Elevated umbilical cord serum TARC/CCL17 levels predict the development of atopic dermatitis in infancy.

BACKGROUND: Thymus-and-activation-regulated chemokine (TARC; CCL17) is related to both allergy and pregnancy, but the relationships of maternal and umbilical cord blood CCL17 to atopic dermatitis (AD) development have not yet been examined. Objective Seventy paired full-term and normal vaginal delivery newborns and their mothers were enrolled in this study. METHODS: To elucidate the pathogenesis and fetomaternal inheritance of AD in infancy, CCL17, IFN-γ-inducible protein 10 kDa (IP-10; CXCL10), soluble HLA-G (sHLA-G), IgE and eosinophil counts were examined using sera from 70 paired umbilical cord and maternal blood samples. RESULTS: Serum CCL17 (r(s) =0.340, P<0.001) and sHLA-G (r(s) =0.600, P<0.001) levels showed high correlations between umbilical cord and maternal blood. Umbilical cord serum levels of CCL17 from neonates destined to develop AD in infancy were higher than in those from neonates who showed no signs of AD during infancy (median 1586.9 vs. 819.6 pg/mL, P<0.001). Serum levels of CCL17 were higher in mothers with AD than in those without AD (median 909.6 vs. 214.1 pg/mL, P<0.001). High umbilical cord serum levels of CCL17 were associated with infantile AD development even in 62 neonates born to mothers without AD (median 1514.4 vs. 740.6 pg/mL, P<0.001) and 38 neonates born to mothers with no allergies (median 1624.2 vs. 740.6 pg/mL, P<0.001). The summary estimates for umbilical cord serum CCL17 in the diagnosis of infantile AD were: sensitivity 85.7% (95% confidence interval: 72.8-98.7), specificity 73.8% (60.5-87.1), positive predictive value 68.6% (53.2-84.0) and negative predictive value 88.6% (78.0-99.1). CONCLUSION AND CLINICAL RELEVANCE: These findings suggest that the umbilical cord blood CCL17 may be involved in the pathogenesis of infantile AD and in fetomaternal inheritance. Serum levels of CCL17 from umbilical cord blood may be a predictive marker for AD in infancy.

Human gammadelta T cells modulate the mite allergen-specific T-helper type 2-skewed immunity.

BACKGROUND: Gammadelta T cells have been described as one of immune regulators in patients with infection, malignancy, and allergy. OBJECTIVE: To elucidate the ability of gammadelta T cells as an allergen immunotherapy candidate, the effectiveness of human gammadelta T cells in allergen-specific T-helper type 2 (Th2)-type T cells was evaluated in vitro. METHODS: House dust mite-specific Th2-type T cell clones, Bacillus Calmette-Guerin (BCG)-specific Th1-type T cell clones, and gammadelta T cell lines were established from the peripheral blood mononuclear cells of two patients with allergic rhinitis. The effectiveness of gammadelta T cells and BCG-specific Th1-type T cell clones in the modulation of allergen-specific Th2 cells in terms of their cytokine productions was evaluated. RESULTS: In response to cognate antigens, the gammadelta T cell lines demonstrated a proliferation and production of IFN-gamma that exceeded that of BCG-specific Th1-type T cell clones (mean stimulation index: 14.5 vs. 2.8, mean IFN-gamma: 130.5 vs. 10.0 pg/mL). When the gammadelta T cell lines and mite-allergen-specific Th2 clones were co-cultured with each other, only the levels of IL-4 (mean, -87%) decreased, but not the levels of IL-5 and IL-13, with an increasing concentration of gammadelta T cell antigen and IFN-gamma production (mean, +730%). CONCLUSION: These results demonstrated that gammadelta T cells derived from allergic patients might thus have a partial ability to modulate allergen-specific Th2-skewed immunity.

Distinct aggregation of beta- and gamma-chains of the high-affinity IgE receptor on cross-linking.

The high-affinity IgE receptor (FcepsilonRI) on mast cells and basophils consists of a ligand-binding alpha-chain and two kinds of signaling chains, a beta-chain and disulfide-linked homodimeric gamma-chains. Crosslinking by multivalent antigen results in the aggregation of the bound IgE/alpha-chain complexes at the cell surface, triggering cell activation, and subsequent internalization through coated pits. However, the precise topographical alterations of the signaling beta- and gamma-chains during stimulation remain unclarified despite their importance in ligand binding/signaling coupling. Here we describe the dynamics of FcepsilonRI subunit distribution in rat basophilic leukemia cells during stimulation as revealed by immunofluorescence and immunogold electron microscopy. Immunolocalization of beta- and gamma-chains was homogeneously distributed on the cell surfaces before stimulation, while crosslinking with multivalent antigen, which elicited optimal degranulation, caused a distinct aggregation of these signaling chains on the cell membrane. Moreover, only gamma- but not beta-chains were aggregated during the stimulation that evoked suboptimal secretion. These findings suggest that high-affinity IgE receptor beta- and gamma-chains do not co-aggregate but for the most part form homogenous aggregates of beta-chains or gamma-chains after crosslinking.

C8/119S mutation of major mite allergen Derf-2 leads to degenerate secondary structure and molecular polymerization and induces potent and exclusive Th1 cell differentiation.

Hyposensitization therapy for atopic diseases has been conducted for decades but suffered from many problems including anaphylactic reactions. We previously developed a mutant protein of the major mite allergen Derf-2, C8/119S, which showed reduced binding to IgE. The C8/119S mutant was shown to exhibit more efficient hyposensitizing effect than Derf-2 in the animal model of allergic bronchial asthma. In the present study, we indicate that C8/119S exhibits markedly augmented immunogenicity for the proliferation of Derf-2-specific human T cells and T cell clones irrespective of the epitope specificity as compared with Derf-2. Furthermore, C8/119S has induced potent and almost exclusive differentiation of Th1 cells from the peripheral blood of atopic patients in vitro. Neither Ag dosage effect nor absence of B cell-mediated Ag presentation could fully account for these effects. C8/119S has been indicated to lose the characteristic beta-barrel structure as judged by circular dichroism spectroscopic analysis and to polymerize solubly in physiological condition. Heating of Derf-2 also caused less stable molecular aggregation, but it hardly affected the secondary structure and failed to induce such a polarity toward the Th1 cell differentiation. These results have indicated that the degenerate secondary structure of C8/119S leading to stable molecular polymerization is primarily responsible for the marked increase in T cell-immunogenicity and the induction of exclusive Th1 cell differentiation in atopic patients. It has been suggested strongly that the recombinant C8/119S protein can provide an effective Ag with the least risk of anaphylaxis for allergen immunotherapy against house dust mite in human.

Comparison of skin prick test with serially diluted wild-type and genetically engineered recombinant Der f2.

BACKGROUND: C8/119S, a genetically engineered less allergenic mutant of group II allergen (Der f2) of house dust mite, Dermatophagoidesfarinae, was constructed in order to reduce the risk of anaphylactic reactions of allergen specific immunotherapy. OBJECTIVE: To further evaluate, with a larger number of mite-allergic patients, the safety of C8/119S for the treatments of humans. METHOD: We tested the dose-dependent responses of 20 mite-allergic volunteers to a skin prick test with C8/119S and wild-type recombinant Der f2 and compared the biologic potentials of these allergens to induce type I allergic reactions. In a separate experiment, we compared IgE binding capacities to C8/119S and to wild-type recombinant Der f2 in individual sera from 34 mite-allergic donors. RESULTS: The concentration of C8/119S needed to induce positive skin prick test (SPT) reaction was at least 100 times more than that of recombinant Der f2 in 95% of the volunteers tested. Consistent with this result, IgE binding data showed that 85% of the mite-allergic donors had little or no detectable IgE bound to C8/119S. Our data also shows that a minority of mite-allergic patients responded in a similar manner to both C8/119S and wild-type recombinant Der f2. CONCLUSION: Our data confirms that C8/119S is much less allergenic and thus can be used safely for immunotherapy of most of mite-allergic patients. Care should still be taken because, in a minority of patients, C8/119S may cause similar type I allergic reactions as does wild-type recombinant Der f2.

[Recent pollen sensitization and its possible involvement in allergic diseases among children in a pediatric allergy clinic].

We studied the rate of sensitization to several pollen allergens as well as to house dust mites in 226 children visiting our pediatric allergy clinic during the past 3 years (from April 1996 to March 1999). The allergens studied were Sugi (Japanese cedar pollen, Cryptomeria japonica), Kamogaya (Dactylis gromerata), Butakusa (ragweed, Ambrosia artemisiifolia), and Der f (house dust mite, Dermatophagoides farinae). The presence of nasal symptoms (either seasonal and perenial) was checked in 97 children visiting the clinic in March 1999. Overall average sensitization rates were 82.3% for Der f, 53.1% for Sugi, 38.5% for Kamogaya, and 17.1% for Butakusa. Among children aged 12 or more, sensitization rates for Sugi and Kamogaya were much higher (68.8%, 56.3%, respectively). Those who had seasonal nasal symptoms showed significantly higher rates of sensitization to the pollens. However, more than half of patients without nasal symptoms, 62.8% of whom had only atopic dermatitis (AD), also showed sensitization to the pollens. Several possible factors accounting for pollen sensitization in children with only AD and no sasal symptoms, such as existence of occult allergic rhinitis, future onset of allergic rhinitis, or pollen as directly aggravating factor of AD, need to be evaluated by careful follow-up of these cases.

Month of birth and prevalence of atopic dermatitis in schoolchildren: dry skin in early infancy as a possible etiologic factor.

BACKGROUND: Month of birth has been shown to affect later development of allergic diseases. OBJECTIVE: We sought to evaluate the relationship between month of birth and the prevalence of atopic dermatitis (AD) in a large-scale general population of schoolchildren and to elucidate the possible mechanism for this relationship. METHODS: Questionnaire data on the prevalence of allergic diseases were obtained for 33,725 schoolchildren aged 7 to 15 years. In a separate study the water-holding capacity of "uninvolved" skin was compared for children with and without AD. RESULTS: We found striking differences in the prevalence of AD according to the month of birth (chi2 = 34.9, P <.0001). Overall, those born in autumn showed the highest (7.5%), and those born in spring showed the lowest (5.5%), prevalence of AD. There was little or no such tendency for the prevalence of bronchial asthma (chi2 = 17.2, P =.103) and allergic rhinitis (chi2 = 24, P =.01). We found no statistical variation across birth month in the ratio of AD with no other allergic disease/total AD, indicating that this deviation was observed whatever the allergic predisposition of the subjects. In a separate study a significantly lower water-holding capacity of uninvolved skin was observed in children with AD even from early infancy. CONCLUSION: These findings lead us to speculate that the climate in early infancy affects the skin condition and that those born in autumn have dry skin in early infancy, which may ultimately result in a higher prevalence of AD among young schoolchildren. This might be at least one of the "nonallergic" etiologic factors of this complex disease.

[Re-evaluation of multi-allergen skin prick test for infants with atopic dermatitis--clinical relevance and evaluation by mothers].

We performed skin-prick tests (SPT) for 8 food and inhalant allergens on 55 infants (between 3 months and 2 years of age) with atopic dermatitis (AD) at their initial visit to our allergy clinic. SPT results were compared with those of radioallergosorbent tests (RAST) and the severity of AD symptoms. We also administered a questionnaire-based survey of 46 patients mothers to see how they evaluated SPT compared to blood tests. SPT for egg white had the highest positive rate (91%) and far exceeded that for other allergens. More than two allergens showed positive in more than half of the patients, and about 30% of them showed positive reactions to more than three allergens. Concordance rate between SPT and RAST was 78.6%. Patients showing positive reactions to multi-allergens tended to have more severe AD symptoms. Mothers appreciated the SPT test and felt that quick results for multi-allergens was the greatest advantage of SPT. More than 90% of the mothers wanted the allergic status of their next children to be evaluated with SPT. Especially, more than 30% of the mothers preferred SPT than RAST as initial screening test. As SPT is harmless, easy to administer even in infancy, and has different advantages for those of RAST, this method deserves further re-evaluation as a means of identifying allergic status especially among infants.

[Autoregressive analysis of variability in heart rate and blood pressure in asthmatic children--difference of severity].

Changes in ECG R-R intervals and blood pressure (lye and stand) were assessed by the autoregressive power spectral analysis method in 40 asthmatic children (age range: 2-16 years, mean +/- SD: 9.4 +/- 4.1 years). Significantly lower low frequency (LF: < or = 0.1 cycle/beat) power and high frequency (HF: 0.1-0.5 cycle/beat) power of R-R intervals were detected in severe type. LF fluctuations in R-R intervals are known to be mediated by the parasympathetic nervous system and the beta-adrenergic nervous system, while HF fluctuations in R-R intervals are mediated by the parasympathetic nervous system, LF fluctuations in systolic blood pressure by the alpha-adrenergic nervous system. The results suggested parasympathetic nervous system disorder especially in severe asthmatic children. Thus, spectral analysis of variability in R-R intervals and blood pressure are a useful tool for quantifying autonomic nervous system activity.

[Non-Fukuyama type merosin-positive congenital muscular dystrophy with delayed muscle fiber type differentiation: a case report].

A patient with non-Fukuyama type merosin-positive congenital muscular dystrophy (nonFCMD) who had severe muscle weakness leading to early death was reported. He was the first product of epileptic mother who had been placed on phenobarbital and phenytoin. The patient had severe respiratory failure and muscle weakness at the neonatal period, and died at 4 months of age. Multiple joint contractures were also noted at birth. Serum creatine kinase was within normal limits (123 IU/l). Electromyography showed a myogenic pattern. Brain computed tomographic (CT) scan and magnetic resonance imaging (MRI) were normal without white matter lucency or pachygyria. Muscle biopsy revealed dystrophic changes and type 2C fiber predominance. Dystrophin, dystrophin-associated glycoproteins and merosin were all positively demonstrated. Although patients with merosin-positive nonFCMD have relatively mild clinical course, our patient had severe muscle weakness with fatal outcome. Defect in muscle fiber maturation and differentiation, such as an increase of undifferentiated type 2C fibers, may be a major factor to influence muscle symptoms in non FCMD.

[Status epilepticus in two patients with Sotos syndrome].

Two patients with Sotos syndrome showed very intractable and prolonged status epilepticus, resulting in poor outcomes. Clinical seizures and EEG abnormalities in patients with Sotos syndrome are sometimes noted, but they are usually mild. These two patients showed hypoplasia of corpus callosum on MRI. We considered the mechanism of intractable seizures, and emphasized the importance of careful management for their seizures and EEG abnormalities.