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Featured researches published by Chiyuki Ueshima.


Allergology International | 2013

PD-1 Regulates the Growth of Human Mastocytosis Cells

Tatsuki R. Kataoka; Masakazu Fujimoto; Koki Moriyoshi; Itsuko Koyanagi; Chiyuki Ueshima; Fumihiko Kono; Tatsuaki Tsuruyama; Yoshimichi Okayama; Chisei Ra; Hironori Haga

BACKGROUND Programmed death-1 (PD-1) is a marker for human neoplastic T cells. Here, we evaluated whether or not PD-1 was also a marker for human mastocytosis, and explored the role of PD-1 in human mastocytosis cells. METHODS Immunohistochemical analysis was used to evaluate the expression of PD-1 in clinical samples of human cutaneous mastocytosis. The expression of PD-1 in human mastocytosis cell lines was checked by RT-PCR, western blotting and flow cytometry. We stimulated human mastocytosis cell lines (LAD2 and HMC1.2) with recombinant ligand for PD-1, PD-L1 (rPD-L1), and tested the proliferative activity and the status of signal molecules by Cell Counting Kit-8 and ELISA, respectively. RESULTS Ten of 30 human cutaneous mastocytosis cases (33.3%) expressed PD-1 protein. We also found that a human mastocytosis line LAD2 cells expressed PD-1 protein on their surfaces. The administration with rPD-L1 suppressed the stem cell factor-dependent growth of the LAD2 cells. And, rPD-L1 activated SHP-1 and SHP-2 simultaneously, and decreased the phosphorylation of AKT, in LAD2 cells. In contrast, we could not detect the expression of PD-1, and the significant effect of rPD-L1 on the mutated KIT-driven growth of HMC1.2 cells. CONCLUSIONS PD-1 could be a marker for human cutaneous mastocytosis and regulate the growth of human PD-1-positive mastocytosis cells.


American Journal of Roentgenology | 2016

Clinical, Morphologic, and Pathologic Features Associated With Increased FDG Uptake in Schwannoma

Kanae Miyake; Yuji Nakamoto; Tatsuki R. Kataoka; Chiyuki Ueshima; Tatsuya Higashi; Tsuyoshi Terashima; Koya Nakatani; Tsuneo Saga; Shunsuke Minami; Kaori Togashi

OBJECTIVE The objective of this study was to investigate the clinical, morphologic, and pathologic features associated with increased 18F-FDG uptake in benign schwannomas. MATERIALS AND METHODS Twenty-two schwannomas in 22 patients (age range, 25-81 years) who had FDG PET or PET/CT scans and subsequently underwent surgical re-section were retrospectively analyzed. The maximum standardized uptake value (SUVmax) was compared with patient age, sex, tumor location (gastrointestinal vs nongastrointestinal origin), tumor size, gross appearance, intratumoral cellularity, intratumoral infiltration of inflammatory cells, presence of peritumoral lymphoid cuffs, and expression status of glucose transporters 1 and 3 on tumor cells. RESULTS The SUVmax of schwannomas ranged from 1.5 to 17.3 (median, 3.7). Significantly higher SUVmax was observed in gastrointestinal schwannomas (n = 4) compared with nongastrointestinal schwannomas (n = 18, p = 0.007) and in schwannomas with peritumoral lymphoid cuffs (n = 5) compared with those without peritumoral lymphoid cuffs (n = 17, p = 0.001). A significant correlation was seen between tumor location and the presence of peritumoral lymphoid cuffs (p < 0.001). Age, sex, tumor size, gross appearance, intratumoral cellularity, intratumoral inflammatory cell infiltration, and expression status of glucose transporters 1 and 3 on tumor cells had no significant correlation with SUVmax. CONCLUSION Gastrointestinal schwannomas and schwannomas with peritumoral lymphoid cuffs may be associated with elevated FDG uptake. Knowledge of the features of schwannomas associated with increased uptake may be helpful to avoid misinterpretation of benign schwannomas as malignancy.


Cancer immunology research | 2015

The Killer Cell Ig-like Receptor 2DL4 Expression in Human Mast Cells and Its Potential Role in Breast Cancer Invasion.

Chiyuki Ueshima; Tatsuki R. Kataoka; Masahiro Hirata; Ayako Furuhata; Eiji Suzuki; Masakazu Toi; Tatsuaki Tsuruyama; Yoshimichi Okayama; Hironori Haga

Ueshima, Kataoka, and colleagues show that nonneoplastic human mast cells express NK-cell receptor KIR2DL4, which interacts directly with HLA-G on tumor cells, enhancing MMP-9 production, invasion, and metastasis of HLA-G+ breast cancer cells in vitro and in vivo. The killer-cell Ig-like receptor (KIR) 2DL4 (CD158d) acts as a receptor for human leukocyte antigen (HLA)-G and is expressed on almost all human natural killer (NK) cells. The expression and function of KIR2DL4 in other hematopoietic cells is poorly understood. Here, we focused on human mast cells, which exhibit cytotoxic activity similar to that of NK cells. KIR2DL4 was detected in all examined human cultured mast cells established from peripheral blood derived from healthy volunteers (PB-mast), the human mast cell line LAD2, and human nonneoplastic mast cells, including those on pathologic specimens. An agonistic antibody against KIR2DL4 decreased KIT-mediated and IgE-triggered responses, and enhanced the granzyme B production by PB-mast and LAD2 cells, by activating Src homology 2–containing protein tyrosine phosphatase (SHP-2). Next, we performed a coculture assay between LAD2 cells and the HLA-G+ cancer cells, MCF-7 and JEG-3, and showed that KIR2DL4 on LAD2 cells enhanced MMP-9 production and the invasive activity of both cell lines via HLA-G. Immunohistochemical analysis revealed that the direct interaction between HLA-G+ breast cancer cells and KIR2DL4+ tissue mast cells (observed in 12 of 36 cases; 33.3%) was statistically correlated with the presence of lymph node metastasis or lymph-vascular invasion (observed in 11 of 12 cases; 91.7%; χ2 = 7.439; P < 0.01; degrees of freedom, 1) in the clinical samples. These findings suggest that the KIR2DL4 on human mast cells facilitates HLA-G–expressing cancer invasion and the subsequent metastasis. Cancer Immunol Res; 3(8); 871–80. ©2015 AACR.


Experimental Dermatology | 2015

NKp46 regulates the production of serine proteases and IL-22 in human mast cells in urticaria pigmentosa

Chiyuki Ueshima; Tatsuki R. Kataoka; Masahiro Hirata; Itsuko Koyanagi; Tetsuya Honda; Tatsuaki Tsuruyama; Yoshimichi Okayama; Akitoshi Seiyama; Hironori Haga

NKp46 (natural cytotoxic receptor 1/CD335) is expressed on natural killer cells and Th2‐type innate lymphocytes. However, NKp46 expression in human mast cells has not yet been reported. Here, we explored the expression of, and possible role played by, NKp46 in such cells. NKp46 protein was expressed in human mast cells in urticaria pigmentosa principally of the tryptase‐positive/chymase‐negative type (MCT), but not in human non‐neoplastic skin mast cells of the tryptase‐positive/chymase‐positive (MCTC) type. NKp46 expression was also evident in the human neoplastic mast cell line HMC1.2. NKp46 knockdown changed the phenotype of this cell line from MCT to MCTC and downregulated GrB production, but did not influence IL‐22 production. An agonistic anti‐NKp46 antibody upregulated production of GrB and IL‐22, but did not change the MCT‐like phenotype of HMC1.2 cells. NKp46 was thus involved in the production of serine proteases and IL‐22 in human mast cells.


Cancer Medicine | 2017

CEACAM1 long isoform has opposite effects on the growth of human mastocytosis and medullary thyroid carcinoma cells

Chiyuki Ueshima; Tatsuki R. Kataoka; Yusuke Takei; Masahiro Hirata; Akihiko Sugimoto; Mitsuyoshi Hirokawa; Yoshimichi Okayama; Richard S. Blumberg; Hironori Haga

Carcinoembryonic antigen‐related cell adhesion molecule 1 (CEACAM1) is expressed in a number of tumor cell types. The immunoreceptor tyrosine‐based inhibitory motif (ITIM)‐containing isoforms of this molecule which possess a long cytoplasmic tail (CEACAM1‐L) generally play inhibitory roles in cell function by interacting with Src homology 2 domain‐containing tyrosine phosphatase (SHP)‐1 and/or SHP‐2. Src family kinases (SFKs) are also known to bind to and phosphorylate CEACAM1‐L isoforms. Here, we report that CEACAM1 was uniquely expressed at high levels in both human neoplastic mast cells (mastocytosis) and medullary thyroid carcinoma cell (MTC) lines, when compared with their expression in nonneoplastic mast cells or nonneoplastic C cells. This expression was mainly derived from CEACAM1‐L isoforms based upon assessment of CEACAM1 mRNA expression. CEACAM1 knockdown upregulated cell growth of HMC1.2 cells harboring KIT mutations detected in clinical mastocytosis, whereas downregulated the growth of TT cells harboring RET mutations detected in clinical MTCs. Immunoblotting, ELISA and immunoprecipitaion analysis showed that activated SHP‐1 is preferentially associated with CEACAM1 in HMC1.2 cells harboring KIT mutations, whereas Src family kinases (SFKs) are preferentially associated with CEACAM1 in TT cells harboring RET mutations. These studies suggest that the dominantly interacting proteins SHP1 or SFK determine whether CEACAM1‐L displays a positive or negative role in tumor cells.


British Journal of Dermatology | 2017

Possible inducible skin-associated lymphoid tissues (iSALT)-like structures with CXCL13(+) fibroblast-like cells in secondary syphilis.

Toshiaki Kogame; Takashi Nomura; Tatsuki R. Kataoka; Masahiro Hirata; Chiyuki Ueshima; Miho Matsui; Kenji Kabashima

DEAR EDITOR, Nonlymphoid organs are not merely the sites of effector T-cell function. Ectopic accumulations of lymphoid cells arise in nonlymphoid organs under long-lived self-perpetuating chronic inflammation. These accumulations are called tertiary lymphoid organs (TLOs), and they function as antigen-presenting sites. TLOs are characterized by their cellular, organizational, chemokine and vascular similarity to lymph nodes. In well-developed TLOs, B and T cells are compartmentalized by CXCL13 from follicular dendritic cells (FDCs) and CCL19/CCL21 from fibroblastic reticular cells, respectively. The vascular system consisting of peripheral lymph node addressin (PNAd)-expressing high endothelial venules (HEVs) and lymphatic vessels is highly organized in TLOs as in lymph nodes. In mucosal areas, mucosa-associated lymphoid tissues function as TLOs. By analogy, the concept of skin-associated lymphoid tissue (SALT) was proposed in the 1980s, on the basis that cells in the skin can capture, process and present antigens. Recently, we identified inducible lymphoid structures composed of macrophages, dermal dendritic cells and effector T cells in mice, which we termed inducible SALT (iSALT). The formation of iSALT is essential to the efficient activation of effector cells in mice. However, it remains unknown whether the concept of iSALT can be applied to the human skin. This question can be addressed by investigating the characteristics of TLOs in chronic inflammatory skin lesions. We speculated that a skin lesion produced by infection with Treponema pallidum would suffice for this purpose for the following reasons. Firstly, plasmacyte infiltration in the cutaneous lesions of secondary syphilis suggests terminal differentiation of B cells locally in the skin. Secondly, CXCL13, a pivotal cytokine for TLO formation, is enriched in cerebrospinal fluid of neurosyphilitic patients. These lines of evidence imply that a lymphoid tissue organizing event could be engendered in syphilitic lesions. Here we studied the cutaneous lesions of secondary syphilis caused by persistent infection with T. pallidum. A 62-year-old man with membranous nephropathy was referred to us for concurrent disseminated noncoalescing asymptomatic macules of 3–5 mm in size on the torso and extremities. Serological tests indicated treponemal infection. The biopsied abdominal skin showed vacuolar lymphocytic interface dermatitis (Fig. 1a, b). Numerous plasma cells were scattered in the papillary dermis and the perivascular region (Fig. 1b). Spirochetes were visualized in the epidermis and lymphoid clusters by anti-T. pallidum polyclonal antibody (Fig. 1c). The perivascular infiltrate consisted of CD20 B cells and CD3 T cells (Fig. 1d, e). In the upper dermis, CXCL13 was detected in the fibroblast-like cells, which were negative for the FDC marker CNA.42 (Fig. 1f, g). CXCL13 cells were not detected in normal skin (Fig. 1j). Some but not all blood vascular endothelial cells (BECs) expressed PNAd (detected by MECA-79), indicating differentiation towards HEVs (Fig. 1h, i). The number of infiltrating lymphocytes was lower around the PNAd-negative BECs. Treatment with oral amoxicillin 1 5 g per day for 8 weeks successfully cleared the eruptions and proteinuria. Two additional cases of secondary syphilis showed essentially the same findings in immunohistochemistry (data not shown). Skin biopsies of secondary syphilis showed basal vacuolar changes with interface dermatitis accompanied by perivascular infiltration of CD4 T cells, CD8 T cells, CD20 B cells, spirochetes and plasma cells. These findings were consistent with those of secondary syphilis. We also found perivascular clusters of T cells that were reminiscent of iSALT, which we observed in a murine model. Moreover, some BECs expressed PNAd, indicating differentiation towards HEVs, a feature of TLOs. HEVs in lymphoid organs function as entry sites for naive lymphocytes and other immune cells in the circulation. Thus, iSALT-like structures in syphilitic lesions may be fuelled by migrating immune cells across these ectopic HEVs. We identified numerous CXCL13 fibroblast-like cells in the upper dermis. It is known that cytokines (such as CCL21, CXCL12 and CXCL13) contribute to TLO formation through recruitment of T cells and dendritic cells. Therefore, we speculate that CXCL13 helped the formation of iSALT-like structures in the upper dermis. The presence of dermal CXCL13 fibroblast-like cells and ectopic HEVs, but not compartmentalization of B and T cells, may indicate that iSALT is an early stage of TLO. The origin of CXCL13 fibroblast-like cells is unclear. In lymph nodes, FDCs express CXCL13 and recruit CXCR5 B cells to form B-cell follicles. However, the CXCL13 fibroblast-like cells in the syphilitic lesions did not react with CNA.42, a monoclonal antibody against FDC. Moreover, B cells were not colocalized with CXCL13 fibroblast-like cells.


Scientific Reports | 2013

CD72 regulates the growth of KIT-mutated leukemia cell line Kasumi-1

Tatsuki R. Kataoka; Atsushi Kumanogoh; Masahiro Hirata; Koki Moriyoshi; Chiyuki Ueshima; Masahiro Kawahara; Tatsuaki Tsuruyama; Hironori Haga

Gain-of-function mutations in KIT, a member of the receptor type tyrosine kinases, are observed in certain neoplasms, including mast cell tumors (MCTs) and acute myelogenous leukemias (AMLs). A MCT line HMC1.2 harboring the KIT mutation was reported to express CD72, which could suppress the cell proliferation. Here, we examined the ability of CD72 to modify the growth of AMLs harboring gain-of-function KIT mutations. CD72 was expressed on the surface of the AML cell line, Kasumi-1. CD72 ligation by an agonistic antibody BU40 or by a natural ligand CD100, suppressed the proliferation of the Kasumi-1 cells and enhanced cell death, as monitored by caspase-3 cleavage. These responses were associated with the phosphorylation of CD72, the formation of the CD72 - SHP-1 complex and dephosphorylation of src family kinases and JNK. Thus, these results seemed to suggest that CD72 was the therapeutic potential for AML, as is the case of MCTs.


International Immunology | 2015

CD72 negatively regulates mouse mast cell functions and down-regulates the expression of KIT and FcεRIα

Tatsuki R. Kataoka; Atsushi Kumanogoh; Nobuyuki Fukuishi; Chiyuki Ueshima; Masahiro Hirata; Koki Moriyoshi; Tatsuaki Tsuruyama; Hironori Haga

CD72 is a transmembrane protein belonging to the C-type lectin family that is expressed by various hematopoietic cells. When bound to its natural ligand, CD100 (semaphorin 4D), CD72 inhibits the KIT-mediated responses of human mast cells, but not IgE/FcεRI-mediated mast cell degranulation. We extended these findings to examine the role of CD72 in mouse mast cells. CD72 expression was detected in mouse bone marrow-derived mast cells (mBMMCs). As for human mast cells, an agonistic antibody against CD72 (K10.6) suppressed the KIT-mediated cell growth of, IL-6 production by and chemotaxis of mBMMCs. However, in contrast to human mast cells, the IgE-triggered degranulation of mBMMCs was suppressed by K10.6. K10.6 did not affect the phosphorylation of SHP-1 in mBMMCs, although SHP-1 mediated the inhibitory effects of CD72 in human mast cells. Administration of K10.6 induced phosphorylation of the ubiquitin ligase Cbl-b and decreased the expression of KIT and FcεRIα on the surface of murine mast cells. We also observed expression of CD72 in a mouse neoplastic cell line, P815, harboring gain-of-function mutations in KIT genes. In addition, we found that K10.6 activated Cbl-b, down-regulated KIT expression and suppressed the mutated KIT-driven growth of these cells. Thus, the mechanism by which CD72 mediates inhibitory effects in mast cells is species-dependent.


Acta Dermato-venereologica | 2016

A Case of Noonan Syndrome with Multiple Subcutaneous Tumours with MAPK-ERK/p38 Activation.

Tetsuya Honda; Tatsuki R. Kataoka; Chiyuki Ueshima; Yoshiki Miyachi; Kenji Kabashima

Noonan syndrome (NS) is an autosomal dominant disorder with a frequency of 1/1,000 to 1/2,500 live births (1, 2). The symptoms of NS include short stature, specific facial features such as hypertelorism and posteriorly rotated ears, epicanthal folds, congenital heart failure, and webbed neck. Although skin tumours are not common features in patients with NS, several cases of NS with multiple granular cell tumours in the skin have been reported (3). Thus far, heterozygous mutations in 9 genes have been documented to underlie this disorder, and approximately 75% of patients clinically diagnosed with NS harbour a mutation in those genes (2). It has been revealed that the genes involved in NS are regulators of rat sarcoma viral oncogene (RAS)-mitogen-activated protein kinase (MAPK) pathways, especially the RASERK pathway, which plays a crucial role in various physiological processes, such as cell proliferation, survival and differentiation (4). Since gene mutations in NS are gain-of-function mutations, it has been suggested that activation of the RAS-MAPK signalling pathway might be involved in the development of NS. However, whether and how such activation is involved in the clinical symptoms of NS remains unclear. We report here a case of NS with atypical multiple subcutaneous tumours with RAS-MAPK activation.


Journal of The European Academy of Dermatology and Venereology | 2018

Presence of SCF/CXCL12 double‐positive large blast‐like cells at the site of cutaneous extramedullary haematopoiesis

T. Kogame; Masahiro Hirata; Tatsuki R. Kataoka; Judith A. Seidel; Chiyuki Ueshima; Miho Matsui; Takashi Nomura; Kenji Kabashima

Extramedullary hematopoiesis (EMH) is observed in the fetal liver and the spleen under physiological conditions, but can rarely occur as pathologic condition after birth. EMH is observed in various anatomical sites in patients with hypoxia-inducing conditions, such as idiopathic myelofibrosis. The nature of the microenvironment for the maintenance of hematopoietic stem cells (HSCs) in EMH is unclear. Recent studies showed that mesenchymal stem/stromal cell (MSC)-derived cells, that can differentiate into various types of cells, play critical roles in the formation of hematopoietic niches. This article is protected by copyright. All rights reserved.

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