Leptin controls hair follicle cycling.

Leptin is a cytokine well known for its ability to control body weight and energy metabolism. Several lines of evidence have recently revealed that leptin also plays an important role in wound healing and immune modulation in skin. Sumikawa et al. Exp Dermatol 2014 evaluated the effect of leptin on hair follicle cycling using mutant and wild-type mice. They report that leptin is produced in dermal papilla cells in hair follicles and that leptin receptor-deficient db/db mice show an abnormality in hair follicle cycling. Moreover, leptin injection induced the transition into the growth stage of the hair cycle (anagen). On this basis, it now deserves exploration whether leptin-mediated signalling is a key stimulus for anagen induction and whether this may be targeted to manage human hair disorders with defect in the control of hair follicle cycling.

Galectin-7, induced by cis-urocanic acid and ultraviolet B irradiation, down-modulates cytokine production by T lymphocytes.

Urocanic acid (UCA) is an epidermal chromophore that undergoes trans to cis isomerization after UVB irradiation. cis-UCA is a potent inhibitor of cutaneous acquired immunity. The aim of this study was to explore the genes, which are upregulated by cis-UCA in normal human epidermal keratinocytes (NHEK) and investigated its role in vitro using human T-lymphocyte cell line, Jurkat cells. DNA microarray analysis and real-time PCR investigation revealed that cis-UCA, not trans-UCA, increased the expression of a gene encoding a ß-galactoside-binding lectin, galectin-7, LGALS7B. Immunohistochemical study demonstrated that galectin-7 was highly expressed in the epidermis in the patients with actinic keratosis. Galectin-7 administration upregulated apoptosis and inhibited the expression of interleukin-2 (IL2) and interferon-γ (IFNG) mRNA in Jurkat cells. Taken together, galectin-7 may play important roles in downregulating the functions of T lymphocytes after UVB irradiation and can be developed into novel immunosuppressive therapies for inflammatory skin diseases.

High frequencies of positive nickel/cobalt patch tests and high sweat nickel concentration in patients with intrinsic atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is classified into extrinsic AD with high serum IgE levels and impaired barrier, and intrinsic AD with low serum IgE levels and unimpaired barrier. Intrinsic AD has a lower frequency of FLG mutations and a higher frequency of circulating Th1 cells, implying that non-protein antigens, represented by metals, may be an exacerbation factor in intrinsic AD. OBJECTIVE: To investigate metal allergy in intrinsic AD. METHODS: Enrolled in this study were 86 Japanese AD patients seen in three university hospitals, consisting of 55 extrinsic and 31 intrinsic AD patients. Patch testing was performed, focusing on nickel, cobalt, and chrome, in parallel with other 14 metals. FLG mutations were analyzed in 49 patients (extrinsic, 29; intrinsic, 20). In 17 patients (extrinsic, 12; intrinsic, 5), sweat was collected from the forearms by exercise, and the concentration of nickel was fluorometrically measured. RESULTS: Nickel, cobalt, and chrome were the major positive metals. Intrinsic AD showed significantly higher percentages of positive reactions than extrinsic AD to nickel (intrinsic 41.9% vs extrinsic 16.4%, P=0.019) and cobalt (38.7% vs 10.9%, P=0.005). There was no significant difference between FLG mutation-bearing and non-bearing patients. The concentration of nickel was higher in the sweat of intrinsic AD than extrinsic AD patients (333.8 vs 89.4ng/g, P=0.0005) and inversely correlated with serum IgE levels. CONCLUSIONS: Nickel and cobalt allergy may be involved in intrinsic AD. Given that the metals are excreted through sweat, intrinsic AD might be exaggerated by highly metal-containing sweat.

Combination of skin-directed therapy and oral etoposide for smoldering adult T-cell leukemia/lymphoma with skin involvement.

Approximately 50% of patients with adult T-cell leukemia/lymphoma (ATLL) have skin involvement, and the smoldering, skin lesion-bearing cases are often treated with various skin-directed therapies, such as phototherapy and radiation therapy. Daily oral administration of etoposide plus prednisolone (EP) is also used for smoldering-type ATLL. However, it remains unclear whether these therapies improve patients' survival. We retrospectively analyzed the prognosis of patients with smoldering, skin lesion-bearing ATLL (n = 62), who were treated, as first therapy, with one skin-directed therapy (n = 29), oral EP alone (n = 14) or a combination of skin-directed therapy and oral EP (n = 19). Multivariate analysis revealed that the hazard ratios (HRs) for the overall survival (OS) and progression-free survival (PFS) with the combination therapy were significantly lower than those with the skin-directed therapy (HR 0.1, p = 0.001; HR 0.2, p = 0.002, respectively). These results suggest that the combination of skin-directed therapy and oral EP improves the clinical outcome of patients with smoldering, skin lesion-bearing ATLL.

Defective epidermal innate immunity and resultant superficial dermatophytosis in adult T-cell leukemia/lymphoma.

PURPOSE: Superficial dermatophytosis is quite commonly seen in patients with adult T-cell leukemia/lymphoma (ATLL), as approximately 50% of the patients develop cutaneous mycotic infections. Because superficially infected fungi in the stratum corneum of the epidermis cannot directly contact with T cells infiltrating in the upper dermis, some perturbation of epidermal innate immunity has been postulated. Interleukin (IL)-17-producing helper T cells (Th17) can induce the keratinocyte production of antimicrobial peptides such as human ß defensin (HBD)-2 and LL-37, which play an essential role in cutaneous innate immunity. EXPERIMENTAL DESIGN: We investigated the frequency of circulating Th17 cells, serum levels of cytokines, and epidermal expression of HBD-1, 2, 3, and LL-37 in ATLL patients with or without superficial dermatophytosis. RESULTS: The frequency of peripheral Th17 cells and the serum level of IL-17 was significantly decreased in ATLL patients, whereas the serum IL-10 and TGF-ß1 levels were increased as compared with healthy controls. Furthermore, ATLL patients with dermatophytosis had higher IL-10 and TGF-ß1 levels and lower IL-17 levels than did those without dermatophytosis. Immunohistochemical study revealed that the epidermal expression of both HBD-2 and LL-37 were significantly lower in ATLL patients with dermatophytosis than in non-ATLL patients with dermatophytosis. CONCLUSIONS: Taken together, these results suggest that the keratinocyte production of antimicrobial peptides promoted by Th17 cells is reduced in ATLL patients, leading to the perturbed innate immunity and the frequent occurrence of superficial dermatophytosis.

A group of atopic dermatitis without IgE elevation or barrier impairment shows a high Th1 frequency: possible immunological state of the intrinsic type.

BACKGROUND: Atopic dermatitis (AD) can be classified into the major extrinsic type with high serum IgE levels and impaired barrier, and the minor intrinsic type with normal IgE levels and unimpaired barrier. OBJECTIVE: To characterize the intrinsic type of Japanese AD patients in the T helper cell polarization in relation to the barrier condition. METHODS: Enrolled in this study were 21 AD patients with IgE<200kU/L (IgE-low group; 82.5±59.6kU/L) having unimpaired barrier, and 48 AD patients with IgE>500kU/L (IgE-high group; 8.050±10.400kU/L). We investigated filaggrin gene (FLG) mutations evaluated in the eight loci common to Japanese patients, circulating Th1, Th2 and Th17 cells by intracellular cytokine staining and flow cytometry, and blood levels of CCL17/TARC, IL-18, and substance P by ELISA. RESULTS: The incidence of FLG mutations was significantly lower in the IgE-low group (10.5%) than the IgE-high group (44.4%) (normal individuals, 3.7%). The percentage of IFN-γ-producing Th1, but not Th2 or Th17, was significantly higher in the IgE-low than IgE-high group. Accordingly, Th2-attracting chemokine CCL17/TARC, was significantly lower in the IgE-low than the IgE-high group. There were no differences between them in serum IL-18 levels, or the plasma substance P levels or its correlation with pruritus. CONCLUSION: The IgE-low group differed from the IgE-high group in that it had much less FLG mutations, increased frequency of Th1 cells, and lower levels of CCL17. In the intrinsic type, non-protein antigens capable of penetrating the unimpaired barrier may induce a Th1 eczematous response.