Shuko Tokuriki

Transmaternal exposure to bisphenol a modulates the development of oral tolerance

Bisphenol A (BPA) is a representative endocrine disruptor that may have adverse effects on human health. Since the development of oral tolerance during infancy may play an important role in the prevention of food allergies, we examined whether transmaternal exposure to BPA influences the development of oral tolerance. To measure antigen-specific responses, female wild-type mice mated with male ovalbumin (OVA)-specific T-cell receptor transgenic (TCR-tg) mice were fed with BPA during pregnancy and while nursing. OVA was administered to OVA-TCR-tg offspring during their weaning period. Oral administration of both high and low doses of OVA suppressed OVA-specific cell proliferation and cytokine production in both BPA-exposed and nonexposed control mice, but the OVA-mediated suppression was significantly more diminished by the BPA exposure. The accumulation of CD4+CD25+Foxp3+ T cells was diminished in the BPA-exposed offspring. Moreover, after low dose OVA administration, serum OVA-specific IgG1 and IgG2a levels were higher in the BPA-exposed offspring than in nonexposed ones. Taken together, our results indicate that transmaternal exposure to BPA seems to modulate the mechanisms underlying tolerance induction; therefore, BPA may partially interrupt the development of oral tolerance.

Determination of asymmetric dimethylarginine, an endogenous nitric oxide synthase inhibitor, in umbilical blood.

Endothelial cells produce nitric oxide (NO), a potent vasodilator. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthase. Little is known about the potential physiological roles of ADMA in a perinatal setting. This study measures concentrations of ADMA in umbilical blood using enzyme-linked immunosorbent assay and those of NO as nitrite/nitrate (NOx(-)) using the Griess assay. Their relationship to the degree of prematurity and maternal clinical condition is examined. Results show that ADMA concentrations in umbilical blood from control newborns were about twice as high as those of lactating women, healthy children, and healthy adults. Umbilical blood NOx(-) concentrations from control newborns were about half of those of lactating women, healthy children, and healthy adults. Consequently, the levels of ADMA relative to NOx(-) were about 4-fold higher in umbilical blood from control newborns than in blood from lactating women, healthy children, and healthy adults. Furthermore, the umbilical blood ADMA concentrations and the ratios of ADMA to NOx(-) in newborns were higher according to their birth prematurity and lower birth weight. The umbilical ADMA concentrations were independent of the delivery mode and maternal preeclampsia. We infer that the high ADMA levels play physiological roles in maintaining vascular tone and blood redistribution to vital organs during birth, thereby favoring the circulatory transition from fetal to neonatal life.

Immunotherapy with oligomannose‐coated liposomes ameliorates allergic symptoms in a murine food allergy model

Allergen‐specific immunotherapy has been anticipated to be a disease‐modifying therapy for food allergies. We previously reported that CD8+ regulatory T cells may prevent antigen‐sensitized mice from developing allergic diarrhea. Because oligomannose‐coated liposomes (OML) have been shown to induce MHC class I‐restricted CD8+ T cell responses, we analyzed the adjuvant activities of OML for inducing regulatory CD8+ T cells and mucosal tolerogenic responses in allergen‐sensitized mice.

Antigen-primed splenic CD8+ T cells impede the development of oral antigen–induced allergic diarrhea

BACKGROUND Although CD4+ T-cell populations are thought to be involved in the pathophysiology of food allergy and oral tolerance, the role of CD8+ T cells remains uncertain. OBJECTIVE We analyzed regulatory effects of adoptively transferred CD8+ T cells on the development of allergic diarrhea in antigen-sensitized mice that had a significantly reduced number of conventional TCRalphabeta+ CD8+ T cells. METHODS Ovalbumin-specific T-cell receptor transgenic mice were systemically sensitized to ovalbumin. Splenic CD8+ T cells purified from ovalbumin-sensitized or nonsensitized wild-type mice or IL-10 knockout mice were adoptively transferred to ovalbumin-sensitized ovalbumin-specific T-cell receptor transgenic mice. Allergic diarrhea induced by oral administration of ovalbumin, ovalbumin-specific immunoglobulin production, and cytokine production in intestines and mesenteric lymph nodes were assessed. RESULTS Adoptive transfer of splenic CD8+ T cells from ovalbumin-primed mice, but not from nonprimed mice, suppressed the development of allergic diarrhea, which was associated with in vivo increased IL-10 mRNA expression and in vitro antigen-specific IL-10 production by mesenteric lymph node cells. Upregulation of serum ovalbumin-specific IgE was not suppressed by ovalbumin-primed CD8+ T-cell transfer. Although administration of IL-10 before ovalbumin challenge failed to alleviate allergic diarrhea, transfer of splenic CD8+ T cells from IL-10 knockout mice showed diminished preventive effects. CONCLUSION Systemic immunization with allergen simultaneously induces regulatory CD8+ T cells that can inhibit the development of allergic diarrhea. IL-10 production by regulatory CD8+ T cells appears to be partially involved in these inhibitory mechanisms.

Biotin and carnitine profiles in preterm infants in Japan.

Biotin plays an important role as a covalently bound coenzyme for carboxylases. Carnitine is essential in β‐oxidation to transport long‐chain fatty acids across the inner mitochondrial membrane. The present study was conducted to assess the risk of biotin and carnitine deficiencies in preterm infants who received enteral feeding with maternal milk and/or standard infant formula made in Japan.

Coupling of the citrulline recycling to endothelial NO production.

Brunetti-Pierri et al. [1] described two hypertensive patients with argininosuccinate lyase deficiency, speculating that the patients’ hypertension might be the result of NO deficiency. Their observation provides some evidence for the physiological importance of coupling of the citrulline–NO cycle to endothelial NO production. Actually, a close link appears to exist between the urea cycle and NO production in vivo. We reported that patients with ornithine transcarbamylase deficiency of late onset type had low serum and urine levels of NO metabolites and that arginine replacement was effective in maintaining NO metabolites at normal levels in these patients [2]. We also reported that patients with argininosuccinate synthetase deficiency showed low serum NO metabolites but high serum asymmetric dimethylarginine (an endogenous NO synthase inhibitor) even under L-arginine supplementation [3]. We also described, in an earlier report, sustained hypercitrullinemia, hypercholesterolemia, and high serum and urine levels of oxidative stress markers in patients with aspartate/ glutamate carrier isoform 2-citrin deficiency, even during its silent period [4]. All these findings support the contention that disturbed NO metabolism and/or enhanced oxidative stress might contribute to the pathophysiology of urea cycle defects. Insights gained from the interaction between urea cycle and NO production will provide adjunctive prophylactic and therapeutic benefits in patients with urea cycle defects, and those with ‘‘endothelial dysfunction syndrome” (including hypertension, diabetes, metabolic syndrome, renal failure) as well. The results obtained by Brunetti-Pierri et al. would be strengthened if they could also determine the levels of NO metabolites,

Biotin and carnitine deficiency due to hypoallergenic formula nutrition in infants with milk allergy.

Amino acid formulas and hydrolyzed formulas given to infants in Japan with milk allergies theoretically contain little, if any, biotin and carnitine. We assessed biotin and carnitine insufficiency in six infants with milk allergy who were fed amino acid formulas and/or hydrolyzed formulas, by measuring urine 3‐hydroxyisovaleric acid (3‐HIA) and serum free carnitine (C0), respectively. All patients presented with elevated urine 3‐HIA and lowered serum C0 compared with post‐menstrual age‐matched infants who were fed breast milk or standard infant formulas. Supplementation with biotin and l‐carnitine immediately improved the insufficiency. Care should be taken to avoid biotin and carnitine deficiency in allergic infants fed amino acid or hydrolyzed formulas.

A case of milk-protein-induced enterocolitis associated with enterotoxigenic E. coli and MRSA infections

Food protein-induced enterocolitis (FPIE) is a severe, cell-mediated gastrointestinal food hypersensitivity typically provoked by cow’s milk [Joint Task Force of AAAAI and ACAAI Food allergy: a practice parameter. XVII. Differential diagnosis of adverse reaction to foods. Ann Allergy Asthma Immunol 96(3 Suppl 2):S40–S44 (2006)]. We present an infant who developed FPIE associated with enterotoxigenic E. coli (ETEC) and methicillin-resistant Staphylococcus aureus (MRSA) infections. The case suggests that enteral infection may have a role in the development of sensitization to food protein and the pathogenesis of FPIE.

Diffuse neonatal hemangiomatosis in a very low-birthweight infant treated with erythropoietin.

Diffuse neonatal hemangiomatosis (DNH) is a rare condition characterized by the concomitant development of multiple cutaneous infantile hemangiomas (IH) and visceral hemangiomas. Recently, an association between erythropoietin treatment and an increased incidence of infantile hemangioma was noted. A Japanese male infant was born via cesarean section at 27 weeks of gestation. Following the commencement of erythropoietin treatment for anemia of prematurity, he developed multiple cutaneous hemangiomas, high cardiac output heart failure and hepatomegaly. Abdominal imaging indicated comorbidity of diffuse infantile hepatic hemanigomas, resulting in the final diagnosis of DNH. The discontinuation of erythropoietin treatment and long‐term therapy with propranolol improved the hepatic lesions and cutaneous hemangiomas. The possibility of multiple organ involvement and the exacerbating effects of erythropoietin treatment should be considered in cases in which multiple cutaneous hemangiomas develop in preterm infants receiving erythropoietin treatment.

Postnatal Changes in Humerus Cortical Bone Thickness Reflect the Development of Metabolic Bone Disease in Preterm Infants

Objective. To use cortical bone thickness (CBT) of the humerus to identify risk factors for the development of metabolic bone disease in preterm infants. Methods. Twenty-seven infants born at <32 weeks of gestational age, with a birth weight of <1,500 g, were enrolled. Humeral CBT was measured from chest radiographs at birth and at 27-28, 31-32, and 36–44 weeks of postmenstrual age (PMA). The risk factors for the development of osteomalacia were statistically analyzed. Results. The humeral CBT at 36–44 weeks of PMA was positively correlated with gestational age and birth weight and negatively correlated with the duration of mechanical ventilation. CBT increased with PMA, except in six very early preterm infants in whom it decreased. Based on logistic regression analysis, gestational age and duration of mechanical ventilation were identified as risk factors for cortical bone thinning. Conclusions. Humeral CBT may serve as a radiologic marker of metabolic bone disease at 36–44 weeks of PMA in preterm infants. Cortical bones of extremely preterm infants are fragile, even when age is corrected for term, and require extreme care to lower the risk of fractures.