Two distinct variants of mycosis fungoides (MF): Folliculotropic MF and erythrodermic MF.

Mycosis fungoides (MF) is the most frequent type of cutaneous T-cell lymphoma. Folliculotropic MF (fMF) and erythrodermic MF (eMF) are two distinct variants of MF. Both variants have been considered aggressive and most cases are less responsive to standard skin-directed therapies than classical MF. We, however, experienced many cases with fMF or eMF who showed indolent clinical courses. In this article, we reviewed 10 cases with fMF and 13 cases with eMF who came to our department between 2005 and 2017. In patients with fMF, monotherapy with topical corticosteroid was effective in two cases (20%) and ultraviolet phototherapy with oral retinoid controlled disease activity in two cases (20%). Five patients with eMF (38%) responded well to ultraviolet phototherapy. In conclusion, patients with early fMF and a subgroup of eMF patients have an indolent disease course, as was proposed among the specialists. Skin-directed therapies are preferable rather than aggressive treatment in those cases.

Keratinocyte Proline-Rich Protein Deficiency in Atopic Dermatitis Leads to Barrier Disruption.

Atopic dermatitis is a common inflammatory skin disease caused by the interaction of genetic and environmental factors. By allelic copy number analysis at missense single-nucleotide polymorphisms on 26 genes with copy number variation, we identified a significant association between atopic dermatitis and human KPRP. Human KPRP expression, which was localized to the upper granular layer of epidermis, was significantly decreased in atopic dermatitis compared with normal skin. KPRP was histologically colocalized with loricrin and was mainly detected in cytoskeleton fractions of human keratinocytes. To further investigate the role of KPRP in skin, Kprp-knockout mice were generated. Heterozygous knockout (Kprp+/-) mice exhibited reduced KPRP expression to level a similar to that of human AD lesional skin. Kprp+/- mice showed abnormal desmosome structure and detachment of lower layers of the stratum corneum. Percutaneous inflammation by topical application of croton oil or oxazolone was enhanced, and epicutaneous immunization with ovalbumin induced a high level of IgE in Kprp+/- mice. Our study, started from allelic copy number analysis in human AD, identified the importance of KPRP, the decrease of which leads to barrier dysfunction.

Chemokines and skin diseases.

Chemokines are small molecules that induce chemotaxis and activation of certain subsets of leukocytes. The expression patterns of chemokines and chemokine receptors are specific to certain organs and cells. Therefore, chemokines are important to elucidate the mechanism of organ-specific human diseases. CCL17 expressed by Langerhans cells, blood endothelial cells, and fibroblasts plays a key role in attracting Th2 cells and tumor cells of adult T-cell leukemia/lymphoma and mycosis fungoides/Sézary syndrome into the skin, developing various Th2-type inflammatory skin diseases as well as cutaneous lymphoma. CCL11 and CCL26 expressed by skin-resident cells, such as fibroblasts, blood endothelial cells, and keratinocytes, induce infiltration of CCR3-expressing cells such as Th2 cells and eosinophils. CCL11 may also serve as an autocrine as well as a paracrine in anaplastic large cell lymphoma. CX3CL1 expressed on blood endothelial cells leads to infiltration of CX3CR1(+) immune cells, such as mast cells, neutrophils, and macrophages, playing important roles in wound healing, tumor immunity, and vasculitis. Biologics targeting chemokines and their receptors are promising strategies for various skin diseases that are resistant to the current therapy.

Effects of the immunosuppressant rapamycin on the expression of human α2(I) collagen and matrix metalloproteinase 1 genes in scleroderma dermal fibroblasts.

BACKGROUND: Rapamycin has been shown to exert an anti-fibrotic effect on skin fibrosis in a certain subset of patients with systemic sclerosis (SSc) and in bleomycin-treated animal models. OBJECTIVES: To investigate the mechanism responsible for the anti-fibrotic effect of rapamycin especially by focusing on human α2(I) collagen (COL1A2) and matrix metalloproteinase 1 (MMP1) genes in normal and systemic sclerosis (SSc) dermal fibroblasts. METHODS: The expression levels of type I procollagen and MMP1 proteins were analyzed by immunoblotting and the mRNA levels of COL1A2 and MMP1 genes were evaluated by quantitative real-time RT-PCR. The activities of COL1A2 and MMP1 promoters were determined by reporter analysis. RESULTS: Rapamycin significantly decreased the levels of type I procollagen protein and COL1A2 mRNA, while significantly increasing the levels of MMP1 protein and mRNA in normal dermal fibroblasts. Similar effects of rapamycin were also observed in SSc dermal fibroblasts. Importantly, the inhibitory and stimulatory effects of rapamycin on the mRNA levels of COL1A2 and MMP1 genes, respectively, were significantly greater in SSc dermal fibroblasts than in normal dermal fibroblasts. In SSc dermal fibroblasts, rapamycin affected the expression of COL1A2 gene at the post-transcriptional level. In contrast, rapamycin altered the expression of MMP1 gene at the transcriptional level through the JNK/c-Jun signaling pathway in those cells. CONCLUSION: Rapamycin has a potential to directly regulate the deposition of type I collagen in extracellular matrix through inhibiting type I collagen synthesis and promoting its degradation by MMP1, suggesting that this drug is useful for the treatment of SSc.

Cilostazol improves lymphatic function by inducing proliferation and stabilization of lymphatic endothelial cells.

BACKGROUND: Cilostazol, an inhibitor of phosphodiesterase type III, is an antiplatelet agent and vasodilator. Some clinical reports have suggested that this drug can improve progressive and refractory lymphedema. OBJECTIVE: In this study, we investigated whether cilostazol has the potential to proliferate lymphatic vessels and to improve lymphatic function using human lymphatic endothelial cells (LECs) and mouse lymphedema models. METHODS: Human LECs were counted at several time points while they were cultured in the presence of cilostazol and/or protein kinase A inhibitor. After receiving a diet including 0.1% cilostazol or control diet, skin tissue and lymphatic function of k-cyclin transgenic (kCYC(+/-)) mice, which have pernicious lymphatic dysfunction, was analyzed. A different lymphedema model was generated in wild type mice by excising circumferential tail skin to remove the superficial lymphatics. After oral administration of cilostazol, tail lymphedema was examined in this mouse model. RESULTS: Proliferation of LECs was promoted in a dose-dependent manner, which was partially inhibited by a protein kinase A inhibitor. Lymphatic vessel count increased in the cilostazol-treated kCYC(+/-) mice over that in the non-treated mice. Lymph flow improved in cilostazol-fed kCYC(+/-) mice as assessed by subcutaneous injection of Evans blue dye into the footpad. Oral administration of cilostazol also decreased lymphedema in a tail of wild type mice. CONCLUSION: Cilostazol promoted growth of human LECs and improved lymph flow and lymphedema in two different mouse lymphedema models. These results suggest that cilostazol would be a promising agent for the treatment of lymphedema.

Lymphatic dysfunction impairs antigen-specific immunization, but augments tissue swelling following contact with allergens.

The lymph transports tissue-resident dendritic cells (DCs) to regional lymph nodes (LNs), having important roles in immune function. The biological effects on tissue inflammation following lymphatic flow obstruction in vivo, however, are not fully known. In this study, we investigated the role of the lymphatic system in contact hypersensitivity (CHS) responses using k-cyclin transgenic (kCYC(+/-)) mice, which demonstrate severe lymphatic dysfunction. kCYC(+/-) mice showed enhanced ear swelling to both DNFB and FITC, as well as stronger irritant responses to croton oil compared with wild-type littermates. Consistently, challenged ears of kCYC(+/-) mice exhibited massive infiltrates of inflammatory cells. In contrast, DC migration to regional LNs, drainage of cell-free antigen to LNs, antigen-specific IFN-γ production, and lymphocyte proliferation were impaired during the sensitization phase of CHS in kCYC(+/-) mice. Transfer experiments using lymphocytes from sensitized mice and real-time PCR analysis of cytokine expression using challenged ear revealed that ear swelling was enhanced because of impaired lymphatic flow. Collectively, we conclude that insufficient lymphatic drainage augments apparent inflammation to topically applied allergens and irritants. The findings add insight into the clinical problem of allergic and irritant contact dermatitis that commonly occurs in humans with peripheral edema of the lower legs.

CCL17 transgenic mice show an enhanced Th2-type response to both allergic and non-allergic stimuli.

CC chemokine ligand (CCL)17 is implicated in the pathogenesis of atopic dermatitis (AD). To study the effect of CCL17 produced by keratinocytes (KC) during inflammation, we created transgenic (Tg) mice in which CCL17 is overexpressed in KC. Th2-type contact hypersensitivity (CHS) was enhanced and Th1-type CHS was suppressed in these mice. Increased numbers of CC chemokine receptor (CCR)4(+) cells and mast cells infiltrated in Tg mice. Levels of IL-4 mRNA were higher and those of IFN-gamma mRNA were lower in both acute and chronic CHS. Higher levels of serum IgE were observed after CHS. Numbers of CCR4(+) cells among PBMC were increased in Tg mice challenged acutely on the trunk. Chronic irritation with croton oil induced dermatitis and an elevation of serum IgE levels. Tg mice showed enhanced ear swelling after tape stripping. CCL17 was thought to modify the inflammation caused by sensitizing reagents as well as irritant reagents by attracting CCR4(+) cells into the lesional skin and creating a Th2-dominant condition. AD-like conditions such as increased number of mast cells and elevated levels of serum IgE were observed. Thus, CCL17 may participate in the pathogenesis of skin diseases such as AD by regulating both allergic and irritant inflammation.