研究者詳細 - 竹内　勤

論文 - 竹内　勤

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Serum levels of IFN-inducible protein-10 relating to the activity of systemic lupus erythematosus

Narumi Shosaku, Takeuchi Tsutomu, Kobayashi Yuko, Konishi Konosuke

Cytokine 12 （ 10 ） 1561 - 1565 2000年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1043-4666

IFN-inducible protein-10 (IP-10) is supposed to act as a specific chemoattractant for Th₁ cells. Since Th₁ cells and IFN-γ are shown to be important for developing systemic lupus erythematosus (SLE), we examined the relationship between serum IP-10 levels and the disease activity. Serum IP-10 levels were markedly increased in the SLE patients depending on the level of disease activity, whereas not in the patients with rheumatoid arthritis (RA). On the other hand, serum MCP-1 levels were increased to a similar extent both in RA and inactive SLE patients, and a little more elevated in active SLE patients. Serum IP-10 levels in SLE patients correlated positively and negatively with levels of anti-DNA antibody and complements, respectively, whereas MCP-1 levels correlated less or not at all. These results suggest that serum IP-10 levels could be a good indicator for the activity of SLE and that IP-10 could play an important immunological role in SLE. (C) 2000 Academic Press.

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Nosocomial pneumonia likely caused by Stenotrophomonas maltophilia in two patients with polymyositis

Amano Koichi, Maruyama Hiroshi, Takeuchi Tsutomu

Internal Medicine 38 （ 11 ） 910 - 916 1999年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0918-2918

We report two cases of polymyositis (PM) complicated with nosocomial pneumonia probably caused by Stenotrophomonas maltophilia, which was resistant to multiple antimicrobials. In the first case, the chest CT findings and high serum endotoxin level as well as sputum culture results were helpful for the proper diagnosis and the therapy was successful. However the second patient died of a lung abscess in spite of the intensive antibiotic therapy. When PM patients develop pneumonia unresponsive to various antibiotics, a multi-drug-resistant bacteria such as Stenotrophomonas maltophilia should be considered as the pathogen.

Preferential localization of CD8⁺ α(E)β₇⁺ T cells around acinar epithelial cells with apoptosis in patients with Sjogren's syndrome

Fujihara Tsutomu, Fujita Hiromi, Tsubota Kazuo, Saito Keiko, Tsuzaka Kensei, Abe Tohru, Takeuchi Tsutomu

Journal of Immunology 163 （ 4 ） 2226 - 2235 1999年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0022-1767

The T lymphocytes that infiltrate the exocrine glands in Sjogren's syndrome (SS) play a key role in damaging glandular epithelial cells, but the mechanisms of tiffs damage by T lymphocytes are not fully understood. To determine the cellular basis of this phenomenon, we focused our attention on the T lymphocytes around acinar epithelial cells in SS. We showed that CD8⁺ but not CD4⁺ T lymphocytes were located around the acinar epithelial cells and that a majority of these CD8⁺ T lymphocytes possess an unique integrin, α(E)β₇ (CD103). The acinar epithelial cell adherent with α(E)β₇ (CD103)+ CD8⁺ T lymphocytes was apoptotic. Both the perforin/granzyme B and Fas/Fas ligand pathways were implicated in the process of programmed cell death in lacrimal glands. These results suggested that α(E)β₇ integrin, by interacting with E-cadherin, mediates the adhesion between CD8⁺ T lymphocytes and acinar epithelial cells in SS and participates in inducing epithelial cell apoptosis, leading to secretory dysfunction of exocrine glands, a hallmark of SS.

1-2). Defective signal transduction via TCR-CD3 complex in patients with systemic lupus erythematosus

Takeuchi Tsutomu, Tsuzaka Kensei, Pang Ming, Abe Tohru

Internal Medicine 38 （ 2 ） 169 1999年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0918-2918

Candida pneumonia in a case of polymyositis complicated with interstitial pneumonitis

Takano Y., Amano K., Aoki K., Takeuchi T.

Japanese Journal of Rheumatology 9 （ 4 ） 397 - 402 1999年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0169-1163

We report a polymyositis patient who developed Candida pneumonia, whose clinical manifestations such as dry cough, dyspnea, fever and elevated LDH looked like a recurrence of interstitial pneumonitis (IP) which she had had at admission. The distribution of the lesions in high resolution computed tomography scan, the high serum level of β-D-glucan and positive Candida antigen test led to make a diagnosis of Candida pneumonia rather than IP, and fluconazole therapy was successful.

Regulation of human leukocyte antigen expression in human conjunctival epithelium

Tsubota Kazuo, Fukagawa Kazumi, Fujihara Tsutomu, Shimmura Shigeto, Saito Ichiro, Saito Keiko, Takeuchi Tsutomu

Investigative Ophthalmology and Visual Science 40 （ 1 ） 28 - 34 1999年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0146-0404

Purpose. To demonstrate that interferon-γ (IFN-γ) is the key cytokine responsible for the upregulation of HLA-DR antigen in conjunctival epithelial cells of Sjogren syndrome (SS) patients. Methods. Flow cytometry of conjunctival epithelial cells from SS and non-SS dry eye patients was performed for the quantification of HLA-DR surface expression. With a conjunctival epithelial cell line (ChWK), HLA-DR regulation by various cytokines was evaluated, and confocal immunocytochemical and western blot analyses were performed to evaluate the activation of nuclear factor-kappa B (NF-κB) and signal transducers and activators of transcription 1 and 3 (STAT1 and STAT3, respectively). Results. HLA-DR expression was upregulated in conjunctival epithelial cells of SS patients but not in non-SS dry eye patient or healthy control subject. IFN-γ was the only cytokine that effectively upregulated HLA-DR expression in ChWK, which was synergistically enhanced by tumor necrosis factor-α (TNF-α). IFN-γ induced the nuclear translocation of NF-κB, but did not activate STAT1 or STAT3 in ChWk. Conclusions. Upregulation of HLA-DR antigen in the conjunctival epithelium of SS patients may be regulated by IFN-γ through the activation of NF-κB.

Conjunctival epithelium expression of HLA-DR in dry eye patients

Tsubota Kazuo, Fujihara Tsutomu, Saito Keiko, Takeuchi Tsutomu

Ophthalmologica 213 （ 1 ） 16 - 19 1999年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0030-3755

Purpose: To compare conjunctival epithelium expression of HLA-DR and ICAM-1 with tear dynamics and ocular surface parameters. Methods: Brush cytology and flow cytometry were used to quantitatively analyze HLA-DR and ICAM-1 expression in 28 dry eye patients. Results: HLA-DR was expressed in 66% of the conjunctival cells of dry eye patients. This expression correlates with that of ICAM-1, as well as with the Schirmer test results (p<0.05). Conclusion: This study confirmed that dry eye consists not only of ocular surface desiccation, but also of upregulation of the HLA-DR and ICAM-1 molecule in the conjunctival epithelium, possibly resulting in increased inflammation.

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Diagnosis of measles viral pneumonia in a patient with Hodgkin's disease by reverse transcription-polymerase chain reaction of serum

Mori Shigehisa, Maruyama Hiroshi, Ito Isao, Tokuhira Michihide, Koide Jun, Takeuchi Tsutomu, Itoyama Shinji, Masunaga Atsuko, Fukushima Masao, Suzuki Hiroshi, Abe Tohru

International Journal of Hematology 68 （ 3 ） 327 - 331 1998年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0925-5710

We report a case of fatal measles viral pneumonia in a patient with Hodgkin's disease who had no rash. The measles viral cDNA was detected in autopsy tissue from the lung by reverse transcription-polymerase chain reaction. This method was then applied successfully to stored serum. The diagnosis of measles viral pneumonia may be improved by the application of RT-PCR using peripheral blood. Sequence analysis of amplified cDNA suggested the virus infecting this patient was a recent strain, predominantly isolated after 1980. The fatal outcome may have been due to a lack of immune response to the newer strain.

Mutations in T cell receptor ζ chain mRNA of peripheral T cells from systemic lupus erythematosus patients

Tsuzaka Kensei, Takeuchi Tsutomu, Onoda Natsuko, Pang Ming, Tohru Abe

Journal of Autoimmunity 11 （ 5 ） 381 - 385 1998年10月

研究論文（学術雑誌）, 査読有り, ISSN 0896-8411

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease of unknown aetiology. Although it has been reported that T cells might be responsible for the pathogenesis of SLE, it remains unclear whether immune aberrations of SLE T cells are the primary event in this pathological process. We have recently reported that tyrosine phosphorylation and expression of the T cell receptor zeta chain (TCR ζ) was significantly decreased in SLE T cells and that two SLE patients exhibited a 36 bp, exon 7 deletion of the TCR ζ mRNA. To investigate further common mutations in TCR ζ mRNA among SLE patients, mRNA was isolated from the peripheral blood T cells of two normal controls, two systemic sclerosis (SSc) patients, and eight SLE patients. TCR ζ cDNA was amplified by RT-PCR. Five out of the eight SLE patients exhibited abnormal migration patterns of the TCR ζ cDNA in PCR single stranded conformational polymorphism analysis. PCR products were ligated into pUC18 and five clones obtained were sequenced. Analysis of the nucleotide sequences revealed that all of the five pUC18 clones from the normal controls and SSc patients had the normal nucleotide sequence, whereas all eight SLE patients had mutations in TCR ζ cDNA accompanied by predicted amino acid substitutions. Mutations found in six of these patients corresponded to those of the third immunoreceptor tyrosine-based activation motif (ITAM) domain or the GTP/GDP binding site in TCR ζ. Thus, these mutations in TCR ζ mRNA could be responsible for the decreased expression of the TCR ζ protein in SLE T cells.

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Up-regulation of αEβ7, a novel integrin adhesion molecule, on T cells from systemic lupus erythematosus patients with specific epithelial involvement

Pang Ming, Abe Tohru, Fujihara Tsutomu, Mori Shigehisa, Tsuzaka Kensei, Amano Kouichi, Koide Jun, Takeuchi Tsutomu

Arthritis and Rheumatism 41 （ 8 ） 1456 - 1463 1998年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0004-3591

Objective. To determine the possible role of a novel integrin, αEβ7, in the pathogenesis of systemic lupus erythematosus (SLE). Methods. Expression of αEβ7 was examined on peripheral blood lymphocytes (PBL) from normal subjects (n = 25) and patients with SLE (n = 31), primary Sjogren's syndrome (n = 7), or polymyositis/dermatomyositis (n = 8) by cytofluorometry and/or immunoprecipitation. Adhesion of αEβ7+ T cells to HSG epithelial cells was investigated using a confocal image analyzer. Results. After phytohemagglutinin stimulation, expression of αEβ7 on PBL, especially on CD8+ T cells, was significantly higher in SLE patients than in normal subjects (P < 0.01). Elevated αEβ7 expression was associated with the presence of oral ulcers or serositis (P < 0.05). Activated SLE T cells with enhanced αEβ7 expression strongly adhered to HSG; this adhesion was partially blocked by anti-αEβ7. Conclusion. Expression and adhesion of αEβ7 on activated PBL was significantly increased in patients with SLE with epithelial involvement. This suggests a role of this novel integrin in tissue-specific retention of activated PBL, due to increased αEβ7-E- cadherin interaction, which may contribute to epithelial inflammation.

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TCR zeta chain lacking exon 7 in two patients with systemic lupus erythematosus

竹内勤

International Immunology 10 （ 7 ） 911 - 921 1998年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0953-8178

Decreased Fcγ receptor III (CD16) expression on peripheral blood mononuclear cells in patients with Sjogren's syndrome

Saito Keiko, Abe Tohru, Takeuchi Tsutomu

Journal of Rheumatology 25 （ 4 ） 689 - 696 1998年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0315-162X

Objective. To examine the expression of surface structures important in natural killer (NK) cell function and the roles of serum factors affecting the expression of surface antigens on these cells in patients with Sjogren's syndrome (SS). Methods. Peripheral blood mononuclear cells (PBMC) of 18 patients with SS were analyzed by immunofluorescence on a flow cytometer. The antigen recognized by autoantibodies in their sera was analyzed by immunofluorescence and by immunoprecipitation. Results. Expression of Fcγ receptor III (CDI 6), an important indicator of NK cytolytic activity, on PBMC was significantly decreased in patients with SS who have extraglandular disease, while the expression of Fcγ RI and II was normal. Moreover, F(ab')₂ of IgG in these patients' sera was shown to bind to CD16+ cells. Immunoprecipitation study showed that it bound to CD16 itself. Conclusion. The depressed expression of CD16 on PBMC and the presence of antibody binding to CD16 in the patients' sera may be, at least in part, responsible for the altered function of NK cells observed in SS.

Lecithin-bound superoxide dismutase in the prevention of neutrophil- induced damage of corneal tissue

Matsumoto Koki, Shimmura Shigeto, Goto Eiki, Saito Keiko, Takeuchi Tsutomu, Miyajima Seiya, Negi Akira, Tsubota Kazuo

Investigative Ophthalmology and Visual Science 39 （ 1 ） 30 - 35 1998年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0146-0404

PURPOSE. To evaluate the effects of a lipophilic analog of superoxide dismutase (SOD) in the prevention of polymorphonuclear leukocyte (PMN)- induced damage to corneal epithelial cells in vitro and in bacterial corneal ulcers in vivo. METHODS. Immortalized human corneal epithelial cells (T- HCEC) were cocultured with human PMNs activated with N-formyl-methionyl- leucyl-phenylalanine for 18 hours, after which lactate dehydrogenase (LDH) activity of the supernatant was measured as a marker of cellular damage. The inhibitory effects of lecithin-bound SOD (PC-SOD) and unmodified SOD, as well as PMNs pretreated with anti-CD 18 monoclonal antibody, were compared with untreated control. The retention of each drug on the ocular surface of healthy volunteers was measured by flow cytometry using brush cytology samples. The protective effects of a 0.1% solution of PC-SOD on Pseudomonas aeruginosa corneal infection in guinea pigs were assessed by inflammatory grading scores and histology. RESULTS. Both PC-SOD and SOD effectively suppressed PMN-induced LDH release in T-HCEC in a dose-dependent manner. LDH release was also attenuated when PMNs were pretreated with anti-CD 18 antibodies, suggesting that adhesion molecules were involved in the process. Brush cytology of conjunctival samples showed that PC-SOD was retained longer on the ocular surface compared with unmodified SOD. PC-SOD significantly prevented excessive tissue damage by infiltrating PMNs in P. aeruginosa corneal infection, whereas in control eyes, perforation of the cornea occurred by 6 days. CONCLUSIONS. PC-SOD was effective in attenuating PMN- related tissue damage to corneal tissue both in vitro and in P. aeruginosa infection in guinea pigs.

TCR ζ chain lacking exon 7 in two patients with systemic lupus erythematosus

Takeuchi Tsutomu, Tsuzaka Kensei, Pang Ming, Amano Kouichi, Koide Jun, Abe Tohru

International Immunology 10 （ 7 ） 911 - 921 1998年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0953-8178

To address the molecular mechanism underlying the functional defects of peripheral T cells in systemic lupus erythematosus (SLE), we focused on early signaling events. We demonstrated that protein expression of the TCR ζ chain was significantly decreased in peripheral T cells from patients with SLE compared to normal controls and patients with systemic sclerosis (SSc). Among those patients showing decreased TCR ζ chain expression, we found two patients with pronounced TCR ζ chain abnormalities, including an aberrant 14 kDa form in one and only trace expression in the other. RT-PCR, SSCP and subsequent cloning of the transcripts revealed that bases 468-503, corresponding to exon 7, were deleted in both patients. Since exon 7 spans the GTP/GDP binding site and N-terminal tyrosine in the third ITAM domain of TCR ζ chain, the transcript lacking exon 7 may be responsible for altered signal transduction via TCR in these SLE patients.

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Respiratory syncytial virus-induced interleukin-4 production by human conjunctival epithelial cells contributes to allergy

Fujishima Hiroshi, Saito Ichiro, Okamoto Yoshitaka, Takeuchi Tsutomu, Tsubota Kazuo

Current Eye Research 17 （ 6 ） 656 - 662 1998年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0271-3683

Purpose. We previously reported allergic conjunctivitis was associated with a local pattern of cytokines and identified respiratory syncytial virus (RSV) in the conjunctival epithelium, in patients with allergic conjunctivitis. We hypothesized that RSV infected the normal conjunctival epithelium and produced interleukin-4 (IL-4), causing an allergic reaction. To determine this event, we studied production of IL-4 by human conjunctival epithelial cells, after infection with RSV. Methods. Conjunctival samples were collected with a special brush and were challenged with 5 x 10⁶ pfu/ml of live RSV. RSV infection was detected by immunocytochemical study and RT-PCR. HLA-DR antigen was expressed by flow cytometry. IL-4 was assayed by a sandwich ELISA. Results. Immunocytochemical study and RT-PCR showed that RSV infected the conjunctival epithelial cells. HLA-DR was demonstrated in the RSV-infected conjunctival epithelial cells. Average concentrations of IL-4 in culture supernatants in infected cells were 3.8 ± 1.8, 3.6 ± 1.1, and 5.4 ± 1.8 pg/ml at 24, 48, and 72 h, respectively. Levels in non-infected cells were 0.33 ± 0.0, 0.59 ± 0.69, and 0.4 ± 0.22 pg/ml, respectively (p > 0.001). Conclusion. Findings suggest that the expression of IL-4 is associated with intracellular infection by RSV in conjunctiva. With our former reports, RSV infection in conjunctival epithelial cells can be suggested as one of the possible environmental pathogens of allergic conjunctivitis.

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Lacrimation and salivation are not related to lymphocytic infiltration in lacrimal and salivary glands in MRL lpr/lpr mice

Fujita Hiromi, Fujihara Tsutomu, Takeuchi Tsutomu, Saito Ichiro, Tsubota Kazuo

Advances in Experimental Medicine and Biology 438 941 - 948 1998年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0065-2598

Granulomatous amoebic encephalitis caused by Acanthamoeba in a patient with systemic lupus erythematosus

Koide J., Okusawa E., Ito T., Mori S., Takeuchi T., Itoyama S., Abe T.

Clinical Rheumatology 17 （ 4 ） 329 - 332 1998年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0770-3198

A 25-year-old chronically immunosuppressed woman with systemic lupus erythematosus (SLE) died after developing subacute granulomatous encephalitis caused by Acanthamoeba. Amoebic trophozoites were also found in the lung, suggesting a primary pulmonary focus of infection. The infectious encephalitis was difficult to differentiate from a flare-up of central nervous system lupus. This case illustrates that Acanthamoeba can cause fatal encephalitis in lupus patients, as well as in patients with acquired immunodeficiency syndrome as previously reported. To our knowledge, this is the first reported case of granulomatous amoebic encephalitis due to Acanthamoeba in a patient with SLE.

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Serum soluble Fas/APO-1 is increased in patients with primary Sjogren's syndrome

Fujihara T., Takeuchi T., Tsubota K., Kayagaki N., Yagita H., Okumura K., Abe T.

Clinical Rheumatology 17 （ 6 ） 496 - 499 1998年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0770-3198

The aim of the study was to elucidate the involvement of Fas antigen in human autoimmune disease, by analysing serum levels of soluble Fas/APO1 protein in patients with various autoimmune diseases, including system lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), polymyositis/dermatomyositis (PM/DM), Behcet's syndrome and Sjogren's syndrome (SjS). The levels of soluble Fas/APO-1 in sera were quantitated by a sandwich enzyme-linked immunosorbent assay. Soluble Fas/APO-1 levels were significantly increased in serum from patients with primary Sjogren's syndrome (1°SjS) compared with control subjects. However, no significant differences in soluble Fas/APO-1 levels were noted in patients with secondary Sjogren's syndrome (2°SjS) nor in patients with any of the other autoimmune diseases. The soluble Fas/APO-1 level in 1°SjS patients with extraglandular diseases was significantly higher than that in patients without extraglandular diseases. These results suggest that soluble Fas/APO-1 protein may play an important role in the pathogenesis of 1°SS.

Reduced protein tyrosine phosphatase (PTPase) activity of CD45 on peripheral blood lymphocytes in patients with systemic lupus erythematosus (SLE)

竹内勤

Clinical and Experimental Immunology 109 （ 1 ） 20 - 26 1997年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0009-9104

Soluble interleukin-2 receptors and serum autoantibodies in dry eye patients

Tsubota Kazuo, Fujihara Tsutomu, Takeuchi Tsutomu

Cornea 16 （ 3 ） 339 - 344 1997年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0277-3740

Purpose. Sjogren's syndrome (SS) is a systemic autoimmune disease characterized by decreased lacrimal and salivary gland function causing dry eye and dry mouth. We examined several parameters as measures of lacrimal function and compared the serum soluble interleukin-2 receptor (sIL-2R) and serum autoantibodies as measures of systemic autoimmune condition. Methods. Serum levels of sIL-2R, antinuclear antibody (ANA), and rheumatoid factor (RF), in 128 patients (16 men, 112 women; average age, 54.3±12.5 years) were measured. The lacrimal function was evaluated clinically. Results. There was no correlation between systemic condition and the cotton-thread test, Schirmer test with or without anesthesia, tear clearance test, tear-function index, or the BUT. However, the Schirmer test with nasal stimulation and rose bengal and fluorescein staining was positively correlated with systemic parameters. Conclusion. We show the correlation of serum sIL-2R, ANA, and RF to lacrimal function, which is good evidence that systemic immune conditions directly affect local lacrimal gland function.

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