A Role of Staphyococcus aureus, Interleukin-18, Nerve Growth Factor and Semaphorin 3A, an Axon Guidance Molecule, in Pathogenesis and Treatment of Atopic Dermatitis.

Staphylococcus aureus (SA) is usually present not only in the skin lesions of atopic dermatitis (AD) but also in the atopic dry skin. SA discharges various toxins and enzymes that injure the skin, results in activation of epidermal keratinocytes, which produce and release IL-18. IL-18 that induces the super Th1 cells secreting IFN-γ and IL-13 is supposed to be involved in development of AD and its pathogenesis. Indeed, the number of SA colonies on the skin surface and the serum IL-18 levels in patients with AD significantly correlated with the skin scores of AD lesions. Also, there is strong positive correlation between the skin scores and serum IL-18 levels in DS-Nh mice (P<0.0001, r=0.64), which develop considerable AD-like legions when they are housed under conventional conditions, but develop skin legions with less severity and less frequency under specific pathogens free (SPF) conditions. Therefore, they are well-known as model mice of AD, in which SA is presumed to be critical factor for the development of AD lesions. Also, theses DS-Nh mice pretreated with Cy developed more remarkable AD-like lesions in comparison with non-treated ones. The levels of INF-r and IL-13 in the supernatants of the lymph node cell cultures stimulated with staphylococcal enterotoxin B (SEB) or ConA were increased in the Cy-treated mice, although the serum levels of total IgE were not. In this experiment, we revealed that Cy-treated mice, to which CD25 +CD4 + reguratory T cells taken from non-treated ones had been transferred, developed the AD-like legions with less severity and less number of SA colonies on the skin surface. Therefore, it is presumed that CD25 +CD4 + reguratory T cells might be involved in the suppression of super Th1 cells which are induced by IL-18 and are involved in the development of AD-like lesions rather than IgE production. The efficient induction of CD25 +CD4 + reguratory T cells is expected for the new type of treatment of AD. We also found that farnesol (F) and xylitol (X) synergistically inhibited biofilm formation by SA, and indeed the ratio of SA in total bacteria at sites to which the FX cream containing F and X had been applied was significantly decreased 1 week later, accompanied with improvement of AD, when compared with that before application and at placebo sites. Therefore, the FX cream is a useful skin-care agent for atopic dry skin colonized by SA. The nerve growth factor (NGF) in the horny layer (the horn NGF) of skin lesions on the cubital fossa was collected by tape stripping and measured using ELISA in AD patients before and after 2 and 4 weeks treatments. Simultaneously, the itch and eruptions on the whole body and on the lesions, in which the horn NGF was measured, were recorded, and also the peripheral blood eosinophil count, serum LDH level and serum total IgE level were examined. The level of NGF was significantly higher in AD patients than in healthy controls, correlated with the severity of itch, erythema, scale/xerosis, the eosinophil count and LDH level, and also significantly decreased after treatments with olopatadine and/or steroid ointment for 2 and 4 weeks. Therefore, the measurement of the NGF by this harmless method seems to be useful to assess the severity of AD and the therapeutic effects on AD. In AD patients, C-fiber in the epidermis increase and sprout, inducing hypersensitivity, which is considered to aggravate the disease. Semaphorin 3A (Sema3A), an axon guidance molecule, is a potent inhibitor of neurite outgrowth of sensory neurons. We administered recombinant Sema3A intracutaneously into the skin lesions of NC/Nga mice, an animal model of AD, and investigated the effect of Sema3A on the skin lesions and their itch. Sema3A dose-dependently improved skin lesions and attenuated the scratching behavior in NC/Nga mice. Histological examinations revealed a decrease in the epidermal thickness, the density of invasive nerve fibers in the epidermis, inflammatory infiltrate including mast cells and CD4 +T cells, and the production of IL-4 in the Sema3A-treated lesions. Because the interruption of the itch-scratch cycle likely contributes to the improvement of the AD-like lesions, Sema3A is expected to become a promising treatment of patients with refractory AD.

Correlation of oral allergy syndrome due to plant-derived foods with pollen sensitization in Japan.

BACKGROUND: The clinical features of patients with oral allergy syndrome (OAS) due to plant-derived foods related to pollen allergy have been rarely reported in Japan. OBJECTIVES: To evaluate the characteristics of OAS and to investigate whether pollen sensitizations are correlated with the prevalence of OAS in Japan. METHODS: We measured specific IgE antibodies against 5 pollens in 622 outpatients (277 males and 345 females; mean age, 37 years) with atopic dermatitis, urticaria, angioedema, and food allergy during a 2-year period. Furthermore, OAS is diagnosed based on anamnesis and positive skin prick test reactions to suspected foods. RESULTS: Eighteen of the 436 patients (4.1%) sensitized to pollens were diagnosed as having OAS. Rates of specific IgE antibody-positive responses against Japanese cedar, ragweed, orchard grass, mugwort, and alder pollen were 69.8%, 35.3%, 29.1%, 24.1%, and 19.6%, respectively. The prevalence of OAS showed a significant positive correlation with sensitization to alder (P < .001). In addition, the most frequent causative foods were found to be apple, peach, and melon. The prevalence of OAS due to apple showed a significant positive correlation with sensitization to alder (P < .001) pollen, due to peach showed a significant positive correlation with sensitization to alder (P < .001) and orchard grass (P < .05) pollen, and due to melon showed a significant positive correlation with sensitization to alder (P < .005), orchard grass (P < .05), and ragweed (P < .05) pollen. CONCLUSION: Sensitization to pollens from species in the Betulaceae family is most strongly implicated in causing OAS in Japan.

[Case of food-dependent exercise-induced anaphylaxis diagnosed by the provocation test with cuttlefish after the pretreatment with 1.5 g of aspirin].

A 29-year-old woman had an episode of urticaria at the age of 17 while exercising after eating fried cuttlefish. For years thereafter, she experienced several episodes of urticaria after eating seafood. At the age of 29, she ate grilled seafood, including cuttlefish for supper after taking loxoprofen for lumbago. One hour later, she developed generalized urticaria accompanied by nausea, abdominal pain, swelling of the lips, and dyspnea while walking; she was taken to a hospital. She was then referred to us for further examination of the etiology of her anaphylactic reactions. The level of specific IgE measured using Immuno CAP was negative for all kinds of foods, including cuttlefish. However, a skin prick test was positive for raw and cooked cuttlefish. Provocation tests were performed on admission by combining the intake of cuttlefish and aspirin under the suspicion of cuttlefish allergy enhanced by nonsteroidal anti-inflammatory drugs and exercise. As a result, she developed no symptoms except for slight itching of the oral mucosa after eating 20 g or 100 g of cuttlefish with or without concomitant administration of 0.5 g of aspirin. Finally, generalized urticaria appeared after challenge with cuttlefish and 1.5 g of aspirin. She was diagnosed with food-dependent exercise-induced anaphylaxis (FDEIA) caused by cuttlefish. She has not developed urticaria since she started to avoid eating cuttlefish. Our results indicated that in provocation tests for the diagnosis of FDEIA, allergic reactions could not only be induced by food intake but could also be enhanced by aspirin in a dose-dependent manner.

[Anaphylaxis due to peach with negative ImmunoCAP result to peach allergens, including rPru p 1, rPru p 3, AND rPru p 4: a report of two cases].

We report two cases of anaphylactic reactions to peach with negative result of ImmunoCAP to peach. Case 1 is a 35-year-old man, who felt an itch in his oral cavity immediately after ingesting a whole fresh peach. He rapidly developed generalized urticaria, dyspnea, vomiting, and loss of consciousness. He recovered after treatment at a local hospital, thereafter he was referred to our hospital because ImmunoCAP conducted for screening allergens revealed a negative test result to peach and the cause of anaphylaxis remained unclear. He had a history of pollinosis. He reported that he previously felt an itch on his oral cavity after ingesting melon, watermelon, apple, and strawberry. Serum total IgE was 436 IU/ml. CAP-RAST revealed negative results to peach, strawberry and kiwi. Skin prick tests (SPTs) with raw peach pulp, canned peach pulp, strawberry and kiwi were positive. Case 2 is a 30-year-old woman who felt an itch on her oral cavity accompanied by blepharedema, rhinorrhea, generalized urticaria, nausea, abdominal pain and diarrhea after eating peach. She had a history of pollinosis. She reported that she previously developed urticaria after ingesting an apple. Serum total IgE was 85 IU/ml. ImmunoCAP revealed negative results to peach and apple. SPTs with canned yellow peach, strawberry and apple were positive. Consequently, the two patients were diagnosed with anaphylaxis due to peach, and allergic symptoms have never recurred since they avoided ingesting peach. Furthermore, in two patients ImmunoCAP to rPru p 1, rPru p 3, and rPru p 4 were negative. However, in IgE-immunoblotting of peach, serum IgE antibodies of two patients were bound to approximately 10 kDa proteins. Meanwhile, the cross-reactivity between Rosaceae fruits, such as peach, apple, apricot, and plum, has been reported. These results suggest that in patients, who are suspected of having peach anaphylaxis and show a negative ImmunoCAP result to peach, the additional testing, such as SPT with peach, should be performed for diagnosis.

Clinical features of four cases with cashew nut allergy and cross-reactivity between cashew nut and pistachio.

BACKGROUND: Few cases of cashew nut (CN) allergy have been reported in Japan. We evaluated the clinical features of 4 cases with CN allergy and investigated the allergens involved. METHODS: In order to investigate the cross-reactivity between CN and pistachios, we performed ImmunoCAP inhibition tests using sera of 4 cases with positive histories of CN allergy and positive results of specific IgE measurement (ImmunoCAP) and skin prick tests. Furthermore, we analyzed the molecular weights of allergens of CN and pistachios by IgE-immunoblotting. RESULTS: Of the 4 cases (male : female = 1:3), there were 3 cases (patient #2-4) and 1 case (patient #1) of anaphylaxis and oral allergy syndrome, respectively. The initial symptom was an oropharyngeal symptom in 3 of the 4 cases, of which 2 cases developed anaphylaxis within 10 minutes after eating only a few pieces of CN. All 4 cases reacted positively to the skin prick test with CN, although 1 case of anaphylaxis tested negatively for CN by ImmunoCAP. Additionally, in 2 cases, IgE-binding to CN and pistachio were inhibited with both pistachios and CN, indicating cross-reactivity between CN and pistachios. IgE-immunoblotting of CN using sera from the 4 cases revealed 2 bands at molecular weights of approximately 33 kd and 42 kd, whereas that of pistachios showed a single band at 36 kd. However, IgE in all 4 sera did not bind to rAna o 2. CONCLUSIONS: In CN allergy, a small amount of CN could induce a severe anaphylactic reaction. Moreover, in cases of suspected CN allergy, reactions to not only CN but also pistachio, which could be cross-reactive to CN, should be examined.

Heme oxygenase 1 attenuates the development of atopic dermatitis-like lesions in mice: implications for human disease.

BACKGROUND: Oxidative stress has been implicated in the exacerbation of atopic dermatitis (AD). OBJECTIVE: We sought to investigate the pathophysiologic roles of inducible antioxidant heme oxygenase (HO) 1 in the development of AD. METHODS: Serum HO-1 levels of patients with AD (n = 100) and age-matched healthy control subjects (n = 72) were determined by means of ELISA. The relationships between serum HO-1 levels and clinical severities, laboratory parameters, and cytokines/chemokines were assessed. Skin lesions of patients with AD and psoriasis were analyzed by means of immunohistochemistry. A murine AD model, DS-Nh, was used to further investigate localization and function of HO-1. Evaluation of symptoms, serum IgE and IL-18 levels, immunoblotting results, and histologic analyses of skin were performed. The effect of intraperitoneally administered hemin, a potent HO-1 inducer, or zinc protoporphyrin IX, an inhibitor of HO, was monitored. RESULTS: Serum HO-1 levels were significantly increased in patients with AD compared with those seen in healthy control subjects and were associated with AD disease severity. Serum HO-1 levels correlated with serum IgE, lactate dehydrogenase, IL-18, and thymus and activation-regulated chemokine levels. HO-1-expressing cells were accumulated in skin lesions of patients with AD and DS-Nh mice. Immunofluorescence of mouse skin lesions revealed that HO-1-positive cells were macrophages and dendritic cells. Treatment with hemin, but not with zinc protoporphyrin IX, attenuated the development of the skin lesions in DS-Nh mice and reduced serum IL-18 levels. CONCLUSION: HO-1 levels were increased in sera and skin lesions of patients with AD. Enhancement of HO-1 attenuated the development of skin lesions in mice, suggesting that HO-1 induction offers a promising therapeutic strategy for AD.

[Correlation of oral allergy syndrome due to plant-derived foods with alder pollen, rbet v 1 and rbet v 2 sensitization in Yokohama region].

BACKGROUND/AIM: Oral allergy syndrome (OAS) to plant foods is often caused by cross-reactivity to pollen. We investigated whether there was any significant correlation between sensitization to the pollen of alder and Japanese cedar flying off in spring and prevalence of OAS in Yokohama region. METHODS: We measured specific IgE antibodies (CAP-FEIA: CAP) against alder and Japanese cedar in 337 outpatients with skin allergy in 2005 (M:F=167:170, 33.4 years of age, on the average). In the patients who showed positive response to CAP against alder and Japanese cedar, we also tested response to CAP against rBet v 1 and rBet v 2. In addition, we statistically analyzed whether there was any correlation between prevalence of OAS and sensitization to the pollen. RESULTS: Ratio of positive response to CAP against alder was 23.4% (79 cases) while that to CAP against Japanese cedar was 73.7% (244 cases). Response to CAP against rBet v 1 and rBet v 2 was tested in 55 cases, and the ratio of positive response to CAP against rBet v 1 was 43.6% (24 cases) while that to CAP against rBet v 2 was 27.3% (15 cases). Prevalence of OAS showed a significant positive correlation (p<0.001) with sensitization to alder, but no correlation with sensitization to Japanese cedar. CONCLUSION: It was suggested that sensitization to alder pollen would be involved in prevalence of OAS in Yokohama region.

[Oral allergy syndrome due to plant-derived foods: a clinical review of 63 patients over a period of 6 years].

BACKGROUND: The clinical features of many patients with oral allergy syndrome (OAS) due to plant-derived foods have rarely been reported in Japan. OBJECTIVES: We aimed to determine the causative foods of OAS due to plant-derived foods based on clinical features and skin prick tests (SPTs). Furthermore, we aimed to elucidate the association between causative foods and sensitized pollens in patients with OAS due to plant-derived foods. METHODS: SPTs and specific IgE measurements (CAP-FEIA: CAP) were performed in relation to foods and pollens in 118 patients with positive histories of OAS due to plant-derived foods. Patients with positive histories and with positive skin test responses were identified as having type I allergy to the causative foods. RESULTS: The mean age of 63 patients with positive histories and positive skin test responses was 29.2 years (range, 2-61 years), and there were twice as many females as male. The most frequent causative foods were found to be apple, peach, kiwi, and melon in 13, 12, 12, and 11 patients, respectively. CAP frequency was shown to be similar to that of SPT regarding apple, whereas it was less than that of SPT regarding melon, peach, and kiwi. A significant correlation between the frequencies of SPT and CAP was found regarding apple (r=0.39, p<0.05) but not peach, kiwi, and melon. Forty-one of 63 patients with OAS (66.1%) had pollinosis and/or allergic rhinitis. In patients with OAS due to apple, the positive ratio of CAP response against alder pollen was higher than that in patients with OAS due to melon. In patients with OAS due to melon, the positive ratio of CAP responses against ragweed pollen, grass pollen, and mugwort pollen was higher than that in patients with OAS due to apple. CONCLUSION: In this study, positive ratios of SPT and CAP tended to differ according to the causative food, showing a smaller potential for reaction than might be suggested by patient history. Therefore, for the time being it would be more accurate to use a skin test for the diagnosis of OAS due to plant-derived foods.