Basophils express major histocompatibility complex class II, CD80 and CD86 and produce interleukin 4 (IL-4) in various conditions. Here we show that when incubated with IL-3 and antigen or complexes of antigen and immunoglobulin E (IgE), basophils internalized, processed and presented antigen as complexes of peptide and major histocompatibility complex class II and produced IL-4. Intravenous administration of ovalbumin-pulsed basophils into naive mice 'preferentially' induced the development of naive ovalbumin-specific CD4+ T cells into T helper type 2 (T(H)2) cells. Mice immunized in this way, when challenged by intravenous administration of ovalbumin, promptly produced ovalbumin-specific IgG1 and IgE. Finally, intravenous administration of IgE complexes rapidly induced T(H)2 cells only in the presence of endogenous basophils, which suggests that basophils are potent antigen-presenting cells that 'preferentially' augment T(H)2-IgE responses by capturing IgE complex.

Generalized pustular psoriasis (GPP) is a rare disease characterized by recurrent fever and systemic flushing accompanied by extensive sterile pustules. The committee of the guidelines was founded as a collaborative project between the Japanese Dermatological Association and the Study Group for Rare Intractable Skin Diseases under the Ministry of Health, Labour, and Welfare Research Project on Overcoming Intractable Diseases. The aim of the guidelines was to provide current information to aid in the treatment of patients with GPP in Japan. Its contents include the diagnostic and severity classification criteria for GPP, its pathogenesis, and recommendations for the treatment of GPP. Since there are few clinical trial data with high levels of evidence for this rare disease, recommendations by the committee are described in the present guidelines.

Transgenic mice expressing the mouse interleukin 33 (IL-33) gene driven by a keratin 14 promoter were generated. The skin-selective expression of the IL-33 gene was enhanced, and intense immunofluorescence for IL-33 was evident in the nuclei of the epidermis. Spontaneous itchy dermatitis developed in those mice at 6-8 wk of age in specific pathogen-free conditions. In the lesional skin, the epidermis was thickened and the eosinophils were infiltrated with increased expression of the eosinophil peroxidase and major basic protein genes. Mast cells were also abundant there, and blood histamine and total IgE levels were high. Those phenotypes closely resemble the features of atopic dermatitis. In peripheral blood and lesional skin, IL-5, IL-13, regulated upon activation, normally Texpressed, and presumably secreted (RANTES)/CCL5, and Eotaxin 1/CCL11 were increased, whereas TNF-α, IFN-γ, and thymic stromal lymphopoietin (TSLP) were unaltered. Furthermore, the proportion of group 2 innate lymphoid cells (ILC2s), which produce IL-5, were significantly increased in the lesional skin, peripheral blood, and regional lymph nodes. The dermatitis with eosinophil infiltration was improved by the administration of an anti-IL-5 antibody. These results suggest that the expression of IL-33 in the skin activates an immune response involving ILC2 and that this process might play a crucial role in the pathogenesis of allergic inflammation that is characteristic of atopic dermatitis.Atopy | natural helper cells | nuocytes

Atopic dermatitis (AD) is characterized by pruritus, barrier disruption, and inflammationincluding type 2 cytokine production. Interleukin-33 (IL-33) is an inflammatory cytokine that is over-expressed in the keratinocytes of patients with AD. IL-33 transgenic mice, which express IL-33 specifically in keratinocytes, spontaneously develop AD-like eczema, suggesting that IL-33 is sufficient for the development of AD. IL-33 stimulates various cells, including group 2 innate lymphoid cells (ILC2s), to produce type 2 cytokines, such as IL-5 and IL-13, and IL-33-stimulated basophils activate ILC2s via IL-4. ILC2s are enriched in human AD skin lesions, and ILC2 isolated from AD lesions, are activated by IL-33, not by thymic stromal lymphopoietin (TSLP). IL-33 induces IL-31, thereby promoting pruritus and scratching behavior. Conversely, scratching the skin promotes IL-33 release from keratinocytes. IL-33 reduces the expression of filaggrin and claudin-1; it also reduces the skin barrier function. However, barrier destruction causes percutaneous exposure to allergens or IL-33 release. Thus, IL-33 is a common point of entry into the itch-scratch cycle of AD. These new findings can facilitate the development of novel therapeutic drugs targeting IL-33.

Atopic dermatitis (AD) is a common inflammatory skin disease of unknown etiology. Cutaneous infection with microbes such asMajor features of AD are pruritus, chronic relapsing course, and genetic predisposition (1-3). AD is divided into two types: (i) AD associated with IgE-mediated responses, affecting 70-80% of patients and termed ''extrinsic AD,'' and (ii) AD without IgEmediated responses, affecting 20-30% of patients and termed ''intrinsic AD.'' Patients with extrinsic AD show preferential deviation toward T helper type 2 (Th2) responses, together with accumulation of Th2 chemokines such as CCL17 (thymus-and activation-regulated chemokine) and CCL22 (monocyte-derived chemokine) in the cutaneous lesions (1, 2). However, recent clinical studies have revealed that the immunological aspects of the skin lesions are quite different among the clinical stages of AD (1-3). Nonetheless, the immunopathological bases for intrinsic AD are still unknown.Recently, we showed that transgenic mice that oversecrete IL-18 from their epidermal cells spontaneously develop AD-like dermatitis under specific pathogen-free (SPF) conditions, and that the deletion of il18, but not stat6, which encodes a signaling molecule necessary for Th2 and IgE responses, protects against the development of AD (4, 5). This finding suggests that excessive cutaneous IL-18 release is a causative factor for intrinsic-type AD. Recent clinical studies have revealed that IL-18 production levels closely parallel disease severity (6-8). Therefore, it is important to clarify whether, and how, endogenous IL-18 contributes to the development of AD when skin is exposed to natural infectious agents.Although it is well documented that cutaneous infection with Staphylococcus aureus exacerbates clinical AD (1, 3), the underlying mechanism is not fully understood. Recently, we demonstrated that protein A (SpA), a surface molecule and virulent factor of S. aureus (9), stimulates mouse epidermal cells to secrete IL-18 (10). However, cutaneous application of SpA alone did not induce major skin alterations in C57BL͞6 mice, despite the fact that it produced elevated serum levels of 10). This outcome led us to assume that additional factors are required for the development of AD. Because skin cleansing with detergent aggravates clinical AD (1, 11), skin barrier destruction seems to be a second important factor in AD development. Inasmuch as NC͞Nga mice, which have a genetically impaired skin barrier due to reduced ceramide production (12), frequently develop AD-like dermatitis after exposure to mites (13-15), we assumed that genetic skin barrier dysfunction was a third prerequisite for the development of AD. Here, we generated an intrinsic AD mouse model by daily application of SpA, after destruction of the skin barrier with a subclinical dose of SDS, a detergent (16). Neutralizing anti-IL-18 Abs could completely protect against SDS͞SpA-induced AD. Furthermore, il18 Ϫ/Ϫ BALB͞c mice evaded development of AD under SDS͞SpA challenge. Our present results clearly demonstrate th...

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IL-33 may down-regulate CLDN1 expression through the ERK/STAT3 pathway in keratinocytes.

Psoriasis is a chronic inflammatory skin disease characterized by the infiltration of T cell and other immune cells to the skin in response to injury or autoantigens. Conventional, as well as unconventional, γδ T cells are recruited to the dermis and epidermis by CCL20 and other chemokines. Together with its receptor CCR6, CCL20 plays a critical role in the development of psoriasiform dermatitis in mouse models. We screened a panel of CCL20 variants designed to form dimers stabilized by intermolecular disulfide bonds. A single-atom substitution yielded a CCL20 variant (CCL20 S64C) that acted as a partial agonist for the chemokine receptor CCR6. CCL20 S64C bound CCR6 and induced intracellular calcium release, consistent with G-protein activation, but exhibited minimal chemotactic activity. Instead, CCL20 S64C inhibited CCR6-mediated T cell migration with nominal impact on other chemokine receptor signaling. When given in an IL-23-dependent mouse model for psoriasis, CCL20 S64C prevented psoriatic inflammation and the up-regulation of IL-17A and IL-22. Our results validate CCR6 as a tractable therapeutic target for psoriasis and demonstrate the value of CCL20 S64C as a lead compound.