Tetsuo Shoda

Antigen-specific T-cell responses in patients with non-IgE-mediated gastrointestinal food allergy are predominantly skewed to TH2

Age (mo) 12 38.0 (26.5-60.0) 65 2.0 (1.0-4.0) Male/female sex 12 7/5 65 40/25 Day of onset 12 — 65 32.5 (7.0-115.5) Symptoms at onset Vomiting 12 0% (0/12) 65 53.8% (35/65) Bloody stool 12 0% (0/12) 65 47.7% (31/65) Diarrhea 12 0% (0/12) 65 47.7% (31/65) Failure to thrive 12 0% (0/12) 65 38.4% (22/65) Lethargy 12 0% (0/12) 65 38.4% (22/65) Fever 12 0% (0/12) 65 18.5% (12/65) Eczema 12 100% (12/12) 65 7.7% (5/65) Wheeze 12 33.3% (3/12) 65 0% (0/65) Laboratory data Milk-specific IgE (IU/mL) 12 56.95 (11.74-90.8) 65 <0.34 (<0.34)

Comparison of gene expression profiles in eosinophilic esophagitis (EoE) between Japan and Western countries

BACKGROUND The prevalence rate of eosinophilic esophagitis (EoE) between Japan and Western countries is quite different. Although multiple factors, including the genetic background, lifestyle and dietary habits, may account for the difference, the pathogenic mechanism of EoE has not been fully clarified in Japanese. To elucidate whether EoEs pathogenic mechanisms differ between those populations, we performed transcriptome analysis of esophageal biopsy specimens from Japanese EoE patients and compared the identified gene signatures with published microarray data for EoE patients in the US. METHODS We prospectively enrolled adult Japanese EoE patients (n = 4) according to the 2011 consensus guidelines for diagnosis of EoE. Age-matched healthy volunteer subjects (n = 4) were also enrolled as controls. We assessed the gene expression profiles of esophageal biopsies using microarray technology and then compared the identified gene signatures with earlier data generated in the US. RESULTS Of 42,545 transcripts represented on the microarray, 385 were differentially expressed between the EoE and control samples (≥2 fold change and adjusted p-value of <0.05). Our microarray data showed strong overlapping with the data from US patients with EoE. An EoE-specific-transcript signature is typically composed of IL-13-inducible and eosinophil-related genes, including eotaxin-3/C-C chemokine ligand 26 (CCL26). CONCLUSIONS This transcriptome study suggests that the pathogenetic mechanisms of EoE in Japan and Western countries are similar. Our findings may contribute to a better understanding of the pathogenesis of EoE and to more accurate diagnosis of this disease in Japanese individuals.

Cell type‐dependent effects of corticosteroid on periostin production by primary human tissue cells

Overproduction of periostin, an IL‐13‐inducible matricellular protein, despite corticosteroid treatment is thought to be involved in the chronicity of allergic inflammation seen in corticosteroid‐refractory tissue fibrosis. Therefore, we hypothesized that some tissue cells must produce periostin in a corticosteroid‐insensitive manner. Here, we show that IL‐4 and IL‐13 each induced comparable levels of periostin production by primary normal human fibroblasts and microvascular endothelial cells derived from lung and skin. Dexamethasone, a corticosteroid, completely inhibited IL‐4/13‐induced, but did not affect TGF‐β‐induced, periostin production by fibroblasts. In contrast, dexamethasone synergistically enhanced IL‐4/13‐induced periostin production by microvascular endothelial cells. TGF‐β did not induce periostin production by microvascular endothelial cells. Our novel findings suggest that IL‐4/13‐induced microvascular endothelium‐derived and/or TGF‐β‐induced fibroblast‐derived periostin might play a pivotal role in corticosteroid‐refractory tissue fibrosis, leading to chronic allergic inflammation in the lung and/or skin.

Recent advances in understanding the roles of vascular endothelial cells in allergic inflammation

Allergic disorders commonly involve both chronic tissue inflammation and remodeling caused by immunological reactions to various antigens on tissue surfaces. Due to their anatomical location, vascular endothelial cells are the final responders to interact with various exogenous factors that come into contact with the epithelial surface, such as pathogen-associated molecular patterns (PAMPs) and antigens. Recent studies have shed light on the important roles of endothelial cells in the development and exacerbation of allergic disorders. For instance, endothelial cells have the greatest potential to produce several key molecules that are deeply involved in allergic inflammation, such as periostin and thymus and activation-regulated chemokine (TARC/CCL17). Additionally, endothelial cells were recently shown to be important functional targets for IL-33--an essential regulator of allergic inflammation. Notably, almost all endothelial cell responses and functions involved in allergic inflammation are not suppressed by corticosteroids. These corticosteroid-refractory endothelial cell responses and functions include TNF-α-associated angiogenesis, leukocyte adhesion, IL-33-mediated responses and periostin and TARC production. Therefore, these unique responses and functions of endothelial cells may be critically involved in the pathogenesis of various allergic disorders, especially their refractory processes. Here, we review recent studies, including ours, which have elucidated previously unknown pathophysiological roles of vascular endothelial cells in allergic inflammation and discuss the possibility of endothelium-targeted therapy for allergic disorders.

Expression of thymus and activation-regulated chemokine (TARC) by human dermal cells, but not epidermal keratinocytes

BACKGROUND Serum levels of thymus and activation-regulated chemokine (TARC/CCL17) have served as a reliable biomarker of disease progression of atopic dermatitis (AD). However, it remains to be scientifically explained why serum TARC levels correlate well with the degree of AD progression. OBJECTIVE We hypothesized that dermal cells, but not epidermal keratinocytes, are major cellular sources of TARC and thus responsible for subclinical skin inflammation. This study aimed to identify the skin cells that can produce TARC protein. METHODS Primary normal human epidermal keratinocytes (NHEK), dermal microvascular endothelial cells (HMVEC-dBl) and dermal fibroblasts (NHDF) were stimulated with TNF-α and IL-4, alone and in combination. TARC mRNA and protein levels were quantified by qPCR and ELISA, respectively. We also investigated the effects of such immunosuppressants as a corticosteroid (dexamethasone) and tacrolimus (FK506) on TARC production, and used various signaling inhibitors to evaluate the signaling pathways involved in TARC expression. RESULTS Although neither TNF-α nor IL-4 alone induced TARC production by any of the tested cell types, together they induced expression of TARC mRNA and appreciable amounts of TARC protein by HMVEC-dBl and NHDF, but not by NHEK. TARC production by those dermal cells was not inhibited by dexamethasone or FK506. TARC production by HMVEC-dBl was completely inhibited by NF-κB and p38 MAPK inhibitors, but not by an ERK inhibitor. CONCLUSION Dermal cells, but not epidermal keratinocytes, may be important cellular sources of TARC in AD skin. Therefore, even if epidermal eczematous lesions seem to be improved, complete inhibition of inflammation in the dermis is thought to be particularly important for suppressing both the TARC blood level and progression of AD. However, immunosuppressants did not directly inhibit TARC production by the dermal cells. Anti-inflammatory therapy may decrease TARC blood levels in AD patients indirectly, via its inhibitory effects on TNF-α- and/or IL-4-producing cells in the dermis.

Timing of eczema onset and risk of food allergy at 3 years of age: A hospital-based prospective birth cohort study

BACKGROUND Although recent studies suggest that eczema in early childhood is important in the development of food allergy, the importance of the timing of eczema onset has not been fully clarified. OBJECTIVE This study aim to identify an association between the timing of eczema onset and development of food allergy in a prospective birth cohort study. METHODS Data were obtained from the Tokyo Childrens Health, Illness and Development (T-CHILD) study, which is a hospital-based birth cohort study currently in progress in Japan. A total of 1550 children were born to the recruited women. Outcome data for children were collected from questionnaires completed at 6 months, 1 and 3 years of age. Association between the timing of eczema onset and development of food allergy was estimated by logistic regression analyses. All analysis were performed using SPSS software with a two-sided 5% significance level. RESULTS Eczema in the first year of life was a significant risk factor in multivariate analysis (aOR 3.90, 95% CI 2.34-6.52, p<0.001). In each age (by month) stratum, infants with onset of eczema within the first 1-2 months after birth had the highest risk of food allergy at 3 years of age (aOR 6.61, 95% CI 3.27-13.34, p<0.001). CONCLUSION Infants with early eczema onset (especially within the first 1-4 months after birth) were found to have an increased risk of developing food allergy at 3 years of age. Our findings may contribute to a better understanding of the timing of eczema onset as a potentially modifiable risk factor and to defining those who may need to be on guard for food allergy.

Yogurt consumption in infancy is inversely associated with atopic dermatitis and food sensitization at 5 years of age: A hospital-based birth cohort study

BACKGROUND Several studies have suggested that habitual yogurt consumption is associated with favorable outcomes for health issues in children. However, the effects of yogurt consumption on allergic diseases and sensitization in children remain poorly understood. OBJECTIVE This prospective birth cohort study aimed to investigate for associations between habitual yogurt consumption in infancy and development of allergic diseases/sensitization at 5 years of age. METHODS Data were obtained from the Tokyo Childrens Health, Illness and Development (T-CHILD) study. A total of 1550 children were born to the recruited women. Consumption of yogurt by children during infancy was determined by using questionnaires completed at 12 months of age. Outcome data for children were collected from the questionnaires and medical check-ups completed at 5 years of age. Possible associations between habitual yogurt consumption in infancy and allergic diseases/sensitization were analyzed by multiple logistic regression analyses. RESULTS We analyzed the data for 1166 children whose parents responded at 5 years of age. Habitual yogurt consumption in infancy and atopic dermatitis at 5 years of age were significantly associated (UKWP criteria: aOR, 0.70; 95% CI, 0.51-0.97; P=0.03). Children with habitual yogurt consumption in infancy were less likely to be sensitized to food allergens (aOR, 0.53; 95% CI, 0.31-0.93; P=0.03), but no associations were seen in regard to any other allergens. CONCLUSIONS Our study demonstrated that habitual consumption of yogurt in infancy has the potential to prevent development of atopic dermatitis and food sensitization, but not other allergic diseases, at 5 years of age.

Serum Biomarkers for the Diagnosis of Eosinophilic Esophagitis and Eosinophilic Gastroenteritis

Objective Clinically useful serum biomarkers for the diagnosis and monitoring of eosinophilic gastrointestinal diseases are not available. This study was conducted to examine the possible value of eosinophil-related proteins as serum biomarkers. Methods The serum concentrations of 49 cytokines, chemokines, and other proteins were measured in 29 patients with eosinophilic gastrointestinal diseases and 80 controls. Results The levels of interleukin (IL)-5, IL-33, eotaxin-3, and thymic stromal lymphopoietin (TSLP), previously reported as possible biomarkers of eosinophilic esophagitis, were not significantly elevated in the serum. In contrast, the B cell-attracting chemokine (BCA)-1/chemokine (C-X-C motif) ligand (CXCL) 13 and hemofiltrate C-C chemokine (HCC)-1/CC chemokine ligand (CCL) 14α levels were significantly elevated, while the granulocyte chemotactic protein (GCP)-2/CXCL6 levels were suppressed in patients with eosinophilic esophagitis as well as in those with eosinophilic gastroenteritis. The cutaneus T cell-attracting chemokine (CTACK)/CCL27, stromal cell-derived factor (SDF)-1/CXCL12, macrophage inflammatory protein (MIP)-3β/CCL19, and squamous cell carcinoma antigen (SCCA) 2 levels were elevated only in patients with eosinophilic esophagitis. However, there were large overlaps of data obtained from the patient and control groups, indicating that these serum biomarkers are not adequately sensitive for clinical use with presently available assay systems. Conclusion Of the 49 investigated serum proteins, none were shown to be adequately sensitive for use as biomarkers for the diagnosis or monitoring of eosinophilic gastrointestinal diseases.

Gene expression profiles of mucosal biopsy specimens in children with eosinophilic gastritis

Background Eosinophilic gastrointestinal disorders (EGID) are clinicopathologically characterized by massive eosinophilic infiltration into the gastrointestinal tract and are classified into eosinophilic esophagitis (EoE), gastritis (EG), gastroenteritis, enteritis and colitis according to the site of infiltration. Studies of the pathogenic mechanism of EoE, whose incidence and prevalence are increasing in Western countries, revealed that eotaxin-3 plays a crucial role in inducing selective recruitment of eosinophils into the esophageal epithelium. In contrast, the pathogenic mechanism of EG remains obscure. In order to elucidate whether EG’s pathogenic mechanism is similar to that of EoE, we performed transcriptome analysis of gastric biopsy specimens from EG patients and compared the identified gene signature to the previous microarray data for EoE patients (J Clin Invest, 116:536-47, 2006).

Double recurrence of group B streptococcus bacteremia in an immunocompetent infant

We report an immunocompetent infantile case wherein group B streptococcus bacteremia recurred two times. The isolated bacteria which colonized in his nasopharyngeal cavity might be a source of repetitive infection. Although the best action has not been established yet, penicillin G as the prophylaxis seemed to be effective in this case.