67 results on '"Takehara, Kazuhiko"'
Search Results
2. CD22 and CD72 contribute to the development of scleroderma in a murine model
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Zhao, Chunyan, Matsushita, Takashi, Ha Nguyen, Vinh Thi, Tennichi, Momoko, Fujimoto, Manabu, Takehara, Kazuhiko, and Hamaguchi, Yasuhito
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- 2020
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3. CD22 and CD72 cooperatively contribute to the development of the reverse Arthus reaction model
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Nguyen, Vinh Thi Ha, Matsushita, Takashi, Zhao, Chunyan, Fujimoto, Manabu, Takehara, Kazuhiko, Tedder, Thomas F., and Hamaguchi, Yasuhito
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- 2019
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4. Plasma CCN2 (connective tissue growth factor; CTGF) is a potential biomarker in idiopathic pulmonary fibrosis (IPF)
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Kono, Masato, Nakamura, Yutaro, Suda, Takafumi, Kato, Masato, Kaida, Yusuke, Hashimoto, Dai, Inui, Naoki, Hamada, Etsuko, Miyazaki, Osamu, Kurashita, Syunsuke, Fukamachi, Isamu, Endo, Koki, Ng, Poh-Sing, Takehara, Kazuhiko, Nakamura, Hirotoshi, Maekawa, Masato, and Chida, Kingo
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- 2011
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5. Clinical characteristics of four myositis-specific autoantibodies with regulatory-approved testing in Japan: A Japanese multi-centre adult myositis patients’ cohort
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Ueda-Hayakawa, Ikuko, Fujimoto, Manabu, Sato, Shinji, Murakami, Akihiro, Kawakami, Atsushi, Mishima, Michiaki, Seishima, Mariko, Suda, Takafumi, Takehara, Kazuhiko, Mimori, Tsuneyo, and Kuwana, Masataka
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- 2021
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6. Proteolytic processing of human growth hormone by multiple tissue kallikreins and regulation by the serine protease inhibitor Kazal-Type5 (SPINK5) protein
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Komatsu, Nahoko, Saijoh, Kiyofumi, Otsuki, Norio, Kishi, Tadaaki, Micheal, Iacovos P., Obiezu, Christina V., Borgono, Carla A., Takehara, Kazuhiko, Jayakumar, Arumugam, Wu, Hua Kang, Clayman, Gary L., and Diamandis, Eleftherios P.
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- 2007
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7. Dual aspects of B cells in tumor immunity; B cells are capable of positive and negative regulation for tumor immunity against B16 melanoma
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Kobayashi, Tadahiro, Matsushita, Takashi, Hamaguchi, Yasuhito, Hasegawa, Minoru, Fujimoto, Manabu, and Takehara, Kazuhiko
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- 2017
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8. Potential Immunologic Targets for Treating Fibrosis in Systemic Sclerosis: A Review Focused on Leukocytes and Cytokines.
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Hasegawa, Minoru and Takehara, Kazuhiko
- Abstract
Objectives: Systemic sclerosis (SSc) is a connective tissue disease characterized by tissue fibrosis. Although the pathogenesis remains unclear, a variety of cells contribute to the fibrotic process via interactions with each other and production of various cytokines. Recent literature related to the immunologic pathogenesis and future strategies for treating the fibrosis of SSc are discussed and, especially, this literature-based review that includes the authors'' perspective, focused on leukocytes and cytokines. Methods: A PubMed search for articles published between January 2005 and January 2012 was conducted using the following keywords: systemic sclerosis, leukocyte, cytokine, growth factor, and chemokine. The reference lists of identified articles were searched for further articles. Results: Targeting profibrogenic cytokines, including transforming growth factor-β, is still a very active area of research in SSc and most cellular studies have focused on the roles of fibroblasts in SSc. However, a growing number of recent studies indicate a role for B cells in the development of SSc and other autoimmune diseases such as systemic lupus erythematosus. Therefore, B-cell-targeted therapies, including currently available monoclonal antibodies against CD19, CD20, CD22, and B-cell-activating factor, belonging to the tumor necrosis factor family represent possible treatment options. Furthermore, the modulation of T-cell costimulatory molecules such as a recombinant fusion protein of cytotoxic T-lymphocyte antigen-4 may be as effective in SSc as it is in treating other autoimmune diseases. Approaches to antagonize interleukin (IL)-1, IL-6, or IL-17A signaling may also be attractive. Conclusions: This review describes recent advances in the treatment of fibrosis in SSc patients focused on immunologic strategies, such as leukocyte- or cytokine-targeted therapies. [Copyright &y& Elsevier]
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- 2012
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9. Antiphospholipid antibodies in patients with autoimmune blistering disease.
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Echigo, Takeshi, Hasegawa, Minoru, Inaoki, Makoto, Yamazaki, Masahide, Sato, Shinichi, and Takehara, Kazuhiko
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MEDICAL research ,DERMATOLOGY ,BIOLOGY ,MEDICINE - Abstract
Objective: Our purpose was to determine the serum levels and frequency of antiphospholipid antibodies (aPLs) and confirm the clinical importance of these antibodies in patients with autoimmune blistering disease (ABD). Methods: IgG and IgM anticardiolipin antibodies (aCL), IgG anticardiolipin-β
2 glycoprotein I complex antibody (aCL/β2 GPI), and IgG antiphosphatidylserine-prothrombin complex antibody (aPS/PT) were examined with an enzyme-linked immunosorbent assay in 71 patients with ABD, including pemphigus vulgaris, pemphigus foliaceus, and bullous pemphigoid. Results: The prevalence of IgG aCL, IgM aCL, aCL/β2 GPI, and IgG aPS/PT was positive for 22.4%, 9.1%, 9.9%, and 25.4% of the ABD patients, respectively, whereas these antibodies were not detected in any of the normal control subjects. Ten of 20 patients with ABD who were attending our hospital in 2004 tested positive for aPLs, and thromboembolism was detected in 7 of 10 patients with aPLs. Limitations: Follow-up studies, especially with a large patient group, will be needed to clarify the clinical relevance of aPLs in ABD. Conclusion: aPLs are frequently detected in patients with ABD. Careful examination and follow-up for thromboembolism may be necessary in ABD patients with aPLs. [Copyright &y& Elsevier]- Published
- 2007
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10. Both Th2 and Th1 chemokines (TARC/CCL17, MDC/CCL22, and Mig/CXCL9) are elevated in sera from patients with atopic dermatitis
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Shimada, Yuka, Takehara, Kazuhiko, and Sato, Shinichi
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SERUM , *BLOOD plasma , *CYTOKINES , *PEPTIDES - Abstract
Background: Chemokines and their receptors are important elements for the selective attraction and activation of various subsets of leukocytes. Expression of CXCR3 ligands, such as monokine induced by IFN-γ (Mig) leads to preferential Th1 recruitment, whereas CCR4 ligands, thymus and activation regulated chemokine (TARC) or macrophage derived chemokine (MDC), mediate preferential Th2 recruitment. Although atopic dermatitis (AD) has been shown to be a Th2-type disease, recent studies have revealed that Th1-type cytokines, such as IFN-γ, especially in chronic skin lesions, play important roles in pathogenesis of AD. Objective: The purpose of this study was to investigate serum levels of Th2 chemokines TARC and MDC and a Th1 chemokine Mig in the same samples from patients with AD and their clinical correlation. Methods: Serum chemokine levels in patients with AD (
n=55 ), contact dermatitis (CD;n=15 ), and normal controls (n=30 ) were examined by ELISA. Results: Serum levels of TARC and MDC in AD patients and CD patients were significantly higher than those found in normal controls. Serum levels of these chemokines were similar for AD patients and CD patients. Furthermore, these levels correlated positively with disease severity, total IgE levels, and peripheral eosinophilia in AD patients. Serum Mig levels in AD patients and CD patients were significantly higher than those in control subjects. However, serum Mig levels were significantly elevated in CD patients relative to AD patients. Furthermore, serum Mig levels correlated positively with levels of both TARC and MDC in AD patients. Conclusion: These results suggest that both Th2 and Th1 chemokines may play roles in the development of AD. [Copyright &y& Elsevier]- Published
- 2004
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11. Antinuclear antibodies in localized scleroderma: unique staining in chromosome spreads
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Kikuchi, Kanako, Takehara, Kazuhiko, and Ishibashi, Yasumasa
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Scleroderma (Disease) -- Physiological aspects ,Autoimmunity -- Research ,Health - Abstract
Localized scleroderma is a chronic disease of unknown origin that causes sclerosis, hardening or thickening of the skin in localized patches. Although it is considered to be limited to the skin, several abnormal immunologic reactions have been observed in conjunction with this disorder. Antinuclear antibodies (ANA), a group of antibodies that react against normal components of the nucleus of a cell, and other abnormal immune reactions that are characteristic of disease have been detected. One ANA, anticentromere antibody, has been identified and is considered specific to a type of systemic scleroderma, a more serious condition which involves sclerosis of other organs. The presence of this antibody in patients with localized scleroderma was analyzed using chromosome tests. Samples of skin cells were taken from 54 patients with localized and linear scleroderma and other related disorders; 10 normal controls were also tested. Anticentromere antibody was first analyzed in patients with systemic scleroderma. ANA was detected in 46 to 67 percent of the patients with localized scleroderma and unique staining patterns were exhibited upon chromosome examination. A resemblance between these patterns and those produced by anticentromere antibodies associated with systemic scleroderma was noted, but significant differences were also observed. Additional research is currently underway regarding the characteristics of these antigens.
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- 1989
12. Expression of Structurally Unaltered Androgen Receptor in Extramammary Paget’s Disease.
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Fujimoto, Akihide, Takata, Minoru, Hatta, Naohito, and Takehara, Kazuhiko
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- 2000
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13. Re-emergence of anti-topoisomerase I antibody with exacerbated development of skin sclerosis in a patient with systemic sclerosis.
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Hamaguchi, Yasuhito, Fujimoto, Manabu, Hasegawa, Minoru, Matsushita, Takashi, and Takehara, Kazuhiko
- Abstract
A 41-year-old woman had noticed sclerodactyly for 9 months before consultation. She was diagnosed as having diffuse cutaneous systemic sclerosis based on the skin sclerosis of her extremities and trunk and assessed by the modified Rodnan skin score method. Her anti–topoisomerase I antibody (anti–topo I) level was 78.1 index (normal range, ≤16 index). With oral prednisolone treatment, her skin sclerosis gradually improved and disappeared. In parallel, her serum anti–topo I levels became undetectable. Prednisolone was eventually discontinued; however, 10 months after discontinuation, anti–topo I reemerged and increased to 102.1 index, accompanied by newly developed skin sclerosis. Prednisolone was re-started, and the skin sclerosis improved, along with a reduction in anti–topo I levels. Therefore, discontinuation of corticosteroids may have triggered the re-emergence of anti–topo I and skin sclerosis. This case suggests a role for anti–topo I in the pathogenesis of systemic sclerosis and an effect of corticosteroids on skin sclerosis and autoantibody production. [Copyright &y& Elsevier]
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- 2010
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14. A novel splenic B1 regulatory cell subset suppresses allergic disease through phosphatidylinositol 3-kinase–Akt pathway activation.
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Matsushita, Takashi, Le Huu, Doanh, Kobayashi, Tadahiro, Hamaguchi, Yasuhito, Hasegawa, Minoru, Naka, Kazuhito, Hirao, Atsushi, Muramatsu, Masamichi, Takehara, Kazuhiko, and Fujimoto, Manabu
- Abstract
Background IL-10–producing regulatory B (B10) cells potently suppress allergic diseases, such as contact hypersensitivity (CHS). Splenic B10 cells share overlapping phenotypic markers with CD5 + B1 B cells, CD1d hi CD21 + CD23 − marginal zone (MZ) B cells, and CD1d hi CD21 + CD23 + T2-MZ precursor B cells but do not exclusively belong to either subset. Objective In this study we investigated the signaling mechanisms and a novel phenotypic parameter of B10 cells. Method We performed microarray analysis comparing IL-10 + and IL-10 − B cells. B cell–specific phosphatase and tensin homolog (PTEN)–deficient mice, which exhibit aberrant activation of the phosphatidylinositol 3-kinase (PI3K)–Akt pathway in B cells, were examined. Results Microarray analysis revealed that the PI3K-Akt pathway is important for IL-10 production in B cells. PI3K-Akt pathway inhibitors reduced B10 cell numbers in vitro . B10 cell numbers were significantly increased in B cell–specific PTEN-deficient mice. The CHS response was significantly diminished in PTEN-deficient mice. Unexpectedly, splenic B10 cells in these mice were found within the B1 B-cell subset but not within the MZ B-cell subset. In wild-type mice not only MZ B10 cells but also B1-B10 cells were identified in the spleen. In addition, these 2 B10 cell subsets were predominantly found within the CD9 + CD80 + B-cell fraction. Conclusion A novel splenic B1 regulatory cell subset (B1-B10 cells) was identified. Our findings show that the PI3K-Akt pathway in B cells is critical for B10 cell development and CHS response and that CD9/CD80 coexpression is a novel phenotypic parameter for both MZ-B10 and B1-B10 cells. [ABSTRACT FROM AUTHOR]
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- 2016
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15. B-cell linker protein expression contributes to controlling allergic and autoimmune diseases by mediating IL-10 production in regulatory B cells.
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Jin, Guihua, Hamaguchi, Yasuhito, Matsushita, Takashi, Hasegawa, Minoru, Le Huu, Doanh, Ishiura, Nobuko, Naka, Kazuhito, Hirao, Atsushi, Takehara, Kazuhiko, and Fujimoto, Manabu
- Abstract
Background: Regulatory B cells that exhibit the cell-surface CD1d
hi CD5+ phenotype and produce IL-10 are termed B10 cells. Although B10 cells exert potent suppressive functions in patients with various allergic and autoimmunity disorders, the precise signaling mechanisms required for B10 cell functions remain unknown. B-cell linker protein (BLNK) is an essential component of the B-cell antigen receptor signaling pathway and is required for optimal B-cell development. Objective: We sought to elucidate the signaling pathways that are responsible for IL-10 production in B10 cells and in vivo mechanisms of how impaired B10 cell functions influence allergic and autoimmune responses. Method: For in vitro assays, splenic CD1dhi CD5+ B cells from BLNK-deficient (BLNK−/− ) mice were analyzed for intracellular signaling pathways and cytokine production. Contact hypersensitivity (CHS) and experimental autoimmune encephalomyelitis were examined by using BLNK−/− mice. Results: Although the CD1dhi CD5+ B-cell population was present in BLNK−/− mice, IL-10 production was impaired both in vitro and in vivo. BLNK−/− mice had exaggerated CHS and experimental autoimmune encephalomyelitis responses, which were normalized by adoptive transfer of splenic CD1dhi CD5+ B cells from wild-type mice. In mice with CHS, BLNK−/− mice exhibited decreased B-cell and regulatory T-cell percentages and increased CD8+ T-cell percentages in the skin and lymph nodes. In vitro BLNK was required for LPS-induced signal transducer and activator of transcription 3 phosphorylation in CD1dhi CD5+ B cells. Finally, secreted IL-10 leads to autocrine expansion of IL-10–producing B cells. Conclusion: BLNK serves as a critical signaling component for B10 cell function by mediating IL-10 production. [Copyright &y& Elsevier]- Published
- 2013
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16. Pathogenesis of systemic sclerosis: Altered B cell function is the key linking systemic autoimmunity and tissue fibrosis
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Hasegawa, Minoru, Fujimoto, Manabu, Takehara, Kazuhiko, and Sato, Shinichi
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AUTOIMMUNITY , *LYMPHOCYTES , *AUTOANTIBODIES , *GROWTH factors - Abstract
Summary: Systemic sclerosis (SSc) is characterized by autoimmunity and tissue fibrosis. There is a close association between specific autoantibodies and clinical features in patients with SSc. A number of studies have demonstrated that various cytokines, such as transforming growth factor-β, modulate the synthesis of extracellular matrix by fibroblasts. However, it is not clear as to how autoimmunity and tissue fibrosis interact with each other. Recent studies have revealed that B cells play a critical role in various systemic autoimmune disorders. CD19 is a central regulator of B cell signaling threshold, and B cells from SSc patients exhibit an increased expression of CD19 that induces SSc-specific autoantibody production in transgenic mice. Furthermore, SSc patients have intrinsic B cell abnormalities characterized by decreased but activated memory B cells, which is possibly due to CD19 overexpression. Similarly, B cells from a tight-skin mouse, a model of SSc, show augmented CD19 signaling and chronic B cell activation. Remarkably, CD19 loss results in inhibition of chronic B cell hyper-reactivity and elimination of autoantibody production, which is associated with improvement in skin fibrosis and a parallel decrease in IL-6 production by B cells. Therefore, augmented cytokine production by B cells is a potential candidate for the induction of skin sclerosis. Alternatively, B cells may influence tissue fibrosis by regulating T cell activation and cytokine production through their antigen-presenting and co-stimulatory abilities. Thus, altered B cell function may result in tissue fibrosis, as well as autoimmunity, in SSc. [Copyright &y& Elsevier]
- Published
- 2005
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17. Elevated expression of CD23 on peripheral blood B lymphocytes from patients with bullous pemphigoid: correlation with increased serum IgE
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Inaoki, Makoto, Sato, Shinichi, and Takehara, Kazuhiko
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LYMPHOCYTES , *LEUCOCYTES , *PEMPHIGUS , *SERUM - Abstract
Background: Increased serum IgE levels are occasionally found in patients with severe bullous pemphigoid (BP). CD23, a low affinity Fc receptor for IgE, is mainly expressed on mature B lymphocytes. Studies have suggested that serum levels of soluble CD23 (sCD23) correlate with serum IgE levels and disease severity in BP. Objective: The purpose of our study is to examine whether the expression of CD23 is elevated in BP and whether this expression correlates with serum IgE levels and disease severity. Methods: We measured CD23 expression on B cells from patients with active BP, pemphigus vulgaris, pemphigus foliaceus, and atopic dermatitis (AD), as well as healthy control subjects, using a flow cytometer. Serum levels of IgE and sCD23 were also measured. Results: The expression of CD23 was significantly higher in BP patients compared with healthy control subjects (
P<0.05 ), whereas the levels were normal in the other bullous diseases. CD23 expression tended to be higher in severe BP compared with moderate BP, and the levels in severe BP were comparable to the levels in AD. Furthermore, CD23 expression correlated positively with serum IgE levels (P<0.002 ), and the IgE levels were significantly higher in severe BP than in moderate BP (P<0.01 ). CD23 expression in BP did not correlate with sCD23 levels. Conclusions: These results suggest that the up-regulated surface CD23 on B cells may be involved in IgE synthesis and inflammatory events in BP. [Copyright &y& Elsevier]- Published
- 2004
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18. Novel Autoantibody to Cu/Zn Superoxide Dismutase in Patients with Localized Scleroderma.
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Nagai, Masaki, Hasegawa, Minoru, Takehara, Kazuhiko, and Sato, Shinichi
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AUTOIMMUNITY , *FIBROMYALGIA , *REACTIVE oxygen species , *SUPEROXIDES , *SCLERODERMA (Disease) , *AUTOANTIBODIES - Abstract
Abnormal production of reactive oxygen species (ROS) induces tissue damage and superoxide dismutase (SOD) that converts superoxide radicals to hydrogen peroxide functions as defense against ROS. Cu/Zn SOD administration has been shown to be effective for various fibrotic conditions by inhibiting the fibrogenic effects of ROS. We hypothesized that autoimmune background in localized scleroderma induced anti-Cu/Zn SOD autoantibodies that inhibited SOD activity and thereby contributed to fibrosis by increasing ROS. ELISA using human purified Cu/Zn SOD revealed that IgG or IgM anti-Cu/Zn SOD Ab was detected in the serum of 89% of localized scleroderma patients, especially 100% of patients with generalized morphea, the severest form of localized scleroderma, but was positive only in the serum of less than 15% of patients with other autoimmune disorders, including systemic sclerosis, systemic lupus erythematosus, dermatomyositis, and autoimmune bullous disorders. The immunoblotting analysis confirmed the presence of IgG anti-Cu/Zn SOD Ab in sera from localized scleroderma patients. Remarkably, anti-Cu/Zn SOD autoantibody could inhibit Cu/Zn SOD enzymatic activity. Collectively, these results indicate that anti-Cu/Zn SOD Ab is a novel, major autoantibody in localized scleroderma, and also suggest that the autoantibody may play a role in the development of fibrosis by directly inhibiting SOD activity. [ABSTRACT FROM AUTHOR]
- Published
- 2004
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19. Enzyme-linked immunosorbent assays for detection of anti-transcriptional intermediary factor-1 gamma and anti-Mi-2 autoantibodies in dermatomyositis.
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Fujimoto, Manabu, Murakami, Akihiro, Kurei, Shunsuke, Okiyama, Naoko, Kawakami, Atsushi, Mishima, Michiaki, Sato, Shinji, Seishima, Mariko, Suda, Takafumi, Mimori, Tsuneyo, Takehara, Kazuhiko, and Kuwana, Masataka
- Subjects
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DERMATOMYOSITIS , *AUTOANTIBODIES , *ENZYME-linked immunosorbent assay , *GENETIC transcription , *SENSITIVITY analysis , *DIAGNOSIS , *PATIENTS , *THERAPEUTICS - Abstract
Background Autoantibodies against transcriptional intermediary factor 1 (TIF1) and Mi-2 are selectively detected in patients with dermatomyositis (DM). To measure these antibodies readily, the development of reliable ELISA systems has been needed. Objective This study aimed to establish enzyme-linked immunosorbent assays (ELISAs) for anti-TIF1γ and anti-Mi-2β antibodies (Abs) and to assess their utility. Methods Serum samples were obtained from 104 patients with classic DM, 68 with clinically amyopathic DM (CADM) and 70 with polymyositis, who were followed up at 8 medical centers across Japan. Serum samples from 190 patients with other connective tissue diseases (CTDs) and 123 healthy individuals were also assessed. Serum antibody levels were examined by ELISAs coated with full-length TIF1γ or Mi-2β proteins produced by a baculovirus expression system. To assess the cross-reactivity, partial-length Mi-2β proteins with or without mutations were produced and examined for reactivity. Results When compared with immunoprecipitation assay, anti-TIF1γ Ab ELISA showed 100% sensitivity and 100% specificity, while anti-Mi-2β Ab ELISA showed 100% sensitivity and 99.6% specificity. Anti-TIF1γ Ab was positive in 30 (28.8%) with classic DM and 4 (5.9%) with CADM, whereas 14 (13.5%) with classic DM, but none with CADM, were positive for anti-Mi-2β Ab. Of 30 anti-TIF1γ Ab-positive DM patients, 23 (67.6%) had malignancy. Anti-Mi-2β Ab-positive serum samples exhibited modest cross-reactivity with the TIF1γ protein due to the homologous amino acid sequence containing cysteines in their plant homeodomains. Conclusion The current study demonstrates the utility of newly established ELISAs for anti-TIF1γ and anti-Mi-2β Abs, which can serve as easier detection systems for routine testing. [ABSTRACT FROM AUTHOR]
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- 2016
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20. Blockade of Syk ameliorates the development of murine sclerodermatous chronic graft-versus-host disease.
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Le Huu, Doanh, Kimura, Hiroshi, Date, Mutsumi, Hamaguchi, Yasuhito, Hasegawa, Minoru, Hau, Khang Tran, Fujimoto, Manabu, Takehara, Kazuhiko, and Matsushita, Takashi
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GRAFT versus host disease , *HEMATOPOIESIS , *PROTEIN-tyrosine kinases , *CD4 antigen , *LABORATORY mice , *CELL proliferation - Abstract
Abstract: Background: Murine sclerodermatous chronic graft-versus-host disease (Scl-cGVHD) is a model for human Scl-cGVHD and systemic sclerosis (SSc). Syk is expressed in most of hematopoietic cells, fibroblasts, and endothelial cells. Syk is a protein tyrosine kinase that has an important role in transmitting signals from a variety of cell surface receptors. Objective: This study aims to investigate the effect of R788 (fostamatinib sodium), an oral prodrug that is rapidly converted to a potent inhibitor of Syk, R406, on Scl-cGVHD. Methods: R788 was orally administered twice a day to allogeneic recipients from day 14 to day 42 after bone marrow transplantation (BMT). In vitro, proliferation of GVHD-derived CD4+ T cells and CD11b+ cells was analyzed by R406. Results: Allogeneic BMT increased Syk phosphorylation in T, B, and CD11b+ cells. The administration of R788 attenuated severity and fibrosis of Scl-cGVHD. The elevated expressions of CXCR4 on T cells, B cells, and CD11b+ cells were significantly down-regulated by R788 treatment. R788 reduced memory CD4+ T cells (CD44hiCD62L−CD4+). R406 inhibited proliferation of GVHD CD4+ T cells and CD11b+ cells in vitro. In addition, R788 treatment, inhibited proliferation of CD11b+ cells in Scl-cGVHD mice. R788 treatment also reduced skin mRNA expressions of MCP-1, MIP-1α, IFN-γ, IL-13, IL-17A, and TGF-β1, but not influenced RANTES, CXCL12, and TFN-α. Conclusion: Blockade of Syk suppressed migration factor of immune cells and antigen-specific memory CD4+ T cells and proliferation and activation of GVHD CD4+ T cells and CD11b+ cells. The current studies suggested that Syk inhibitor is a potential candidate for use in treating patients with Scl-cGVHD and SSc. [Copyright &y& Elsevier]
- Published
- 2014
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21. Dermokine inhibits ELR+CXC chemokine expression and delays early skin wound healing
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Hasegawa, Minoru, Higashi, Kiyoshi, Matsushita, Takashi, Hamaguchi, Yasuhito, Saito, Koichi, Fujimoto, Manabu, and Takehara, Kazuhiko
- Subjects
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CHEMOKINES , *EPITHELIAL cells , *SKIN injuries , *WOUND healing , *PHOSPHORYLATION , *KERATINOCYTES - Abstract
Summary: Background: Dermokine-β is abundant in stratified epithelia and in differentiating keratinocytes in culture. We have recently shown that treatment of keratinocytes with dermokine-β attenuates phosphorylation of extracellular signal-regulated kinase, however, the roles of dermokine-β in vivo remain unknown. Objective: Dermokine-β is overexpressed in marginal keratinocytes during wound healing. This study was conducted to investigate the roles of dermokine-β in the wound healing process. Methods: Recombinant human dermokine-β or its active peptide was topically applied to excisional wounds in mice and the relative wound area was calculated. Histological and chemokine expression analyses in wounds were also performed. The chemokine expression levels as well as the chemotactic activity of dermokine-β in cultured keratinocytes were determined. Results: Topical application of recombinant dermokine-β as well as its carboxy-terminal domain peptide inhibited mouse wound healing at an early phase, reduced infiltration of neutrophils and macrophages into the wounds, inhibited angiogenesis, and decreased the number of myofibroblasts in the wounds. Treatment with dermokine-β augmented IL-10 expression, but attenuated expression of transforming growth factor-β and tumor necrosis factor-α. In addition, application of dermokine-β to skin wounds reduced the expression of CXCL1 and CXCL5, both of which are chemoattractant for neutrophils into wounds. Both dermokine-β and its active peptide decreased the expression of CXCL1, CXCL6, and CXCL8 in cultured human keratinocytes. Treatment of human keratinocytes with dermokine-β inhibited neutrophil chemotaxis. Conclusion: These results suggest that dermokine-β delays early cutaneous wound healing in part by inhibiting expression of CXC chemokines containing the ERL-sequence motif. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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22. Chemokine receptors CCR2 and CX3CR1 regulate skin fibrosis in the mouse model of cytokine-induced systemic sclerosis
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Arai, Minako, Ikawa, Yuka, Chujo, Sonoko, Hamaguchi, Yasuhito, Ishida, Wataru, Shirasaki, Fumiaki, Hasegawa, Minoru, Mukaida, Naofumi, Fujimoto, Manabu, and Takehara, Kazuhiko
- Subjects
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CHEMOKINE receptors , *SYSTEMIC scleroderma , *EXTRACELLULAR matrix , *CYTOKINES , *LABORATORY mice , *TRANSFORMING growth factors - Abstract
Abstract: Background: Skin fibrotic disorders such as systemic sclerosis (SSc) are characterized by an excessive accumulation of extracellular matrix (ECM), and develop under the influence of certain cytokines. We previously established a mouse model of skin fibrosis induced by exogenous application of cytokines. We have revealed that both the number of macrophages and the levels of macrophage chemoattractant protein-1 (MCP-1) mRNA positively correlate with the extent of skin fibrosis. Macrophages can be divided into two subsets, the first expressing CCR2, and the second expressing CX3CR1. Objective: To elucidate the role of skin infiltrating macrophages based on CCR2 and CX3CR1 in this cytokine-induced murine fibrosis model. Methods: We examined the amounts of collagen deposited in granulation tissues, the numbers of macrophages and the levels of several mRNA in wild type (WT) mice, CCR2−/− mice, and CX3CR1−/− mice during injections of transforming growth factor-β (TGF-β) followed by injections of connective tissue growth factor (CTGF). Results: TGF-β injection increased the expressions of MCP-1, fractalkine, CCR2 and CX3CR1 mRNA in WT mice. The overproduction of collagen induced by TGF-β was significantly reduced by CCR2 deficiency, while collagen contents induced by CTGF were restored to wild-type levels. In contrast, overproduction of collagen in CX3CR1-deficient mice decreased nearly 50% by both TGF-β and CTGF stimulations. Conclusion: The involvement of CCR2/MCP-1 interaction (CCR2-dependent loop) was during the TGF-β phase. In contrast, the fractalkine/CX3CR1 interaction contributes to the initiation of fibrosis by TGF-β and its maintenance by CTGF. Collectively, two subsets of macrophages both cooperatively and independently play important roles in the development of fibrosis. [Copyright &y& Elsevier]
- Published
- 2013
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23. Circulating γ/δ T cells in systemic sclerosis exhibit activated phenotype and enhance gene expression of proalpha2(I) collagen of fibroblasts
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Ueda-Hayakawa, Ikuko, Hasegawa, Minoru, Hamaguchi, Yasuhito, Takehara, Kazuhiko, and Fujimoto, Manabu
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T cells , *SYSTEMIC scleroderma , *PHENOTYPES , *FIBROBLASTS , *CYTOMETRY , *REVERSE transcriptase polymerase chain reaction , *MESSENGER RNA - Abstract
Abstract: Background: Systemic sclerosis (SSc) is a systemic inflammatory and fibrotic disease characterized by activation of circulating T lymphocytes. Objective: To determine phenotypic abnormalities of γ/δ T cells and whether γ/δ T cells influence fibroblasts activation in SSc patients. Methods: Number and proportion of peripheral γ/δ T lymphocytes, and their expressions of cell surface molecules were evaluated by flow cytometry. Isolated γ/δ T cells were cocultured with fibroblast, and mRNA expressions of proalpha1(I) collagen and proalpha2(I) collagen (COL1A2) of fibroblasts were analyzed by real time RT-PCR. γ/δ T cell infiltrations in the skin were examined histopathologically. Results: No significant difference in number and proportion of γ/δ T cells was observed in SSc patients compared to healthy controls (HCs). Geometric mean fluorescence intensity (GMFI) of CD16 and CD69 on γ/δ T cells was significantly increased in patients with diffuse cutaneous SSc (dcSSc) compared to HCs. CD62L expression was significantly decreased in patients with dcSSc compared to HCs. The percentage of CD69 positive γ/δ T cells was significantly higher in patients with SSc than HCs. COL1A2 mRNA expression was significantly higher in fibroblasts cocultured with γ/δ T cells from SSc than that from HCs in cell contact independent manner. Additionally, γ/δ T cell infiltrations were observed in SSc patients’ skin. Conclusion: Our results suggest that γ/δ T cells showed activated phenotype in SSc and suggest that SSc γ/δ T cells may play an important role on fibrotic process by upregulation of COL1A2 mRNA expression in fibroblasts. [Copyright &y& Elsevier]
- Published
- 2013
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24. IL-6 Blockade Attenuates the Development of Murine Sclerodermatous Chronic Graft-Versus-Host Disease.
- Author
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Le Huu, Doanh, Matsushita, Takashi, Jin, Guihua, Hamaguchi, Yasuhito, Hasegawa, Minoru, Takehara, Kazuhiko, and Fujimoto, Manabu
- Subjects
- *
GRAFT versus host disease , *SCLERODERMA (Disease) treatment , *INTERLEUKIN-6 , *SYSTEMIC scleroderma , *EXTRACELLULAR matrix , *BONE marrow , *SYMPTOMS , *LABORATORY mice - Abstract
Systemic sclerosis (scleroderma) is a connective tissue disease characterized by excessive extracellular matrix deposition in the skin and visceral organs. Serum IL-6 levels are reported to be elevated in human scleroderma and chronic graft-versus-host disease (cGVHD) patients. IL-6 blockade using anti-IL-6 receptor mAb (anti-IL-6R mAb) results in amelioration of the pathologic symptoms of some autoimmune diseases such as rheumatoid arthritis and juvenile idiopathic arthritis. In this study, we examined the effects of anti-IL-6R mAb on either prevention or treatment of murine sclerodermatous cGVHD (Scl-cGVHD). We found that serum IL-6 levels in Scl-cGVHD mice gradually increased after bone marrow transplantation. Administration of anti-IL-6R mAb attenuated the development of severe Scl-cGVHD and fibrosis and resulted in an increase in CD4+CD25+FoxP3+ regulatory T cells. However, treatment of established Scl-cGVHD with anti-IL-6R mAb showed no effects on disease severity. The effects of anti-IL-6R mAb were mostly inhibited by anti-CD25 mAb. Together, our results indicate that IL-6 has an important role in the pathogenesis of Scl-cGVHD. IL-6 blockade may be an effective approach for preventing Scl-cGVHD and treating cGVHD and scleroderma in humans. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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25. Basophils and mast cells play critical roles for leukocyte recruitment in IgE-mediated cutaneous reverse passive Arthus reaction
- Author
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Jin, Guihua, Matsushita, Takashi, Hamaguchi, Yasuhito, Le Huu, Doanh, Ishii, Takayuki, Hasegawa, Minoru, Obata, Kazushige, Karasuyama, Hajime, Takehara, Kazuhiko, and Fujimoto, Manabu
- Subjects
- *
BASOPHILS , *MAST cells , *LEUCOCYTES , *IMMUNOGLOBULIN E , *SKIN diseases , *ALLERGIES , *INFLAMMATION - Abstract
Abstract: Background: The pathogenic role of IgE has been implicated in a variety of allergic and inflammatory diseases. We have previously established an IgE-mediated cutaneous reverse passive Arthus model in which eosinophil infiltration is a prominent feature. This uniquely provides a model of type III hypersensitivity in which Fc classes of Ig that forms immune complex differentially determine the disease manifestation. Objective: To investigate the mechanisms of how mast cells and basophils regulate this IgE-mediated Arthus reaction. Methods: IgE-mediated cutaneous reverse passive Arthus reaction was induced in wild-type C57BL/6 or WBB6F1-+/+ mice and mast-cell-deficient WBB6F1-W/Wv mice by intradermal injection of IgE anti-trinitrophenyl antibodies followed immediately by intravenous administration of trinitrophenyl bovine serum albumin. Basophils were depleted in vivo using anti-CD200R3 monoclonal antibody prior to the IC challenge. Results: Hemorrhage and infiltration of eosinophils, neutrophils, and basophils were significantly reduced but were not completely abrogated in WBB6F1-W/Wv mice compared with those in wild-type WBB6F1-+/+ mice. Wild-type C57BL/6 mice treated by basophil-depleting mAb also showed significantly decreased hemorrhage and inflammatory cell infiltration, especially that of eosinophils, compared with control mice. Furthermore, basophil depletion in WBB6F1-W/Wv mice led to nearly complete inhibition of eosinophil recruitment. By contrast, basophil depletion did not further decrease neutrophil infiltration in WBB6F1-W/Wv mice. Conclusion: While mast cells play a central role, basophils also have an important function, especially for eosinophil recruitment, in IgE-mediated cutaneous reverse passive Arthus reaction. [Copyright &y& Elsevier]
- Published
- 2012
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26. The Loss of MCP-1 Attenuates Cutaneous Ischemia–Reperfusion Injury in a Mouse Model of Pressure Ulcer.
- Author
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Saito, Yuki, Hasegawa, Minoru, Fujimoto, Manabu, Matsushita, Takashi, Horikawa, Mayuka, Takenaka, Motoi, Ogawa, Fumihide, Sugama, Junko, Steeber, Douglas A, Sato, Shinichi, and Takehara, Kazuhiko
- Subjects
- *
ISCHEMIA , *MONOCYTES , *NEUTROPHILS , *CYTOKINES , *NITRIC oxide - Abstract
The formation of pressure ulcers is dependent on multiple factors including ischemia–reperfusion (IR). This study assessed the mechanism of a previously reported murine model of cutaneous IR injury. Three cycles of IR (days 1–3) by external application of two magnetic plates were performed to induce pressure ulcer formation. Increased infiltration of neutrophils and macrophages, and augmented expression of proinflammatory cytokines and inducible nitric oxide synthase (iNOS), were observed during IR cycles. In this model, monocyte chemoattractant protein-1 (MCP-1) was remarkably increased at day 1 in the skin followed by inflammatory cell infiltration. Therefore, IR cycles were performed in MCP-1-deficient (MCP-1−/−) mice to evaluate the role of this chemokine in pressure ulcer development. MCP-1−/− mice showed reduced macrophage infiltration and expression of tumor-necrosis factor-α (TNF)-α and iNOS during IR cycles leading to attenuated apoptosis and skin injury. Importantly, MCP-1 played a role in apoptosis and injury via inducing iNOS during the reperfusion rather than the ischemic period. These findings indicate that MCP-1 may be a critical factor for macrophage recruitment and subsequent skin inflammation and injury during IR cycles. We propose that this is a useful model for investigating the mechanism of pressure ulcer formation using various transgenic mice.Journal of Investigative Dermatology (2008) 128, 1838–1851; doi:10.1038/sj.jid.5701258; published online 24 January 2008 [ABSTRACT FROM AUTHOR]
- Published
- 2008
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27. Correlation between SPINK5 Gene Mutations and Clinical Manifestations in Netherton Syndrome Patients.
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Komatsu, Nahoko, Saijoh, Kiyofumi, Jayakumar, Arumugam, Clayman, Gary L., Tohyama, Mikiko, Suga, Yasushi, Mizuno, Yuki, Tsukamoto, Katsuhiko, Taniuchi, Katsushige, Takehara, Kazuhiko, and Diamandis, Eleftherios P.
- Subjects
- *
SERINE proteinases , *KALLIKREIN , *GENETIC mutation , *PATIENTS , *CHYMOTRYPSIN , *DERMATOLOGY - Abstract
Netherton syndrome (NS) is a congenital ichthyosiform dermatosis caused by serine protease inhibitor Kazal-type 5 (SPINK5) mutations. Tissue kallikreins (KLKs) and lymphoepithelial Kazal-type-related inhibitor (LEKTI) (SPINK5 product) may contribute to the balance of serine proteases/inhibitors in skin and influence skin barrier function and desquamation. SPINK5 mutations, causing NS, lead to truncated LEKTI; each NS patient possesses LEKTI of a different length, depending on the location of mutations. This study aims to elucidate genotype/phenotype correlations in Japanese NS patients and to characterize the functions of each LEKTI domain. Since we were unable to demonstrate truncated proteins in tissue from patients with NS, we used recombinant protein to test the hypothesis that the length of LEKTI correlated with protease inhibitory activity. Genotype/phenotype correlations were observed with cutaneous severity, growth retardation, skin infection, stratum corneum (SC) protease activities, and KLK levels in the SC. Predominant inhibition by LEKTI domains against overall SC protease activities was trypsin-like (Phe-Ser-Arg-) activity by LEKTI domains 6–12, plasmin- and trypsin-like (Pro-Phe-Arg-) activities by domains 12–15, chymotrypsin-like activity by all domains, and furin-like activity by none. KLK levels were significantly elevated in the SC and serum of NS patients. These data link LEKTI domain deficiency and clinical manifestations in NS patients and pinpoints to possibilities for targeted therapeutic interventions.Journal of Investigative Dermatology (2008) 128, 1148–1159; doi:10.1038/sj.jid.5701153; published online 8 November 2007 [ABSTRACT FROM AUTHOR]
- Published
- 2008
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28. BAFF Antagonist Attenuates the Development of Skin Fibrosis in Tight-Skin Mice.
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Matsushita, Takashi, Fujimoto, Manabu, Hasegawa, Minoru, Matsushita, Yukiyo, Komura, Kazuhiro, Ogawa, Fumihide, Watanabe, Rei, Takehara, Kazuhiko, and Sato, Shinichi
- Subjects
- *
MOUSE diseases , *SYSTEMIC scleroderma , *FIBROSIS , *AUTOIMMUNITY , *ENZYME-linked immunosorbent assay , *TUMOR necrosis factors , *SERUM , *SKIN diseases - Abstract
The tight-skin (TSK/+) mouse, a genetic model for systemic sclerosis (SSc), develops cutaneous fibrosis and autoimmunity. Although immunological abnormalities have been demonstrated in TSK/+ mice, the roles of B-cell-activating factor belonging to the tumor necrosis factor family (BAFF), a potent B-cell survival factor, have not been investigated. Serum BAFF levels in TSK/+ mice were examined by ELISA. Newborn TSK/+ mice were treated with BAFF antagonist, and then skin fibrosis of 8-week-old mice was assessed. Serum BAFF levels were significantly elevated in TSK/+ mice. Remarkably, BAFF antagonist inhibited the development of skin fibrosis, hyper-γ-globulinemia, and the autoantibody production in TSK/+ mice. The skin from TSK/+ mice showed upregulated expressions of fibrogenic cytokines, such as IL-6 and IL-10, while BAFF antagonist significantly suppressed them. Reciprocally, BAFF antagonist augmented antifibrogenic cytokines, such as IFN-γ, in the skin of TSK/+ mice. Furthermore, TSK/+ B cells with BAFF stimulation had a significantly enhanced ability to produce IL-6. The results suggest that BAFF/BAFF receptor system is critical for the development of skin fibrosis in TSK/+ mice and could be a potent therapeutical target.Journal of Investigative Dermatology (2007) 127, 2772–2780; doi:10.1038/sj.jid.5700919; published online 21 June 2007 [ABSTRACT FROM AUTHOR]
- Published
- 2007
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29. Elevated Human Tissue Kallikrein Levels in the Stratum Corneum and Serum of Peeling Skin Syndrome-Type B Patients Suggests an Over-desquamation of Corneocytes.
- Author
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Komatsu, Nahoko, Suga, Yasushi, Saijoh, Kiyofumi, Liu, Amber C., Khan, Saba, Mizuno, Yuki, Ikeda, Shigaku, Hua-Kang Wu, Jayakumar, Arumugam, Clayman, Gary L., Shirasaki, Fumiaki, Takehara, Kazuhiko, and Diamandis, Eleftherios P.
- Subjects
- *
LETTERS to the editor , *SKIN diseases - Abstract
A letter to the editor is presented in response to the article "Elevated Human Tissue Kallikrein Levels in the Stratum Corneum and Serum of Peeling Skin Syndrome-Type B Patients Suggests an Over-desquamation of Corneocytes," that was published in the June 2006 issue.
- Published
- 2006
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30. Quantification of Eight Tissue Kallikreins in the Stratum Corneum and Sweat.
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Komatsu, Nahoko, Tsai, Brian, Sidiropoulos, Michael, Saijoh, Kiyofumi, Levesque, Michael A., Takehara, Kazuhiko, and Diamandis, Eleftherios P.
- Subjects
- *
LETTERS to the editor , *TISSUES - Abstract
A letter to the editor is presented which discusses the quantification of eight tissue kallikerins in the stratum corneum and sweat.
- Published
- 2006
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31. Quantification of Human Tissue Kallikreins in the Stratum Corneum: Dependence on Age and Gender.
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Komatsu, Nahoko, Saijoh, Kiyofumi, Sidiropoulos, Michael, Tsai, Brian, Levesque, Michael A., Elliott, Marc B., Takehara, Kazuhiko, and Diamandis, Eleftherios P.
- Subjects
- *
AGING , *SERINE proteinases , *KALLIKREIN , *TRYPSIN , *CHYMOTRYPSIN , *PROTEOLYTIC enzymes - Abstract
Human tissue kallikreins are a family of 15 trypsin or chymotrypsin-like secreted serine proteases (hK1–hK15). hK5, hK6, hK7, hK8, and hK13 have been identified in the stratum corneum (SC), stratum granulosum, and skin appendages. It has been reported that hK5 and hK7 degrade desmosomes/corneodesmosomes, suggesting that kallikreins are responsible for desquamation. We report the quantification of hK5, hK6, hK7, hK8, hK10, hK11, hK13, and hK14 in the SC by ELISA and their variation among age groups. The total SC trypsin and chymotrypsin-like activities were also measured. The amount of hK7, hK8, and hK11 (ng per mg dry weight) were high, and varied from 6 to 14, hK5 (2.0–4.0) was present at intermediate levels, and hK10 (0.65–1.0), hK14 (0.1–0.3), hK6 (0.1–0.3), and hK13 (0.02–0.1) were present at lower levels. hK6 and hK14 were significantly lower in females between 20 and 59 y. hK5, hK7, hK10, hK11, and hK14 were not significantly different across the age groups. hK8 was lowest at extremes of age (highest at 30–39 y), hK6 was lower at >30 y, and hK13 was lower at >20 y. Overall trypsin-like activity did not differ across age groups but was higher in subjects <11 y. Overall chymotrypsin-like activity was not related to age. In conclusion, we found multiple kallikreins in the SC and suggest that these enzymes may be responsible for desquamation through an enzymatic cascade pathway. [ABSTRACT FROM AUTHOR]
- Published
- 2005
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32. Abnormal Natural Killer Cell Function in Systemic Sclerosis: Altered Cytokine Production and Defective Killing Activity.
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Horikawa, Mayuka, Hasegawa, Minoru, Komura, Kazuhiro, Hayakawa, Ikuko, Yanaba, Koichi, Matsushita, Takashi, Takehara, Kazuhiko, and Sato, Shinichi
- Subjects
- *
KILLER cells , *CYTOKINES , *CELLULAR immunity , *IMMUNOREGULATION , *AUTOANTIBODIES , *CONNECTIVE tissues , *BIOLOGICAL transport - Abstract
Natural killer (NK) cells are innate immune effectors that produce various immunoregulatory cytokines. Recent studies have shown that NK cells are involved in the initiation of autoimmunity. In this study, we determined abnormalities of NK cells in systemic sclerosis (SSc), an autoimmune connective tissue disease, by assessing the frequency and absolute number, activation marker expression, cytokine production, and killing activity. The frequency and absolute number of NK cells increased in diffuse cutaneous SSc (dcSSc), whereas they were normal in limited cutaneous SSc (lcSSc). NK cells from both dcSSc and lcSSc patients exhibited activated phenotypes characterized by up-regulated CD16 and CD69 expression and downregulated CD62L expression. Interferon (IFN)-γ production by non-stimulated NK cells from both dcSSc and lcSSc patients was increased compared to the normal control, whereas on stimulation, a reduced amount of IFN-γ was produced. Interleukin (IL)-5 and IL-10 production by non-stimulated NK cells and IL-6 production by stimulated NK cells were augmented in dcSSc patients, but not in lcSSc patients. Despite the augmented cytokine production by non-stimulated NK cells, natural cytotoxicity activity and granzyme B secretion was reduced in NK cells from dcSSc and lcSSc patients. These results suggested that altered NK cell function contributes to immunological abnormalities in SSc. [ABSTRACT FROM AUTHOR]
- Published
- 2005
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- View/download PDF
33. Altered B lymphocyte function induces systemic autoimmunity in systemic sclerosis
- Author
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Sato, Shinichi, Fujimoto, Manabu, Hasegawa, Minoru, Takehara, Kazuhiko, and Tedder, Thomas F.
- Subjects
- *
SYSTEMIC scleroderma , *EXTRACELLULAR matrix , *IMMUNOREGULATION , *CELLULAR immunity - Abstract
Abstract: Systemic sclerosis (SSc) is a connective tissue disease characterized by excessive extracellular matrix deposition in the skin and visceral organs. SSc is associated with immune activation characterized by autoantibody production, lymphocyte activation, and release of various cytokines. The presence of autoantibodies is a central feature of immune activation in SSc. Although autoantibodies are thought to be closely linked to the pathogenesis of SSc, the pathogenic relationship between systemic autoimmunity and the clinical manifestations of SSc, including skin fibrosis, remains unknown. Recent studies have revealed that B cells play a critical role in systemic autoimmunity and disease expression through various functions, including cytokine production in addition to autoantibody production. The B cell signaling thresholds are regulated by response regulators that augment or diminish B cell signals during responses to self and foreign antigens. Abnormal regulation of the response regulator function and expression may result in autoantibody production. Among these response regulators, CD19, which is a critical cell-surface signal transduction molecule of B cells, is the most potent positive regulator. Transgenic mice that overexpress CD19 by ∼3-fold lose tolerance and generate autoantibodies spontaneously. B cells from SSc patients exhibit a 20%-increase in CD19 expression that induces SSc-specific autoantibody production in transgenic mice. Furthermore, SSc patients have intrinsic B cell abnormalities characterized by expanded naive B cells, activated but diminished memory B cells, and chronic hyper-reactivity of memory B cells, possibly due to CD19 overexpression. Similarly, B cells from a tight-skin mouse, a model of SSc, show augmented CD19 signaling and chronic hyper-reactivity. Remarkably, CD19 loss results in inhibition of chronic B cell hyper-reactivity and elimination of autoantibody production, which is associated with improvement in skin fibrosis and a parallel decrease in IL-6 production by B cells. Thus, chronic B cell activation resulting from augmented CD19 signaling leads to skin fibrosis possibly through IL-6 overproduction, as well as autoantibody production, in tight-skin mice and SSc patients. [Copyright &y& Elsevier]
- Published
- 2005
- Full Text
- View/download PDF
34. Altered B lymphocyte function induces systemic autoimmunity in systemic sclerosis
- Author
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Sato, Shinichi, Fujimoto, Manabu, Hasegawa, Minoru, Takehara, Kazuhiko, and Tedder, Thomas F.
- Subjects
- *
SYSTEMIC scleroderma , *LYMPHOCYTES , *LEUCOCYTES , *AUTOIMMUNITY - Abstract
Systemic sclerosis (SSc) is a connective tissue disease characterized by excessive extracellular matrix deposition in the skin and visceral organs. SSc is associated with immune activation characterized by autoantibody production, lymphocyte activation, and release of various cytokines. The presence of autoantibodies is a central feature of immune activation in SSc. Although autoantibodies are thought to be closely linked to the pathogenesis of SSc, the pathogenic relationship between systemic autoimmunity and the clinical manifestations of SSc, including skin fibrosis, remains unknown. Recent studies have revealed that B cells play a critical role in systemic autoimmunity and disease expression through various functions, including cytokine production in addition to autoantibody production. The B cell signaling thresholds are regulated by response regulators that augment or diminish B cell signals during responses to self and foreign antigens. Abnormal regulation of the response regulator function and expression may result in autoantibody production. Among these response regulators, CD19, which is a critical cell-surface signal transduction molecule of B cells, is the most potent positive regulator. Transgenic mice that overexpress CD19 by ∼3-fold lose tolerance and generate autoantibodies spontaneously. B cells from SSc patients exhibit a 20%-increase in CD19 expression that induces SSc-specific autoantibody production in transgenic mice. Furthermore, SSc patients have intrinsic B cell abnormalities characterized by expanded naive B cells, activated but diminished memory B cells, and chronic hyper-reactivity of memory B cells, possibly due to CD19 overexpression. Similarly, B cells from a tight-skin mouse, a model of SSc, show augmented CD19 signaling and chronic hyper-reactivity. Remarkably, CD19 loss results in inhibition of chronic B cell hyper-reactivity and elimination of autoantibody production, which is associated with improvement in skin fibrosis and a parallel decrease in IL-6 production by B cells. Thus, chronic B cell activation resulting from augmented CD19 signaling leads to skin fibrosis possibly through IL-6 overproduction, as well as autoantibody production, in tight-skin mice and SSc patients. [Copyright &y& Elsevier]
- Published
- 2004
- Full Text
- View/download PDF
35. Serum levels of a Th1 chemoattractant IP-10 and Th2 chemoattractants, TARC and MDC, are elevated in patients with systemic sclerosis
- Author
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Fujii, Hidetaka, Shimada, Yuka, Hasegawa, Minoru, Takehara, Kazuhiko, and Sato, Shinichi
- Subjects
- *
SYSTEMIC scleroderma , *COLLAGEN diseases , *CHEMOKINES , *INFLAMMATORY mediators - Abstract
Background: Although abnormalities of various chemokines are detected in systemic sclerosis (SSc), there are few findings concerning Th1 or Th2 chemoattractants. Objective: To determine whether serum levels of chemokines preferentially chemotactic for Th1 cells (IP-10 and MIG) and predominantly chemotactic for Th2 cells (TARC and MDC) are elevated and whether they correlate with clinical features in patients with SSc. Methods: Serum samples from patients with diffuse cutaneous SSc (dSSc;
n=34 ), limited cutaneous SSc (lSSc;n=30 ), dermatomyositis (DM;n=15 ), systemic lupus erythematosus (SLE;n=22 ), and normal controls (n=30 ) were examined by sandwich ELISA. Results: Serum TARC levels were significantly elevated in dSSc patients (P<0.0002 ) and lSSc patients (P<0.0001 ) compared with normal controls. Similarly, serum MDC levels were significantly increased in patients with dSSc (P<0.02 ) or lSSc (P<0.05 ) relative to normal controls. In addition, serum IP-10 was detected significantly more frequently in patients with dSSc (44%), lSSc (30%), or DM (53%) than normal controls (0%) and patients with SLE (0%). Furthermore, elevated TARC levels correlated with the presence of pitting scars and anti-topoisomerase I antibody, increased titers of anti-topoisomerase I and antinuclear antibody, and decreased glomerular filtration rate. Increased MDC levels were associated with pitting scars and younger ages at onset. Conclusion: These results suggest that both Th2 chemoattractants, TARC and MDC, and a Th1 chemoattractant IP-10 play a role in the development of SSc. [Copyright &y& Elsevier]- Published
- 2004
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- View/download PDF
36. Expression and Localization of Tissue Kallikrein mRNAs in Human Epidermis and Appendages.
- Author
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Komatsu, Nahoko, Takata, Minoru, Otsuki, Norio, Toyama, Tadashi, Ohka, Rie, Takehara, Kazuhiko, and Saijoh, Kiyofumi
- Subjects
- *
KALLIKREIN , *EPIDERMIS , *MESSENGER RNA - Abstract
Tissue kallikreins are a group of serine proteases that are found in many organs and biologic fluids. Tissue kallikrein genes (KLKs) are found on chromosome 19q13.3–4 as a gene cluster encoding 15 different serine proteases. In skin, two tissue kallikrein proteins, hK5 and hK7, are expressed in the stratum corneum and are known to be involved in desquamation of corneocytes. The possible involvement of other kallikrein proteins has not been clarified, however, nor has the significance of each member in the serine protease activity of skin been delineated. In the study described here, we examined expression and localization of KLK mRNA in normal human skin by means of RT-PCR and in situ hybridization. Quantitative RT-PCR analysis showed abundant expression of KLK1 and KLK11 mRNA, moderate expression of KLK4, KLK5, KLK6, KLK7, and KLK13 mRNA, and low expression of KLK8 mRNA in normal human skin. For KLK4, KLK8, and KLK13 mRNA, splice variants were identified to be their major mRNA species. Two variants for KLK13 mRNA were novel. The amount of the serine protease inhibitor Kazal-type 5 (SPINK5) mRNA was comparable to KLK1 and KLK11 mRNA. In situ hybridization revealed intense expression of all KLK mRNA studied except KLK12 mRNA in the stratum granulosum of normal epidermis, where SPINK5 mRNA coexisted. Excluding KLK13 mRNA, they are also expressed in hair sheath, eccrine sweat glands, and sebaceous glands. Coexpression of various KLK and SPINK5 mRNA suggests that their proteins are the candidates to balance and maintain serine protease activities in both the skin and appendages. [ABSTRACT FROM AUTHOR]
- Published
- 2003
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- View/download PDF
37. Ligand-dependent Inhibition of B16 Melanoma Cell Migration and Invasion via Endogenous S1P[sub 2] G Protein-coupled Receptor.
- Author
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Arikawa, Kayo, Takuwa, Noriko, Yamaguchi, Hironori, Sugimoto, Naotoshi, Kitayama, Joji, Nagawa, Hirokazu, Takehara, Kazuhiko, and Takuwa, Yoh
- Subjects
- *
MELANOMA , *CELL migration , *LIGANDS (Biochemistry) - Abstract
We investigated mechanisms for inhibition of B16 melanoma cell migration and invasion by sphingosine-1-phosphate (SIP), which is the ligand for the Edg family G protein-coupled receptors and also implicated as an intracellular second messenger. S1P, dihydro-S1P, and sphingosylphosphorylcholine inhibited B16 cell migration and invasion with the relative potencies expected as S1P[sub 2] receptor agonists. The S1P[sub 2]-selective antagonist JTE013 completely abolished the responses to these agonists. In addition, JTE013 abrogated the inhibition by sphingosine, which is the SIP precursor but not an agonist for SIP receptors, indicating that the sphingosine effects were mediated via S1P[sub 2] stimulation, most likely by SIP that was converted from sphingosine. SIP induced inhibition and activation, respectively, of Rac and RhoA in B16 cells, which were abrogated by JTE013. Adenovirus-mediated expression of N[sup 17]Rac mimicked SIP inhibition of migration, whereas C3 toxin pretreatment, but not Rho kinase inhibitors, reversed the SIP inhibition. Overexpression of S1P[sub 2] sensitized, and that of either S1P[sub 1] or S1P[sub 3] desensitized, B16 cells to SIP inhibition of Rac and migration. In JTE013-pretreated, S1P[sub 3]-overexpressing B16 cells, SIP stimulated cellular RhoA but failed to inhibit either Rac or migration, indicating that RhoA stimulation itself is not sufficient for inhibition of migration. These results provide compelling evidence that endogenously expressed S1P[sub 2] negatively regulates cell motility and invasion through ligand-dependent reciprocal regulation of cellular Rac and RhoA activities. In the presence of JTE013, S1P instead stimulated Rac and migration in B16 cells that overexpress either S1P[sub 1] or S1P[sub 3], unveiling counteractions between S1P[sub 2] and S1P[sub 1] or S1P[sub 3] chemotactic receptor. [ABSTRACT FROM AUTHOR]
- Published
- 2003
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- View/download PDF
38. Function Blocking Autoantibodies Against Matrix Metalloproteinase-1 in Patients with Systemic Sclerosis.
- Author
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Sato, Shinichi, Hayakawa, Ikuko, Hasegawa, Minoru, Fujimoto, Manabu, and Takehara, Kazuhiko
- Subjects
- *
SYSTEMIC scleroderma , *METALLOPROTEINASES - Abstract
Studies the hypothesis that systemic autoimmunity in systemic sclerosis (SSc) induced anti-matrix metalloproteinase-1 (MMP) autoantibodies that inhibited matrix metallo-proteinase-1 activity, resulting in collagen accumulation. Characteristics of SSc; Observation related to enzyme-linked immunosorbent assay using human recombinant matrix metalloproteinase-1; Frequency of anti-MMP-1 antibody in collagen diseases.
- Published
- 2003
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39. Elevated Stratum Corneum Hydrolytic Activity in Netherton Syndrome Suggests an Inhibitory Regulation of Desquamation by SPINK5-Derived Peptides.
- Author
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Komatsu, Nahoko, Takata, Minoru, Otsuki, Norio, Ohka, Rie, Amano, Osamu, Takehara, Kazuhiko, and Saijoh, Kiyofumi
- Subjects
- *
HYDROLASES , *GENETIC disorders - Abstract
Netherton syndrome is a congenital ichthyosis associated with erythroderma, hair shaft defects, and atopic features. The mutations of the secretory serine protease inhibitor Kazal-type 5 gene have been identified in Netherton syndrome patients; however, the actual physiologic substrates of the serine protease inhibitor Kazal-type 5 proprotein are unknown, and how the genetic defects cause characteristic skin phenotype remains uncertain. Here, we describe the serine protease inhibitor Kazal-type 5 gene mutations, including two novel non-sense mutations, and genotype–phenotype correlation in three Netherton syndrome patients in two unrelated Japanese families. Furthermore, based on the reappraisal of the structure of the serine protease inhibitor Kazal-type 5 proprotein, demonstration of the presence of carboxypeptidase in normal keratinocytes, and the observation of mRNA localization of the serine protease inhibitor Kazal-type 5 transcripts in the uppermost epidermis as well as pilosebaceous units, we propose a hypothetical model of proteolytic processing of the serine protease inhibitor Kazal-type 5 proprotein in the epidermis and inhibitory regulation of corneocyte desquamation by a set of serine protease inhibitor Kazal-type 5-derived peptides. This hypothesis is supported by the marked increase of trypsin-like hydrolytic activity demonstrated in stratum corneum samples from our Netherton syndrome patients. The findings in this study suggest that the defective inhibitory regulation of desquamation due to the serine protease inhibitor Kazal-type 5 gene mutations may cause over-desquamation of corneocytes in Netherton syndrome, leading to severe skin permeability barrier dysfunction. [ABSTRACT FROM AUTHOR]
- Published
- 2002
- Full Text
- View/download PDF
40. No Evidence of Deregulated Patched-Hedgehog Signaling Pathway in Trichoblastomas and Other Tumors Arising Within Nevus Sebaceous.
- Author
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Takata, Minoru, Tojo, Michiko, Hatta, Naohito, Ohara, Kuniaki, Yamada, Mizuki, and Takehara, Kazuhiko
- Subjects
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BASAL cell carcinoma , *MICROSATELLITE repeats - Abstract
Nevus sebaceous is a congenital malformation of the skin within which a number of neoplasms showing adnexal differentiation may arise. Recently, deletions in the patched gene region were reported in nevus sebaceous and constitutive activation of the patched-hedgehog signaling pathway was implicated in the development of tumors arising within nevus sebaceous. To substantiate further a role of the patched-hedgehog signaling pathway in secondary tumors arising within nevus sebaceous, we examined 11 nevus sebaceous associated with secondary tumors for loss of heterozygosity of the patched gene region by microsatellite polymerase chain reaction and patched mRNA expression by in situ hybridization. Unexpectedly, however, none of the tumors (including eight trichoblastomas) and nevus sebaceous lesions showed loss of heterozygosity at any polymorphic loci close to the patched gene. Further more, none of the nevus sebaceous lesions and secondary tumors gave detectable signals for patched mRNA. In contrast, four of 11 sporadic basal cell carcinomas, that were examined for comparison, showed loss of heterozygosity at the patched gene locus (p < 0.05), and moderate to strong signals for patched mRNA was observed in all seven basal cell carcinoma tumors examined (p < 0.0001). Additional investigation by reverse transcription–polymerase chain reaction in four basal cell carcinomas and two nevus sebaceous tumors also showed the expression of Gli-1, another target gene in the patched-hedgehog signaling pathway, in all the basal cell carcinomas samples but not in any of the nevus sebaceous tumors examined. The findings in this study do not support the view that the deregulation of the patched-hedgehog signaling pathway is involved in the pathogenesis of nevus sebaceous and associated tumors, and show that, although morphologically similar, trichoblastomas and basal cell carcinomas have a different molecular pathogenesis. [ABSTRACT FROM AUTHOR]
- Published
- 2001
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41. Comparison of Genetic Profiles Between Primary Melanomas and their Metastases Reveals Genetic Alterations and Clonal Evolution During Progression.
- Author
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Morita, Reiji, Fujimoto, Akihide, Hatta, Naohito, Takehara, Kazuhiko, and Takata, Minoru
- Subjects
- *
MELANOMA , *METASTASIS , *GENETICS - Abstract
To examine for the genetic basis of metastatic progression in cutaneous melanoma, we have compared loss of heterozygosity (LOH) of several selected chromosome regions that are implicated in the initiation and progression of melanoma, and alterations of the p16[sup INK4a] gene in 14 pairs of primary tumor and synchronous or asynchronous metastasis excised from the same patients. The most frequent genetic alteration during metastatic progression detected was the loss of p16[sup INK4a] protein expression (four of 14 cases), whereas no somatic p16[sup INK4a] gene mutations were found in any primary or metastatic tumors. LOH analyses showed that most of the chromosome losses including 6q, 8p, 9p, 9q, and 18q were shared between primary tumors and their metastases. Nevertheless, LOH of 6q and 11q and LOH of 7q not detected in primary tumors were, respectively, observed in two lymph node metastases. These results suggest that loss of p16[sup INK4a] protein expression (but not p16[sup INK4a] gene mutation) and the losses of chromosome arms 6q, 7q, and 11q play an important role in the acquisition of metastatic potential in sporadic melanoma. Furthermore, comparison of genetic profiles between the primary tumor and its metastasis revealed in several cases that heterogeous tumor cell populations might already exist at the early stage of tumorigenesis and evolve independently in the primary tumor and its metastasis, strongly suggesting that metastatic progression of sporadic melanoma is not accounted for by a linear progression model. [ABSTRACT FROM AUTHOR]
- Published
- 1998
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42. Loss of heterozygosity of chromosome 9P21 and P16INK4a status in sporadic cutaneous melanoma
- Author
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Takata, Minoru, Fujimoto, Akihide, Morita, Reiji, Hatta, Naohito, and Takehara, Kazuhiko
- Published
- 1998
- Full Text
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43. The relationship between anti-epiligrin cicatricial pemphigoid and gastric carcinoma
- Author
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Taniuchi, Katushige, Matsui, Chihiro, Mori, Toshifumi, Kawara, Shigeru, Takata, Minoru, and Takehara, Kazuhiko
- Published
- 1998
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44. Connective Tissue Growth Factor Gene Expression in Tissue Sections From Localized Scleroderma, Keloid, and Other Fibrotic Skin Disorders.
- Author
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Igarashi, Atsuyuki, Nashiro, Kiyoko, Kikuchi, Kanako, Sato, Shinichi, Ihn, Hironobu, Fujimoto, Manabu, Grotendorst, Gary R., and Takehara, Kazuhiko
- Subjects
- *
CONNECTIVE tissues , *GROWTH factors , *GENE expression , *SCLERODERMA (Disease) , *SKIN diseases , *FIBROBLASTS , *IN situ hybridization , *MESSENGER RNA - Abstract
Connective tissue growth factor (CTGF) is a novel peptide that exhibits platelet-derived growth factor- like activities and is produced by skin fibroblasts after activation with transforming growth factor-β. Coordinate expression of transforming growth factor-β followed by CTGF during wound repair suggests a cascade process for control of tissue regeneration. We recently reported a significant correlation between CTGF mRNA expression and histologic sclerosis in systemic sclerosis. To confirm the relation between CTGF and skin fibrosis, we investigated CTGF gene expression in tissue sections from patients with localized scleroderma, keloid, and other sclerotic skin disorders using nonradioactive in situ hybridization. In localized scleroderma, the fibroblasts with positive signals for CTGF mRNA were scattered throughout the sclerotic lesions with no preferential distribution around the inflammatory cells or perivascular regions, whereas the adjacent nonaffected dermis was negative for CTGF mRNA. In keloid tissue, the fibroblasts positive for CTGF mRNA were diffusely distributed, especially in the peripheral expanding lesions. In scar tissue, however, the fibroblasts in the fibrotic lesions showed partially positive signals for CTGF mRNA. In eosinophilic fasciitis, nodular fasciitis, and Dupuytren's contracture, CTGF mRNA was also expressed partially in the fibroblasts of the fibrotic lesions. Our findings reinforce a correlation between CTGF gene expression and skin sclerosis and support the hypothesis that transforming growth factor-β plays an important role in the pathogenesis of fibrosis, as it is the only inducer for CTGF identified to date. [ABSTRACT FROM AUTHOR]
- Published
- 1996
- Full Text
- View/download PDF
45. Significant Correlation Between Connective Tissue Growth Factor Gene Expression and Skin Sclerosis in Tissue Sections from Patients with Systemic Sclerosis.
- Author
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Igarashi, Atsuyuki, Nashiro, Kiyoko, Kikuchi, Kanako, Sato, Shinichi, Ihn, Hironobu, Grotendorst, Gary R., and Takehara, Kazuhiko
- Subjects
- *
SYSTEMIC scleroderma , *CONNECTIVE tissues , *GROWTH factors , *CYTOKINES , *GENE expression , *COLLAGEN diseases - Abstract
The role of some growth factors and cytokines in the pathogenesis of systemic sclerosis (SSc) has been suggested. In particular, the contribution of transforming growth factor β in the progression of skin sclerosis is suspected. Connective tissue growth factor (CTGF) was originally identified in human umbilical vein endothelial cells, and a recent study has revealed that human skin fibroblasts produce CTGF after stimulation with transforming growth factor β. In the present study, the distribution of CTGF gene expression in tissue sections from patients with SSc was investigated by digoxigenin-labeled in situ hybridization. Strong CTGF nRNA signals were observed in the fibroblasts in sclerotic lesions, especially in the deep dermis, of the skin specimens from patients with SSc, whereas there was no expression in the skin from normal controls. The number of fibroblasts with positive hybridization signals was more abundant in the dermis from the sclerotic stage than in that from the inflammatory stage. Our findings indicate a correlation between CTGF gene expression and skin sclerosis and support the hypothesis that transforming growth factor-β plays an important role in the pathogenesis of SSc, because transforming growth factor β is the only inducer for CTGF identified to date. [ABSTRACT FROM AUTHOR]
- Published
- 1995
- Full Text
- View/download PDF
46. Growth Regulation in Scleroderma Fibroblasts: Increased Response to Transforming Growth Factor-β1.
- Author
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Kikuchi, Kanako, Kadono, Takafumi, Ihn, Hironobu, Sato, Shinichi, Igarashi, Atsuyuki, Nakagawa, Hidemi, Tamaki, Kunihiko, and Takehara, Kazuhiko
- Subjects
- *
SCLERODERMA (Disease) , *FIBROBLASTS , *GROWTH factors , *RNA , *CELLS , *DERMATOLOGY - Abstract
We investigated the responses of normal and scleroderma fibroblasts to various growth Factors, especially transforming growth factor-β1 (TGF-β1). The effects of various growth Factors on [3H]thymidine incorporation in normal and scleroderma fibroblasts were examined. [125KI]-labeled platelet-derived growth factor (PDGF)-BB binding in scleroderma and normal fibroblasts was examined both in the presence and absence of TGF-β1 (1 ng/ml). Cytoplasmic protein was isolated and analyzed by Western blotting. Total RNA from fibroblasts was also isolated and analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR) using specific primer sets. Mitogenic responses to TGF-β1 (0.33-1 ng/ml) in seven scleroderma fibroblast strains were significantly greater than those in normal controls. [125KI]-PDGFBB binding to scleroderma fibroblasts was increased after TGF-β1 stimulation. The increased response to TGF-β1 was shown to be mediated through PDGFlike protein induction; TGF-βl-treated scleroderma fibroblasts produced greater amounts of 36-kD PDGF-like protein, which was reported previously as connective tissue growth Factor (CTGF), than did TGF-β1-treated normal fibroblasts. TGF-β1 treatment also upregulated PDGF-α receptor expression in scleroderma fibroblasts but not in normal dermal fibroblasts, mRNA expression of CTGF and PDGF-α receptor was correlated with the above protein expression. These observations suggest that the increased growth response to TGF-β1 in scleroderma fibroblasts is mediated through the induction of CTGF and PDGF-α receptor. [ABSTRACT FROM AUTHOR]
- Published
- 1995
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47. Elevated serum placenta growth factor (PlGF) levels in patients with systemic sclerosis: A possible role in the development of skin but not lung fibrosis
- Author
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Hamaguchi, Yasuhito, Hasegawa, Minoru, Tanaka, Chihiro, Kumada, Sayako, Sato, Shinichi, Takehara, Kazuhiko, and Fujimoto, Manabu
- Published
- 2010
- Full Text
- View/download PDF
48. Clinical association of serum CD137 (4-1BB) levels in patients with systemic sclerosis
- Author
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Hamaguchi, Yasuhito, Hasegawa, Minoru, Matsushita, Takashi, Komura, Kazuhiro, Takehara, Kazuhiko, and Fujimoto, Manabu
- Published
- 2009
- Full Text
- View/download PDF
49. Clinical association of serum interleukin-17 levels in systemic sclerosis: Is systemic sclerosis a Th17 disease?
- Author
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Murata, Maki, Fujimoto, Manabu, Matsushita, Takashi, Hamaguchi, Yasuhito, Hasegawa, Minoru, Takehara, Kazuhiko, Komura, Kazuhiro, and Sato, Shinichi
- Published
- 2008
- Full Text
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50. Prevalence and clinical characteristics of anti-Mi-2 antibodies in Japanese patients with dermatomyositis
- Author
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Komura, Kazuhiro, Fujimoto, Manabu, Matsushita, Takashi, Kaji, Kenzo, Kondo, Miki, Hirano, Takashi, Orito, Hidemitsu, Horikawa, Mayuka, Hamaguchi, Yasuhito, Hasegawa, Minoru, Takehara, Kazuhiko, and Sato, Shinichi
- Published
- 2005
- Full Text
- View/download PDF
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