Takashi Kusunoki

Essential role of Id2 in negative regulation of IgE class switching.

Serum concentrations of immunoglobulin E (IgE) in normal circumstances are kept much lower than those of other Ig isotypes to avoid allergic reactions. B cells lacking Id2 have increased E2A activity, which leads to specific enhancement of germline transcription of the immunoglobulin ε locus. As a consequence, Id2-deficient B cells undergo class switch recombination (CSR) to IgE at a much higher frequency than wild-type B cells. In contrast, Id2 is induced in wild-type B cells by transforming growth factor-β1 (TGF-β1) and suppresses IgE CSR. Our results provide evidence for the inhibitory and selective role of Id2 in IgE CSR in response to TGF-β1. Id2 might act as molecular safeguard to suppress IgE CSR to prevent serious complications such as allergic hypersensitivity during the normal course of immune responses.

Obesity and the prevalence of allergic diseases in schoolchildren

Although the association between obesity and bronchial asthma (BA) has been gaining more attention, few studies have been conducted concerning the relationship between obesity and other allergic diseases. The objective of this study was to determine whether and how childhood obesity is associated with allergic diseases other than BA, such as atopic dermatitis (AD), allergic rhinitis (AR), allergic conjunctivitis (AC), and either AR or AC (AR/AC). A questionnaire was administered to the parents of 50,086 Japanese schoolchildren. Associations between childhood obesity and the various allergic diseases were evaluated by univariate and multivariate logistic models. Significant associations were found between higher body mass index (BMI) and AD (p = 0.03), and lower BMI and AC (p < 0.0001), and AR/AC (p < 0.0001). There was a significantly higher prevalence of BA in girls with obesity (p = 0.009) than in those without obesity. Significantly lower prevalence of AC (p = 0.01) and AR/AC (p = 0.002) among children with obesity, and AR (p = 0.04) and AR/AC (p = 0.0004) among boys with obesity were observed than those without obesity. Those who were obese and had AD were significantly more likely to have severe symptoms (p = 0.01). Overall, childhood obesity has positive associations with BA prevalence and AD severity, whereas it has negative associations with AR and AC prevalence, especially among boys. Changes in the immunologic balance accompanied by obesity might have different effects on each type of allergic disease. Exploring the mechanisms by which childhood obesity affects allergic status should lead to new management options for childhood allergy.

Tyrosine phosphorylation and its possible role in superoxide production by human neutrophils stimulated with FMLP and IgG

Superoxide production by human neutrophils stimulated with FMLP and soluble aggregated human IgG were inhibited in a dose dependent manner by two kinds of tyrosine kinase inhibitors, erbstatin and genistein. Superoxide production stimulated with surface bound IgG, however, was scarcely inhibited by either inhibitor. Protein tyrosine phosphorylation studies with immunoblotting revealed specific tyrosine phosphorylation of a 40 Kd protein by soluble aggregated and surface bound IgG, and that of a 39 Kd protein, as well as the 40 Kd protein, by FMLP. These were all inhibited by the tyrosine kinase inhibitors. These data suggest that superoxide production induced by FMLP and soluble aggregated IgG are, at least in part, tyrosine kinase dependent, but the tyrosine kinases and/or substrates of tyrosine kinases involved may be different. In addition, tyrosine kinase independent pathways are also suggested to be involved in superoxide production by stimulation with surface bound IgG.

Breastfeeding and the prevalence of allergic diseases in schoolchildren: Does reverse causation matter?

Kusunoki T, Morimoto T, Nishikomori R, Yasumi T, Heike T, Mukaida K, Fujii T, Nakahata T. Breastfeeding and the prevalence of allergic diseases in schoolchildren: Does reverse causation matter?
Pediatr Allergy Immunol 2010: 21: 60–66.
© 2010 John Wiley & Sons A/S

Allergic status of schoolchildren with food allergy to eggs, milk or wheat in infancy.

Although children allergic to eggs, milk or wheat in infancy tend to become tolerant by school age, the allergic status of these children at school age has not been well evaluated. To investigate the allergic status of schoolchildren who avoided eggs, milk or wheat because of an immediate‐type allergic reaction at <1‐yr‐old (food avoiders in infancy), we conducted a large‐scale questionnaire‐based survey of schoolchildren. A questionnaire on allergic diseases was distributed to the parents of 14,669 schoolchildren aged 7 to 15 yr in 30 schools in Kyoto, Japan. Of these, 13,215 responded (response rate, 90.1%). The rate of 7‐yr‐old children who were food avoiders in infancy was 5.4%. This rate decreased as the current age of the children increased, down to 3% in 15‐yr‐old children, indicating that food allergy in infancy tended to become more prevalent over the past 8 yr. Although more than 80% became tolerant to these foods by school age, the prevalence of bronchial asthma, atopic dermatitis, allergic rhinitis and allergic conjunctivitis were significantly higher in this group. Moreover, avoidance of other foods (buckwheat, shellfish, fruits and others) at school age was seen at much higher frequencies than in non‐food avoiders in infancy (adjusted odds ratio, 7.7; confidence interval, 5.9–10.2). This risk did not differ significantly between those who did and did not develop tolerance to eggs, milk and wheat by 3 yr old. In conclusion, food avoiders in infancy appear to have a higher risk of not only other allergic diseases (‘atopic march’) but also allergy to other foods (‘food allergen march’) at school age, indicating the need for continuous attention to food allergy.

Involvement of CD11b/CD18 in enhanced neutrophil adhesion by Fc gamma receptor stimulation.

Neutrophils showed a rapid and transient adhesion to immunoglobulin G (IgG)‐coated plates compared with their adhesion to bovine serum albumin (BSA)‐coated plates: the adhesion reached a peak after 15 min of incubation and then gradually returned to almost the basal state in 60 min. The addition of monomeric IgG or anti‐FcγRII monoclonal antibody (mAb) (IV.3) suppressed the increase in adhesion, whereas anti‐FcγRIII mAb (3G8) was hardly effective, indicating that the interaction of FcγR, especially FcγRII, with coated IgG is involved in the process. Adhesion was also blocked by cytochalasin B, suggesting that functional actin filament structures are crucial. Protein kinase inhibitors, erbstatin and genistein, inhibited the adhesion in a dose‐dependent manner. The adhesion was inhibited by anti‐CDllb (Ml/70) and anti‐CD18 (MHM23, TS1/18) mAbs. Moreover, neutrophils from a patient with complete leukocyte adhesion deficiency syndrome did not show increased adhesion to IgG‐coated plates. The adhesion of neutrophils to fibrinogen‐ and BSA‐coated plates was also increased when FcγR was stimulated in the fluid phase with soluble aggregated IgG, which was also inhibited by anti‐CDllb mAb. Stimulation of neutrophil FcγR with soluble aggregated IgG enhanced the expression of CDllb in concert with the enhanced adhesion. These data collectively suggest that stimulation via FcγR evokes a tyrosine kinase‐dependent and actin filament‐dependent intracellular signal that enhances the specific and nonspecific adhesive activity of neutrophils, presumably through the activation of CDllb/CD18. J. Leukoc. Biol. 55: 735–742; 1994.

Changing prevalence and severity of childhood allergic diseases in kyoto, Japan, from 1996 to 2006.

BACKGROUND Published data regarding changes in the prevalence of childhood allergic diseases in Japan have been limited. METHODS To observe changes in the recent trends of the childhood allergy epidemic in Japan, a population-based questionnaire survey of allergic diseases was conducted among 13,215 schoolchildren, aged 7 to 15 years, in Kyoto, Japan in 2006. The results were compared with those obtained in the 1996 survey using the same scale and methods in the same region. RESULTS The prevalences of bronchial asthma (BA), atopic dermatitis (AD), allergic rhinitis (AR), and allergic conjunctivitis (AC) in 1996 and 2006 were 5.1% and 5.0% (p = 0.58), 4.2% and 5.6% (p < 0.0001), 20.3% and 27.4% (p < 0.0001), and 13.3% and 25.2% (p < 0.0001), respectively. Although the distribution of BA severity improved, the severity distribution of AD, AR, and AC all deteriorated. The lifetime prevalence (present prevalence and past history combined) of BA increased from 6.5% to 7.6% (p < 0.0001). The sex ratio analysis showed that the female predominance in the prevalence of AD observed in 1996 disappeared in 2006, indicating a particular rise in AD prevalence among boys. CONCLUSIONS Overall, the results indicate that the rising trend of allergic diseases, especially in AD, AR, and AC, continues among schoolchildren living in Kyoto, Japan. Special attention should be paid to skin and nasoocular symptoms.

Birth order effect on childhood food allergy

To cite this article: Kusunoki T, Mukaida K, Morimoto T, Sakuma M, Yasumi T, Nishikomori R, Heike T. Birth order effect on childhood food allergy. Pediatric Allergy Immunology 2012: 23: 250–254.

Limited Ability of Antigen-Specific Th1 Responses to Inhibit Th2 Cell Development In Vivo

Th1 and Th2 cells mutually antagonize each other’s differentiation. Consequently, allergen-specific Th1 cells are believed to be able to suppress the development of Th2 cells and to prevent the development of atopic disorders. To determine whether a pre-existing Ag-specific Th1 response can affect the development of Th2 cells in vivo, we used an immunization model of Ag-pulsed murine dendritic cell (DC) transfer to induce distinct Th responses. When transferred into naive mice, Ag-pulsed CD8α+ DCs induced a Th1 response and the production of IgG2a, whereas CD8α− DCs primed a Th2 response and the production of IgE. In the presence of a pre-existing Ag-specific Th2 environment due to Ag-pulsed CD8α− DC transfer, CD8α+ DCs failed to prime Th1 cells. In contrast, CD8α− DCs could prime a Th2 response in the presence of a pre-existing Ag-specific Th1 environment. Moreover, exogenous IL-4 abolished the Th1-inducing potential of CD8α+ DCs in vitro, but the addition of IFN-γ did not effectively inhibit the potential of CD8α− DCs to prime IL-4-producing cells. Thus, Th1 and Th2 cells differ in their potential to inhibit the development of the other. This suggests that the early induction of allergen-specific Th1 cells before allergy sensitization will not prevent the development of atopic disorders.

Relationships between atopy and lung function: results from a sample of one hundred medical students in Japan

BACKGROUND The prevalence of allergic diseases has been increasing dramatically and several studies have shown that atopy is related to asthmatic symptoms and bronchial hyperresponsiveness. OBJECTIVE To observe the relationships between atopic status and asthmatic predisposition (obstructive change in lung function) in apparently healthy young adults in Japan. METHODS A sample of 100 healthy Japanese medical students were subjected to a skin prick test for 11 common aeroallergens and food allergens, and their spirometric lung function was measured. RESULTS Surprisingly, 90% of them showed a positive prick test result for at least one of the 11 allergens tested, and 59% of them showed allergic responses to more than three allergens. The positive rate for Dermatophagoidesfarinae (Der) was the highest (71.0%), followed by house dust (57.0%), Dactylois gloinerata (42.0%), Cryptomeria gromerata (Cry) (40.0%), and cat fur (39.0%). Furthermore, there was no statistical difference in the positive rates for Der and Cry between groups with and without either the present illness or past history of any of the three major allergic diseases: bronchial asthma (BA), atopic dermatitis (AD), or allergic rhinitis (AR). Compared with the positive rates for these aeroallergens, those for food allergens were much lower (4% to 9%). Several lung function parameters, including the levels of FEV1% and %V50 which reflect obstructive pulmonary changes, showed significant negative correlation to the number of skin prick test-positive allergens. The same correlation was observed for groups without either the present illness or past history of BA. CONCLUSION These data suggest that those who are multi-allergic tend to feature subclinical asthma-like changes in their lung functions. Further studies are needed to determine whether this multi-allergic status can lead to future onset of asthma or other allergic diseases.