. Currently, the management of egg allergy is essentially minimal elimination based on the correct identification of the causative allergen. Although oral immunotherapy is promising as a tolerance induction protocol, several questions and concerns still remain, predominantly regarding safety.

Effect of Japanese cedar specific immunotherapy on allergen-specific TH2 cells in peripheral blood

BACKGROUND The involvement of a shift from TH2 to TH1 responses in peripheral blood in pollen subcutaneous immunotherapy (SCIT) has been contentious, partly because of difficulties analyzing antigen-specific TH cells. OBJECTIVES To use recent technical advances to establish a more direct and simple method to analyze antigen-specific TH cells and to clarify the involvement of a TH2/TH1 shift in peripheral blood in pollen specific immunotherapy. METHODS After short-term (6-hour) antigen stimulation, antigen-specific TH cells in peripheral blood of Japanese children and young adults with Japanese cedar pollinosis undergoing SCIT were analyzed by multicolor flow cytometry for the presence of the activation marker CD154 and intracellular cytokines. RESULTS Twenty-eight patients between 5 and 22 years of age were enrolled in the study; 22 had started SCIT after enrolling in the study (SCIT group), and the remaining 6 were planning to start SCIT in the next off-season (control group). The number of Japanese cedar-specific interleukin (IL) 5-, IL-4-, interferon γ-, IL-17A-, IL-10-, and tumor necrosis factor α-producing TH cells without antigen-driven cell proliferation was determined. The seasonal increase in the number of Japanese cedar-specific IL-5- and IL-4-producing TH cells seen in the control group was suppressed in the SCIT group (P < .005 and <.001, respectively). CONCLUSION We report a powerful method for the analysis of antigen-specific TH cells in peripheral blood. This method will contribute to our understanding of immune mechanisms of immunotherapy and help us develop more sophisticated allergen specific immunotherapy.

Three infants with rotavirus gastroenteritis complicated by severe gastrointestinal bleeding

Rotavirus gastroenteritis causes substantial morbidity and mortality worldwide in children. We report three infants with rotavirus gastroenteritis complicated by various severity of gastrointestinal bleeding. Two patients (cases 1 and 2) recovered completely without any specific treatments. One patient (case 3) died despite extensive treatments including a red blood cell transfusion and endoscopic hemostatic therapy. Rotavirus genotypes G1P[8] and G9P[8] were detected in cases 2 and 3, respectively. Rotavirus antigenemia levels were not high at the onset of melena, suggesting that systemic rotaviral infection does not play an important role in causing melena. J. Med. Virol. 88:171–174, 2016.

The First Nationwide Survey and Genetic Analyses of Bardet-Biedl Syndrome in Japan

Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder characterized by central obesity, mental impairment, rod-cone dystrophy, polydactyly, hypogonadism in males, and renal abnormalities. The causative genes have been identified as BBS1-19. In Western countries, this disease is often reported, but remains undiagnosed in many patients until later in life, while only a few patients with no mutations identified have been reported in Japan. We thus conducted the first nationwide survey of BBS in Japan by sending questionnaires to 2,166 clinical departments with board-certified specialists and found 7 patients with clinically definite BBS. We performed exome analyses combined with analyses of mRNA and protein in these patients. We identified 2 novel mutations in the BBS5 gene (p.R89X and IVS7-27 T>G) in 2 sibling patients. The latter mutation that resided far from the authentic splicing site was associated with skipping of exon 8. We also found 3 previously reported mutations in the BBS2 (p.R413X and p.R480X) and BBS7 (p.C243Y) genes in 2 patients. To our knowledge, a nationwide survey of BBS has not been reported in any other country. In addition, this is the first study to identify genetic alterations in Japanese patients with BBS. Our results indicate that BBS in Japan is genetically heterogeneous and at least partly shares genetic features with BBS in other countries.

Identification of novel FATP4 mutations in a Japanese patient with ichthyosis prematurity syndrome

Ichthyosis prematurity syndrome (IPS) is a rare autosomal recessive disorder characterized by prematurity, a thick caseous scale at birth and lifelong atopic diathesis. Here, we describe the first Japanese case of IPS and report novel compound heterozygous mutations (p.C403Y and p.R510H) in fatty acid transport protein 4 (FATP4). She is the first reported patient of Asian origin, entirely distinct from the Scandinavian population, in whom the heterozygote carrier frequency is very high.

IgE-dependent mechanism and successful desensitization of erythritol allergy

Erythritol, a 4-carbon sugar alcohol, is widely used as a food and symptoms for 4 months. We then performed an OFC (second OFC) drug additive because of its chemical inertness, sweetness, and nontoxic nature. It is also contained in natural foods, such as fruits and mushrooms, and fermented foods, such as soy sauce.1 We previously described a female patient who experienced many episodes of anaphylaxis; she was diagnosed as having an erythritol allergy using a skin prick test, basophil activation test (BAT) using the CD203c expression, and oral food challenge (OFC).2 However, the underlying immunologic mechanism of erythritol allergy was not fully elucidated. We administered oral immunotherapy (OIT) because the patient experienced repeated, unexpected episodes of severe anaphylaxis after the diagnosis. The ingestion of 0.3 g of 99% erythritol (Pal Sweet calorie zero) in the OFC provoked multiple urticaria and a runny nose in the patient. Subsequently, we performed OIT with a starting dose of 0.1 g with daily administration of montelukast and epinastine. At the start of the OIT, the patient was admitted to our hospital for 3 days to introduce the antigen (rush phase of OIT), which allowed her to tolerate 0.5 g of 99% erythritol at discharge. We instructed the patient to increase the daily dose by 0.1 g when she could ingest the dose without any symptoms on 14 consecutive days. However, the actual dose escalation needed to be sustained because she sometimes had an allergic symptom after an intake (Fig 1). Daily montelukast and epinastine administration was continued throughout the OIT. Although urticaria occasionally developed, especially just after increasing the antigen dose, severe symptoms, such as respiratory symptoms, did not develop throughout the OIT. After 1 year of OIT, the patient achieved a maintenance dose of 1.8 g, which is a common 1-serving dose of 99% erythritol in a cup of coffee. However, she still occasionally experienced urticaria, especially after self-judged discontinuation of ingesting antigen. After 2 years, she continued the maintenance dose without any