Rina Nakajima

Elevated serum galectin‐9 levels in patients with atopic dermatitis

Galectin‐9 is a member of the galectin family that has a wide spectrum of biological functions. Among them, galectin‐9 has been known mainly as a potent chemoattractant for eosinophils. In addition, galectin‐9 alters the T‐cell balance by negatively regulating T‐helper (Th)1 and Th17 cells, resulting in Th2 polarization. Atopic dermatitis (AD) is a skin allergic disease characterized by peripheral eosinophilia, mast cell activation and predominance of Th2 cells. To investigate possible roles of galectin‐9 in AD, we measured serum galectin‐9 levels in AD patients and investigated galectin‐9 expression in lesional skin by immunohistochemistry. Serum galectin‐9 levels in patients with AD were significantly higher than those in healthy controls and correlated with the Eczema Area and Severity Index. Serum galectin‐9 levels were decreased after treatment, accompanied by improvement of skin lesions. Immunohistochemical study revealed that galectin‐9 was expressed on epidermal keratinocytes and mast cells in lesional skin of AD. Our results suggest that elevated galectin‐9 expression is associated with progression of AD and that galectin‐9 could be a therapeutic target in AD.

Increased syndecan-4 expression in sera and skin of patients with atopic dermatitis

Syndecan-4 (SDC-4) is a cell surface proteoglycan, which participates in signaling during cell adhesion, migration, proliferation, endocytosis, and mechanotransduction, and is expressed on various cells, including endothelial cells, epithelial cells, T cells, and eosinophils. Emerging evidences have suggested that SDC-4 might contribute to Th2-driven allergic immune responses. Here, we examined the role of SDC-4 in patients with atopic dermatitis (AD). Serum SDC-4 levels in AD patients were significantly higher than in healthy individuals, and they increased according to the disease severity. Importantly, they positively correlated with Eczema Area and Severity Index and itch visual analogue scale scores. Furthermore, serum SDC-4 levels decreased after treatment. We also analyzed SDC-4 expression in AD lesional skin. SDC-4 mRNA levels in AD skin were significantly higher than those of normal skin. Immunohistochemical staining revealed that SDC-4 was highly expressed in the epidermis and endothelial cells in AD lesional skin. Taken together, our study has demonstrated that SDC-4 expression was increased in sera and skin of AD patients, suggesting that SDC-4 may contribute to the development of AD.

Exacerbated Immune Complex-Mediated Vascular Injury in Mice with Heterozygous Deficiency of Aryl Hydrocarbon Receptor through Upregulation of Fcγ Receptor III Expression on Macrophages

Aryl hydrocarbon receptor (AhR), which was discovered as a receptor for environmental concomitants, plays an important role widely in the immune system. In this study, we assessed AhR involvement in immune-complex-mediated vascular injury by examining the reverse-passive Arthus reaction in AhR heterozygous knockout (AhR+/-) mice. In the cutaneous Arthus reaction, dermal edema was severer in AhR+/- mice than in wild-type mice. The number of infiltrating neutrophils and mRNA expression levels of CXC chemokine ligand 1 and IL-6 were also increased in AhR+/- mice. Similarly, in the peritoneal Arthus reaction, infiltration of neutrophils was increased in AhR+/- mice. Peritoneal macrophages from AhR+/- mice expressed higher levels of Fcγ receptor III and produced higher levels of CXC chemokine ligand 1 and IL-6 after immune complex treatment. In addition, AhR occupied the promoter regions of Fcγ receptor III gene in peritoneal macrophages in a ligand-dependent manner. Depletion of macrophages reduced the cutaneous Arthus reaction in AhR+/- mice, and adoptive transfer of AhR+/- mice macrophages into wild-type mice exacerbated the peritoneal Arthus reaction. Furthermore, AhR expression was decreased and Fcγ receptor III expression was increased in CD14+ monocytes in peripheral blood from patients with immune-complex-mediated vasculitis compared with those from healthy controls. These results suggest that downregulation of AhR is associated with the exacerbation of immune-complex-mediated vascular injury.

Serum amyloid A levels in the blood of patients with atopic dermatitis and cutaneous T-cell lymphoma

Serum amyloid A (SAA) is an acute phase protein, which activates immune cells and induces cytokines and chemokine. SAA levels in blood have been reported to be elevated in case of inflammation, infections, neoplasia and tissue injury. In this study, we examined SAA levels in the blood of patients with atopic dermatitis (AD) and cutaneous T‐cell lymphoma (CTCL). SAA levels in sera of AD patients, those of CTCL patients and those of healthy controls were not significantly different. When AD or CTCL patients were classified by disease severity, there was still no difference in SAA levels. In AD patients, however, SAA levels positively correlated with the number of eosinophils in peripheral blood and serum soluble interleukin‐2 receptor (sIL‐2R) levels. There were significant correlations between SAA levels in blood and the number of white blood cells in peripheral blood and serum sIL‐2R levels in CTCL patients. AD patients without topical steroid treatment and CTCL patients without narrowband ultraviolet B therapy showed increased levels of SAA, which suggested that SAA levels may easily fluctuate with treatment. These results imply a possible contribution of SAA in development of AD and CTCL.

Increased interleukin-36γ expression in skin and sera of patients with atopic dermatitis and mycosis fungoides/Sézary syndrome

Interleukin (IL)‐36γ is expressed by keratinocytes and functions as a key initiator of inflammation in the skin. IL‐36γ expression is enhanced by tumor necrosis factor‐α and IL‐17A, having a strong association with psoriasis. In this study, we examined the role of IL‐36γ in atopic dermatitis (AD) and mycosis fungoides (MF)/Sézary syndrome (SS). Serum levels of IL‐36γ in AD patients and MF/SS patients were elevated compared with those of healthy controls. Importantly, serum IL‐36γ levels in AD patients positively correlated with Eczema Area and Severity Index and those of MF/SS patients positively correlated with serum soluble IL‐2 receptor levels. IL‐36γ mRNA levels in AD skin and MF/SS skin were significantly higher than those of normal skin. IL‐36γ mRNA levels in MF/SS skin positively correlated with IL‐17A mRNA levels. Immunohistochemical staining revealed that IL‐36γ was highly expressed in keratinocytes in lesional skin of AD and MF/SS. Taken together, our study demonstrated that IL‐36γ expression was increased in sera and skin of patients with AD and MF/SS as was reported in psoriatic patients.

Decreased IL-10-producing regulatory B cells in patients with advanced mycosis fungoides

BackgroundHistorically, B cells have been considered as positive regulators of humoral immune responses. Specific B-cell subsets, however, negatively regulate immune responses and are termed “regulatory B cells” (Bregs). Recently, Bregs have been linked to not only inflammatory and autoimmune diseases, but also malignancies via suppressing antitumour immunity.ObjectivesTo investigate the involvement of Bregs in advanced mycosis fungoides (MF).Materials&MethodsThe frequency ofCD19+CD24hiCD27+ memoryBcells andCD19+CD24hiCD38hi transitional B cells (which enrich IL-10-producing Bregs) was examined in peripheral blood from patients with advanced MF (n = 11) and healthy controls (n = 9) by flow cytometry. The frequency of IL-10-producing Bregs was also measured by flow cytometry. The correlation between frequency or number of B-cell subsets and disease severity markers was also analysed.ResultsThe frequency of CD19+CD24hiCD27+ B cells, CD19+CD24hiCD38hi B cells, and IL-10-producing B cells was decreased in peripheral blood of advanced MF patients. The frequency and number of these B-cell subsets inversely correlated with serum soluble IL-2 receptor and serum lactate dehydrogenase levels.ConclusionsThe development of IL-10-producing Bregs is impaired in patients with advanced MF and a decrease in IL-10-producing Bregs may play an important role in the progression of advanced MF.

Aberrant CD137 ligand expression induced by GATA6 overexpression promotes tumor progression in cutaneous T-cell lymphoma

CD137 and its ligand, CD137L, are expressed on activated T cells and antigen-presenting cells, respectively. Recent studies have shown that CD137L and CD137 are aberrantly expressed by tumor cells, especially in some hematopoietic malignancies, and interactions between these molecules on tumor cells promote tumor growth. In this study, we investigated the roles of CD137L and CD137 in cutaneous T-cell lymphoma (CTCL), represented by mycosis fungoides and Sézary syndrome. Flow cytometric analysis showed that primary Sézary cells and CTCL cell lines (Hut78, MyLa, HH, SeAx, and MJ) aberrantly expressed CD137L. CD137L expression by tumor cells in CTCL was also confirmed by immunohistochemistry. Anti-CD137L-neutralizing antibody inhibited proliferation, survival, CXCR4-mediated migration, and in vivo growth in CTCL cell lines through inhibition of phosphorylation of AKT, extracellular signal-regulated kinase 1/2, p38 MAPK, and JNK. Moreover, suppression of CD137L signaling decreased antiapoptotic proteins Bcl-2 and phosphorylated Bad. We also explored the transcription factor regulating CD137L expression. Because GATA6 has been proposed as an oncogene in many types of tumors with aberrant CD137L expression, we examined GATA6 expression and the involvement of GATA6 in CD137L expression in CTCL. DNA hypomethylation and histone acetylation induced GATA6 overexpression in CTCL cells. Furthermore, chromatin immunoprecipitation, luciferase reporter assay, and knockdown by short hairpin RNA showed that GATA6 directly upregulated CD137L expression. Inhibition of GATA6 resulted in decreased survival and in vivo growth in CTCL cells. Collectively, our findings prompt a novel therapeutic approach to CTCL based on the discovery that the GATA6/CD137L axis plays an important role in the tumorigenesis of CTCL.

Paradoxical antitumor effects of pazopanib in a cutaneous angiosarcoma patient

Figure 1. Clinical features of cutaneous angiosarcoma treated with pazopanib. (a) Recurrence on the left posterior auricular lesion before pazopanib treatment. (b) Pazopanib treatment for 8 weeks was effective in improving erythema, edema and ulcer. (c) Recurrence on the right temporal region of the head occurred 5 days after pazopanib treatment. (d) The lesion was getting worse although pazopanib had been administrated for 8 weeks.

Increased endocan expression in lesional skin and decreased endocan expression in sera in atopic dermatitis

Endocan is a novel human endothelial cell‐specific molecule and is mainly expressed in endothelial cells in various tissues. Endocan has the capacity to inhibit leukocytes binding to the vascular endothelium. It also can promote the angiogenesis alongside vascular endothelial growth factor A. Through these functions, endocan has been implicated in the pathogenesis of various inflammatory diseases. To investigate the possible roles of endocan in atopic dermatitis (AD), we examined endocan expression in lesional skin and sera in patients with AD. Endocan mRNA and protein levels were increased in lesional skin of AD compared with healthy skin and endocan was expressed on epidermal keratinocytes and dermal endothelial cells. On the other hand, serum endocan levels in patients with AD were significantly lower than those in healthy controls. Our results suggest that elevated endocan expression in lesional skin may be associated with development of AD through angiogenesis and that decreased endocan expression in sera may be associated with increased leukocyte recruitment in AD.