CCR7 is regarded as an essential chemokine receptor for cutaneous dendritic cell (DC) migration into the regional lymph nodes. However, complete migratory inhibition cannot be obtained in CCR7-deficient mice, suggesting that there exist other chemokine receptors involved in this process. Initially, we found that CXCR4 was highly expressed on migrated cutaneous DCs and that its ligand, CXCL12, was detected in the LYVE-1 ؉ lymphatic vessels in the skin. FITC-induced cutaneous DC migration into the draining lymph nodes was impaired by the specific CXCR4 antagonist 4-F-Benzoyl-TN14003. Among FITC ؉ cells, Langerin

Psoriasis is a common chronic inflammatory skin disease that involves dysregulated interplay between immune cells and keratinocytes. Recently, it has been reported that IL-23 induces CCR6+ γδ T cells, which have the pivotal role in psoriasis-like skin inflammation in mice of producing IL-17A and IL-22. Langerhans cells (LCs) are a subset of dendritic cells that reside in the epidermis and regulate immune responses. The role of LCs has been extensively investigated in contact hypersensitivity, but their role in psoriasis remains to be clarified. In this study, we focused on Th17-related factors and assessed the role of LCs and γδ T cells in the development of psoriasis using a mouse psoriasis model triggered by topical application of imiquimod (IMQ). LC depletion by means of diphtheria toxin (DT) in Langerin DT receptor-knocked-in mice suppressed hyperkeratosis, parakeratosis, and ear swelling in the IMQ-treated regions. In addition, LC-depleted mice showed decreased levels of Th17-related cytokines in IMQ-treated skin lesions. Moreover, the IMQ-treated skin of LC-depleted mice showed a decreased number of IL-17A-producing CCR6+ γδ T cells. These results suggest that LCs are required for the development of psoriasis-like lesions induced by IMQ in mice.

Cutaneous involvement is seen in ϳ 50% of adult T-cell leukemia/lymphoma (ATLL) patients. We investigated the association between skin eruption type and prognosis in 119 ATLL patients. ATLL eruptions were categorized into patch (6.7%), plaque (26.9%), multipapular (19.3%), nodulotumoral (38.7%), erythrodermic (4.2%), and purpuric (4.2%) types. When the T stage of the tumor-nodemetastasis-blood (TNMB) classification of mycosis fungoides/Sézary syndrome was applied to ATLL staging, 16.0% were T1, 17.7% T2, 38.7% T3, and 4.2% T4, and the remaining 23.5% were of the multipapular and purpuric types. For the patch type, the mean survival time (median survival time could not be estimated) was 188.4 months. The median survival times (in months) for the remaining types were as follows: plaque, 114.9; multipapular, 17.3; nodulotumoral, 17.3; erythrodermic, 3.0; and purpuric, 4.4. Kaplan-Meier curves of overall survival showed that the erythrodermic type had the poorest prognosis, followed by the nodulotumoral and multipapular types. The patch and plaque types were associated with better survival rates. Multivariate analysis demonstrated that the hazard ratios of the erythrodermic and nodulotumoral types were significantly higher than that of the patch type, and that the eruption type is an independent prognostic factor for ATLL. The overall survival was worse as the T stage became more advanced: the multipapular type and T2 were comparable, and the purpuric type had a significantly poorer prognosis than T1. (Blood. 2011;117(15): 3961-3967)

There are immediate, late-phase, and delayed-type reactions to exogenous agents. In IFN-gamma-knockout (IFN-gamma(-/-)) and wild-type B6 mice, we examined the response to picryl chloride (PCl) for assessing delayed-type reactions, and the responses to repeatedly challenged FITC for immediate and late-phase reactions. The delayed-type hypersensitivity was depressed in IFN-gamma(-/-) mice, and the immediate and late-phase reactions were enhanced in IFN-gamma(-/-) mice. As skin-infiltrating lymphocytes were scarce at the PCl-challenged site of IFN-gamma(-/-) mice, we investigated chemokine production by keratinocytes and Langerhans cells (LCs). A real-time PCR analysis demonstrated that Th1 chemokines (CXCL9 and CXCL10) and Th2 chemokines (CCL17 and CCL22) were derived mainly from keratinocytes and LCs, respectively. Challenge with PCl or FITC augmented keratinocyte expression of Th1 chemokines in wild-type but not in IFN-gamma(-/-) mice, and Th2 chemokine production by LCs was induced by repeated FITC in IFN-gamma(-/-) mice. Finally, transfer of carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeled draining lymph node cells from hapten-sensitized B6 mice or lymph node cells from sensitized green fluorescent protein (GFP) mice to naive IFN-gamma(-/-) mice revealed less infiltration of CFSE(+) or GFP(+) lymphocytes at the challenged site. Our study suggests that one of the crucial actions of IFN-gamma is upregulation of keratinocyte production of Th1 chemokines and downregulation of LC production of Th2 chemokines.

Our study demonstrated that the expression of functional innate immune receptors is augmented by the pathogen-associated molecules in a ligand-feed forward or nonrelated manner in keratinocytes, and histamine promotes their expression and the resultant production of cytokines and defensins.

Although skin grafting is a common surgical technique, the immunological state of grafted skin remains unelucidated. An experimental model has shown that the development of murine contact hypersensitivity (CHS) is depressed when mice are sensitized with a hapten through full-thickness grafted skin. We explored the immunological mechanisms underlying this hyposensitization, focusing on the fate of Langerhans cells (LCs). When FITC was applied to grafted skin, FITC-bearing LCs were capable of migrating to the draining lymph nodes. Epidermal cell suspensions isolated from the grafted skin produced a high amount of IL-10 as assessed by real-time PCR. Adoptive transfer of immune lymph node cells from the sensitized mice suppressed the CHS response of recipients in an antigen-specific manner. CD4(+)CD25(+) but not CD4(+)CD25(-) T cells purified from lymph node cells were responsible for this suppression. Finally, we detected high expression of receptor activators of nuclear factor kappa-B ligand (RANKL) in the grafted skin, and found that recombinant RANKL stimulated LCs to produce IL-10. These findings suggest that the hyposensitization of CHS through the grafted skin is not attributable merely to the reduction of LC number but that IL-10-producing LCs exert a downmodulatory effect by inducing regulatory T cells.

Extramammary Paget's disease that occurs in non-apocrine-bearing regions is referred to as ectopic and has been rarely reported. A 62-year-old man presented with a slowly progressive, asymptomatic light-brown plaque on his back. Histopathological examination revealed the presence of large pale cells with prominent nuclei, which proliferated diffusely and focally in the epidermis. Immuno-histochemically the tumour cells were positive for CK7, GCDFP-15, CEA, and p63. Based on these findings, we diagnosed the tumour as ectopic extramammary Paget's disease. We reviewed the English and Japanese literature and found 29 previously reported cases of ectopic extramammary Paget's disease, including our case, with a predominance of occurrence in the Asian population. The germinative milk line is known to be a possible site where extramammary Paget's disease occurs. Like-wise, some germinative apocrine-differentiating cells might exist on the trunk preferentially in Asians. Attention should be paid to the development of ectopic as well as triple or quadruple EMPD in Asians.

The mechanism underlying the local UVB-induced immunosuppression is a central issue to be clarified in photoimmunology. There have been reported a considerable number of cells and factors that participate in the sensitization phase-dependent suppression, including Langerhans cells (LCs), regulatory T cells, IL-10, and TNF-α. The recent important finding that LC-depleted mice rather exhibit enhanced contact hypersensitivity responses urged us to re-evaluate the role of LCs along with dermal dendritic cells (dDCs) in the mechanism of UVB-induced immunosuppression. We studied the surface expression of OX40 ligand (OX40L) and the intracellular expression of IL-10 in LCs and dDCs from UVB-irradiated (300 mJ/cm2) skin of BALB/c mice and those migrating to the regional lymph nodes from UVB-irradiated, hapten-painted mice. In epidermal and dermal cell suspensions prepared from the UVB-irradiated skin, LCs expressed OX40L as well as CD86 and produced IL-10 at a higher level than Langerin‒ dDCs. The UVB-induced immunosuppression was attenuated by the administration of IL-10–neutralizing or OX40L-blocking Abs. In mice whose UVB-irradiated, hapten-painted skin was dissected 1 d after hapten application, the contact hypersensitivity response was restored, because this treatment allowed dDCs but not LCs to migrate to the draining lymph nodes. Moreover, LC-depleted mice by using Langerin-diphtheria toxin receptor–knocked-in mice showed impaired UVB-induced immunosuppression. These results suggest that IL-10–producing and OX40L-expressing LCs in the UVB-exposed skin are mandatory for the induction of Ag-specific regulatory T cells.