Akiko Yamada

Increased oxidative stress in childhood atopic dermatitis.

Atopic dermatitis (AD) is a chronic inflammatory skin disease of unknown etiology. To examine the involvement of impaired homeostasis of oxygen/nitrogen radicals in childhood AD, we compared the levels of urinary 8-hydroxy-2-deoxyguanosine (marker of oxidative stress), nitrite/nitrate (marker of nitric oxide synthesis) and selenium (marker of selenium store) in 27 children with AD to those of 25 healthy control children. Urinary 8-hydroxy-2-deoxyguanosine was significantly higher and nitrite/nitrate levels were significantly lower in patients with AD than in the control. Urinary selenium levels were similar in both groups. Our findings suggest that impaired homeostasis of oxygen/nitrogen radicals and increased oxidative stress are involved in the pathophysiology of childhood AD, and indicate that suppression of oxidative stress might be a potentially useful strategy for the treatment of AD.

Early sensitization to house dust mite is a major risk factor for subsequent development of bronchial asthma in Japanese infants with atopic dermatitis: results of a 4-year followup study

BACKGROUNDnBronchial asthma (BA) often develops in children with atopic dermatitis (AD). Identification of factors that could predict the development of asthma in children with AD is useful for early intervention.nnnOBJECTIVEnWe undertook a 4-year followup study to clarify the factors involved in the development of BA in infants with AD.nnnMETHODSnWe registered 169 infants with AD who were free of BA at registration and examined the prevalence and characteristics of the subsequent development of BA among these patients.nnnRESULTSnAmong the patients followed for 4 years, approximately 45% experienced asthma-like respiratory symptoms, and 35% were diagnosed as asthmatic patients by pediatric allergologists. Patients who developed BA showed early appearance of house dust mite (HDM)-specific immunoglobulin E (IgE) and persistently high levels of food-specific IgE. Male sex, a positive family history of BA, and the appearance of HDM-specific IgE were identified as significant risk factors for the early development of BA, but the significance of these parameters decreased thereafter. A positive family history of AD, the outcome of skin lesions, and keeping furred pets were also identified as risk factors in a part of the followup period. Among the parameters examined, the early appearance of HDM-specific IgE was the most significant risk factor.nnnCONCLUSIONnAppearance of HDM-specific IgE antibodies in early childhood, which seems to be mainly influenced by genetic factors, is a major risk factor for the subsequent development of BA in children with AD, but the influence decreases after longer followup.

Dysregulation of IL-13 production by cord blood CD4+ T cells is associated with the subsequent development of atopic disease in infants.

Early intervention strategies in allergic diseases will be dependent on identification of newborns at high risk for later development of atopic disease. In this cohort study of 106 neonates, we investigated whether cytokine production property and responsiveness to IL-12 of neonatal CD4+ T cells were associated with the subsequent development of atopic disease and whether a skewed cytokine production property was intrinsic to helper T cells. To exclude the effects of contaminating cells, highly purified cord blood CD4+ T cells were stimulated with anti-CD3 MAb and recombinant B7-2 molecule in the presence or absence of IL-12. Production of IL-13 and interferon-γ was determined by ELISA. The infants were assessed at 12 mo for the development of atopic diseases. CD4+ T cells of neonates who manifested allergic symptoms (atopic group) produced higher levels of IL-13 compared with those of the nonatopic group in both the presence and absence of IL-12. No significant difference was noted between the two groups with respect to interferon-γ production. Moreover, higher IL-13 production was also observed in neonates with chronic eczema than those with short-term eczema. Our data suggest that increased production of IL-13 by neonatal CD4+ T cells is a useful marker of newborns at high risk for subsequent development of atopic diseases and that an intrinsic abnormality of CD4+ T cell is associated with the pathogeneses of atopic disease, especially atopic dermatitis in infants.

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.

Erythromycin Differentially Inhibits Lipopolysaccharide- or Poly(I:C)-Induced but Not Peptidoglycan-Induced Activation of Human Monocyte-Derived Dendritic Cells

Erythromycin (EM) has attracted attention because of its anti-inflammatory effect. Because dendritic cells (DCs) are the most potent APCs involved in numerous pathologic processes including innate immunity, we examined effects of EM on the activation of human DCs by pathogen-derived stimuli. Monocyte-derived DCs were pretreated with EM and subsequently stimulated with peptidoglycan, polyriboinosinic:polyribocytidylic acid (poly(I:C)), or LPS. The activation of DCs was assessed by surface molecule expression and cytokine production. To reveal the signaling pathways affected by EM, TLR expression, NF-κB, IFN regulatory factor-3, and AP-1 activation were examined. EM inhibited costimulatory molecule expression and cytokine production that was induced by poly(I:C) and LPS but not by peptidoglycan. EM pretreatment down- and up-regulated mRNA levels of TLR3 and TLR2, respectively, but did not affect that of TLR4. EM suppressed IFN regulatory factor-3 activation and IFN-β production but not AP-1 activation induced by poly(I:C) and LPS. The inhibitory effect of EM on NF-κB activation was observed only in poly(I:C)-stimulated DCs. EM selectively suppressed activation of DCs induced by LPS and poly(I:C) in different ways, suggesting that the immuno-modulating effects of EM depend on the nature of pathogens. These results might explain why EM prevents the virus-induced exacerbation in the chronic inflammatory respiratory diseases and give us the clue to design new drugs to treat these diseases.

Steroid-sparing effect of tacrolimus in a patient with juvenile dermatomyositis presenting poor bioavailability of cyclosporine A

Cyclosporine A is known to have a steroid-sparing effect in patients with juvenile dermatomyositis. On the other hand, the clinical usefulness of tacrolimus, another immunosuppressive drug, for the treatment of juvenile dermatomyositis has not yet been reported. Here we present a case of steroid-dependent juvenile dermatomyositis in whom the steroid dosage was successfully tapered by the administration of tacrolimus. A 13-year-old Japanese girl had a 4-year history of dermatomyositis, which was diagnosed by the presence of Gottron papules, a heliotrope rash, and muscular weakness (Fig. 1). The patient was started on prednisolone (2 mg/kg per day) and showed good clinical response. However, she relapsed with elevated CRP levels and muscular pain during tapering off of the steroid use and required high doses of prednisolone (0.5–1mg/kg per day) to control the symptoms for 2.5 years (Fig. 2). Azathioprine was also administered but did not produce any steroid-sparing effects. Methotrexate was introduced and discontinued due to hepatotoxicity; high dose c-globulin treatment was tried and discontinued because of meningismus. Subsequently, the patient received cyclosporine A (7.5 mg/kg per day, b.i.d.); the plasma concentrations remained around 140 ng/ml even 2 h after administration, resulting in a failure to reduce the steroid level. Rather than increasing the dosage of cyclosporine A, we chose to give the patient tacrolimus, with the informed consent of her parents. Two weeks after the commencement of tacrolimus (0.12 mg/kg per day), with trough levels around 6 ng/ml, the patient’s CRP and erythrocyte sedimentation rate levels were normalised and muscle strength gradually returned. Since the last remission, she has never complained about her muscular pain for 2 years. Moreover the prednisolone was successfully tapered to 0.06 mg/kg per day without either any symptoms of relapse or elevation of CRP for 1 year (Fig. 2). The bioavailability of the oral formulation of cyclosporine A is variable even as a microemulsion [4]. Compared with adults, paediatric patients show poorer absorption, accelerated metabolism, and more rapid clearance of cyclosporine A, so they often require higher doses to achieve therapeutic plasma levels [1]. For the treatment of juvenile dermatomyositis, an oral dose of 2.5 to 7.5 mg/kg per day is generally recommended [2]. In this case, even though a sufficient dosage of cyclosporine A was administered, the patient’s plasma concentration failed to achieve therapeutic levels. Although the precise mechanisms for the low plasma concentration were not determined, steroid-induced obesity and hyperlipidaemia might be contributing factors. Fig. 1 Gottron papules (A) and a heliotrope rash (B) on our patient’s hand and face

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

BACKGROUNDnAlthough 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.nnnOBJECTIVEnWe 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.nnnMETHODSnOvalbumin-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.nnnRESULTSnAdoptive 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.nnnCONCLUSIONnSystemic 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.

Two cases of anaphylactic reaction to gelatin induced by a chloral hydrate suppository.

An accumulating number of reports have pointed out the importance of gelatin allergy in young children, which sometimes leads to a fatal outcome due to anaphylaxis.1,2 In Japan, most vaccines have been replaced with gelatin-free forms, whereas gelatin is still contained in many drugs and baby foods. Therefore, it is necessary to be aware of gelatincontaining products. We have experienced two patients with anaphylactic symptoms induced by a chloral hydrate suppository, which contained gelatin, used for sedation before an electroencephalography (EEG) examination. Here, we present the clinical course of the patients and discuss the acquisition and mechanism of gelatin allergy.

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.

Salivary-type hyperamylasemia in theophylline poisoning

Theophylline and related xanthine preparations remain a valued therapy for many childhood illnesses, including bronchial asthma and apnea of prematurity. Although appropriate pediatric dosage regimens have been established, the risk of inadvertent theophylline poisoning is still present because of its narrow therapeutic index. The clinical manifestations of acute theophylline intoxication have been well characterized. We, however, experienced an unusual finding of salivary-type hyperamylasemia in an asthmatic boy who received an overdose of aminophylline infusions and subsequent inhalation of β 2-agonist.