Osamu Koro

Chemical mediators in atopic dermatitis: Involvement of leukotriene B4 released by a type I allergic reaction in the pathogenesis of atopic dermatitis

BACKGROUND The mediators produced from a type I allergic reaction have not yet been able to explain the pathogenesis of atopic dermatitis (AD). OBJECTIVE The purpose of this study was to elucidate the involvement of leukotriene (LT) B4 produced from a type I allergic reaction in the pathogenesis of AD. METHOD The release of LTB4 was measured both in vitro, in passively sensitized and antigen-challenged human skin slices, as well as in vivo, in skin chambers on patients with AD. RESULTS LTB4 was released from in vitro human skin by stimulation of the antigen (54.9 +/- 14.6 pg/g wet weight of skin by antigen challenge and 28.0 +/- 11.1 pg/g in control skin, P <.002). Antigen-specific release of LTB4 and histamine was also observed in vivo in nonlesional skin from the patients with AD by using the skin chamber technique. CONCLUSION LTB4 release during type I allergic reaction in human skin has been determined in vitro. The released LTB4 possibly contributes to cellular response at the acute inflammatory lesion of AD.

IgE-mediated Hypersensitivity Against Human Sweat Antigen in Patients with Atopic Dermatitis

Sweating aggravates itch in atopic dermatitis, but the mechanism is unclear. In this study, we examined the involvement of type I hypersensitivity in the aggravation of atopic dermatitis by sweating. Skin tests with autologous sweat were positive in 56 of 66 patients (84.4%) with atopic dermatitis, but only in 3 of 27 healthy volunteers (11.1%). Sweat samples from both patients and healthy volunteers induced varying degrees of histamine release from basophils of patients with atopic dermatitis. However, the histamine release was impaired by removal of IgE on the basophils. Incubation of basophils with myeloma IgE before sensitization with serum of patients blocked the ability to release histamine-induced sweat. IgE antibody against antigen(s) in sweat may be present in serum of patients with atopic dermatitis. Key words:

Safe and Effective Treatment of Refractory Facial Lesions in Atopic Dermatitis Using Topical Tacrolimus following Corticosteroid Discontinuation

Background: Topical corticosteroids are commonly applied in atopic dermatitis (AD) treatment. However, their chronic use may be associated with significant side effects at the application site. Skin atrophy and other undesirable effects are frequently seen after long-term corticosteroid treatment. In addition, when application of corticosteroids is discontinued, a rebound phenomenon in the facial lesions can occur within several days. Topical tacrolimus, an immunosuppressant currently used to prevent rejection after solid-organ transplantation, presents a potential alternative therapeutic agent for AD. Objective: The present study is the first trial designed to evaluate the efficacy and safety of topically applied tacrolimus ointment after corticosteroid discontinuation without a washout phase in severe, long-term facial AD. Patients/Methods: Forty-seven patients with facial refractory AD were recruited, of whom 38 had undergone topical corticosteroid treatment for at least 4 weeks before enrollment (group 1) and the other 9 had not received steroid treatment (group 2). All 47 patients received 0.1% tacrolimus ointment, and the severity index and pruritus score were assessed as an AD clinical activity index every week and compared with baseline data. Results: Both the severity index and pruritus score improved significantly in group 1 after 1 and 2 weeks of application (p < 0.01, respectively). Group 2 showed the greatest improvement at 4 weeks (p < 0.05). In this trial, none of the patients experienced a rebound phenomenon associated with tacrolimus treatment. A transient sensation of burning at the application site was the only adverse event in 31 of the 47 (66%) enrolled patients, but this condition improved after several days. Spectrophotometric assessment of the facial lesion following treatment revealed significant improvement in group 1 (p < 0.05). Conclusion: The present results indicate that topical tacrolimus treatment following corticosteroid discontinuation is safe and effective in refractory facial AD.

Substance P- and antigen-induced release of leukotriene B4, prostaglandin D2 and histamine from guinea pig skin by different mechanisms in vitro

Abstract Substance P (SP) induces increased vascular permeability, vasodilatation and granulocyte infiltration upon intradermal injection. Studies with antagonists and mast cell-deficient mice have suggested that granulocyte infiltration in response SP is mediated by leukotriene (LT) B 4 derived from mast cells. However, the release of LTB 4 has not been detected using mast cells isolated from human skin. Here we report the release of LTB 4 , prostaglandin (PG) D 2 and histamine from guinea pig skin tissue in response to SP. The release of these agents occurred in a dose-dependent manner over a concentration range of SP from 1 × 10 –6 to 3 × 10 –4 M . No detectable PGE 2 was released at any concentration up to 3 × 10 –4 M SP. The kinetics of histamine release induced in response to SP was more rapid than that induced by antigen. By comparison, SP-induced and antigen-induced release of LTB 4 and PGD 2 were similar, but slower than the histamine release. In the absence of extracellular Ca 2+ , release of histamine and PGD 2 in response to SP was partially impaired, but to a lesser extent than that induced by antigen. On the other hand, LTB 4 release in response to both SP and antigen was abolished under the same conditions. These results indicate that SP induces the release of LTB 4 , as well as histamine and PGD 2 , in the skin most likely from mast cells by a mechanism which may be different from that of mediator release in response to antigen.

The release of leukotriene B4 from human skin in response to substance P: evidence for the functional heterogeneity of human skin mast cells among individuals

Substance P is located in cutaneous nerve fibres and induces wheal and flare responses, accompanied by granulocyte infiltration, upon intradermal injection. Studies with animal skin and rat peritoneal mast cells have suggested that substance P induces the release of histamine and leukotriene B4 (LTB4), a potent chemoattractant for granulocytes, from skin mast cells. However, the release of LTB4 has not been detected from mast cells enzymatically isolated from human skin. In order to investigate the mechanism of granulocyte infiltration induced by substance P in human skin, we studied the release of LTB4 and histamine in response to substance P, and the effect of dexamethasone using human skin obtained from 22 nonallergic individuals. Histamine was released from all skin tissue samples in a dose‐dependent manner. However, the amount of LTB4 release, both constitutive and inducible, was variable among skin preparations. Substance P induced a large release of LTB4 from the skin of eight donors (twice to six times that of the spontaneous release), but no or only negligible release from the skin of 14 donors. The amount of constitutive release of LTB4 correlated with the amount of tissue histamine. Dexamethasone selectively abolished the inducible release of LTB4, without an effect on histamine release and the constitutive release of LTB4. These results suggest that substance P induces the release of LTB4 in a certain population of human individuals by a glucocorticosteroid‐dependent mechanism, and plays an important role in neurogenic inflammation with granulocyte infiltration.

Correlation between deposition of immuno-components and infiltration pattern of polymorphonuclear leukocytes in the lesions of chronic urticaria.

Urticaria is often associated with perivascular infiltration of leukocytes into the lesions. Although mast cell‐derived chemical mediators are considered to play crucial roles in the infiltration of leukocytes as well as in the dermal edema, other mechanisms for the leukocyte infiltration have not been well defined. This study revealed that approximately 25% of the cases of chronic idiopathic urticaria in whom wheals had continued for more than 12h had deposition of immuno‐components in the lesions, although histological examination of the lesions did not show leukocytoclastic vasculitis. In these lesions with deposition of immuno‐components, both neutrophils and eosinophils had infiltrated at a constant ratio (approximately 2:1), whereas, in the lesions without deposition, a variable population of leukocytes was seen. This result suggests that activation of complements occurs in the lesions of a considerable percentage of patients with chronic idiopathic urticaria and that the complement fragments influence the infiltration patterns of polymorphonuclear leukocytes.

A Japanese family with dominant pretibial dystrophic epidermolysis bullosa: Identification of a new glycine substitution in the triple-helical collagenous domain of type VII collagen

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English version of the concluding report published in 2001 by the Advisory Committee on Atopic Dermatitis Severity Classification Criteria of the Japanese Dermatological Association

The Japanese Dermatological Association established an advisory committee in 1995 to develop a severity scoring system for atopic dermatitis (AD). Its interim and concluding reports were published in Japanese in the Japanese Journal of Dermatology (108: 1491–1496, 1998 and 111: 2023–2033, 2001). Because of the strong demand for an English version, we have decided to publish the reports in English. This manuscript is the English version of the concluding report. The interim report suggested that eruption components such as erythema, papule, erosion, crust, excoriation and lichenification with extent of involved areas in five body regions, including the head and neck, anterior and posterior trunks, and upper and lower limbs, were important items for assessing AD severity. Additionally, it was recommended that streamlining of eruption components was mandatory for improving the statistical validity and reliability. The committee members subsequently concentrated their efforts on this task, and finally proposed an Atopic Dermatitis Severity Classification Criteria of the Japanese Dermatological Association.

Regulation of inflammation in urticaria.

Urticaria is characterized by wheal and flare, which usually disappear within several hours. However, there are some cases with severe and/or prolonged eruptions lasting more than 24 hours and resistant to treatments by ordinary histamine antagonists. Histology of such cases accompanies various cell infiltrations, such as eosinophils and neutrophils. In order to know the mechanism of such infiltrations, we studied the release of chemotactic activities from skin slices for neutrophils and eosinophils. The factor was identified with LTB4 by HPLC analysis and released either by antigens or substance P. Moreover, studies with skin chambers on patients with chronic urticaria revealed spontaneous release of substance P, suggesting the involvement of neuropeptides in the pathogenesis of chronic urticaria. Incubation of skin slices with dexamethasone scarcely inhibited histamine release, but almost abolished release of LTB4 in response to antigens. Recently-developed histamine H1-antagonists, called anti-allergic drugs, inhibited both degranulation and TNFα releases from rat mast cell (RBL-2H3) line, but concentrations required to inhibit TNFα release was about one tenth of those to inhibit degranulation. Inhibition of LTB4 and TNFα from mast cells may partially account for clinical efficacy of corticosteroids and some anti-allergic drugs for treatment of chronic idiopathic urticaria.