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Biomedical subjects

Minoru Hasegawa

Publications and source records attributed to Minoru Hasegawa.

At least 19 recordsLinked to original sources
PubMed2006

Elevated serum BAFF levels in patients with systemic sclerosis: enhanced BAFF signaling in systemic sclerosis B lymphocytes.

OBJECTIVE: To determine serum levels of BAFF, a potent B cell survival factor, in patients with systemic sclerosis (SSc) and relate the results to the clinical features of SSc. METHODS: Serum BAFF levels in 83 patients with SSc were examined by enzyme-linked immunosorbent assay (ELISA). In a longitudinal study, 131 serum samples obtained from 21 patients with SSc were analyzed. The expression of BAFF messenger RNA (mRNA) in the skin was quantified by real-time reverse transcription-polymerase chain reaction. The expression of BAFF receptor (BAFFR) on CD19+ B cells was assessed by flow cytometry. The production of IgG and interleukin-6 (IL-6) by isolated B cells was examined by ELISA. RESULTS: Serum BAFF levels were elevated in SSc patients compared with healthy controls and correlated positively with the extent of skin fibrosis. Among the 21 patients with SSc in the longitudinal study, 7 had decreased BAFF levels, 11 had levels that remained unchanged, and 3 patients had increased levels. Decreasing BAFF levels were accompanied by regression of skin sclerosis, whereas increasing levels of BAFF were associated with the new onset or worsening of organ involvement. BAFF mRNA expression was up-regulated in the affected skin of patients with early diffuse cutaneous SSc. BAFFR expression on B cells was increased in SSc patients relative to healthy controls. Furthermore, SSc B cells that were stimulated by BAFF exhibited an enhanced ability to produce IgG and IL-6. CONCLUSION: These results suggest that BAFF and its signaling in B cells contribute to B cell abnormalities and disease development in patients with SSc.

Adult↗
PubMed2005

Anti-DNA topoisomerase II alpha autoantibodies in Japanese patients with systemic sclerosis.

The pathogenesis and etiology of systemic sclerosis (SSc) remain unknown, but the presence of several autoantibodies is recognized as one of its prominent features. The clinical significance of anti-DNA topoisomerase II alpha antibody (anti-topo II alpha Ab) remains unknown in Japanese patients with SSc. To determine the prevalence and clinical correlation of anti-topo II alpha Ab in Japanese patients with SSc. Serum samples were obtained from 103 Japanese patients with SSc. Control serum samples were obtained from 43 healthy Japanese volunteers. Anti-topo II alpha Abs were determined by enzyme linked-immunosorbent assay.IgG anti-topo II alpha Ab levels were significantly increased in SSc patients (n=103) compared to normal controls (n=43; P<0.005). IgG or IgM anti-topo II alpha Ab was detected in 19% (20/103) of SSc patients when absorbance values higher than the mean+2SD of control serum samples were considered positive. By contrast, IgG or IgM anti-topo II alpha Ab was observed in only 7% (3/43) of healthy individuals. The presence of pulmonary fibrosis was more frequently detected in SSc patients with IgG anti-topo II alpha Ab than those without the Ab (P<0.05). Moreover, % DLco and % VC were significantly decreased in SSc patients with anti-topo II alpha Ab relative to those without the Ab (P<0.05 and P<0.01, respectively). The elevated levels of both erythrocyte sedimentation rate and C-reactive protein were also more frequently observed in SSc patients positive for IgG anti-topo II alpha Ab (P<0.005). The results of the present study indicate that anti-topo II alpha Ab represent one of the autoantibody specificities detected on SSc patients and may be regarded a serological marker of pulmonary fibrosis in Japanese patients with SSc.

Adult↗
PubMed2005

Successful treatment with sildenafil in systemic sclerosis patients with isolated pulmonary arterial hypertension: two case reports.

We describe two systemic sclerosis (SSc) patients with isolated pulmonary arterial hypertension (PAH) who were given treatment with 50 mg oral sildenafil per day. We evaluated the efficacy of oral sildenafil for isolated PAH in SSc patients by direct assessment with cardiac catheterization before and 6 months after the initiation of sildenafil. Right-heart catheterization demonstrated decreased mean pulmonary artery pressure, decreased pulmonary vascular resistance, and increased cardiac output after treatment with sildenafil. Brain natriuretic peptide levels were gradually decreased. The 6-min walking distance was greatly extended. Moreover, the physical conditions of both patients were much improved. We recognized no adverse events. We propose that oral sildenafil may be beneficial as a selective pulmonary vasodilator and as long-term treatment in SSc patients with isolated PAH.

Female↗
PubMed2005

Serum pulmonary and activation-regulated chemokine/CCL18 levels in patients with systemic sclerosis: a sensitive indicator of active pulmonary fibrosis.

OBJECTIVE: To clarify the clinical significance of serum levels of pulmonary and activation-regulated chemokine (PARC) in the diagnosis and monitoring of pulmonary fibrosis (PF) in patients with systemic sclerosis (SSc) and to compare PARC levels with KL-6 antigen or surfactant protein D (SP-D) levels. METHODS: Serum PARC levels were determined by enzyme-linked immunosorbent assay in 123 SSc patients. In a retrospective longitudinal study, correlation of serum PARC levels with the activity of PF was assessed in 21 SSc patients with active PF. RESULTS: PARC levels at the first visit were higher in patients with SSc than in patients with systemic lupus erythematosus (SLE) or healthy controls. Increased serum PARC levels were associated with involvement of PF, decreased diffusing capacity for carbon monoxide, and decreased vital capacity in SSc patients. In the longitudinal study, serum PARC levels were significantly decreased in SSc patients with inactive PF compared with those with active PF. CONCLUSION: Elevated serum PARC levels correlated with PF and more sensitively reflected the PF activity than did serum KL-6 or SP-D levels in SSc. Serum PARC levels may be a useful new serum marker for active PF in SSc.

Antigens↗
PubMed2005

Pathogenesis of systemic sclerosis: altered B cell function is the key linking systemic autoimmunity and tissue fibrosis.

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-beta, 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.

Animals↗
PubMed2005

Abnormal natural killer cell function in systemic sclerosis: altered cytokine production and defective killing activity.

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)-gamma 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-gamma 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.

Adult↗
PubMed2005

[B lymphocyte].

Recent studies have revealed that B cells play a critical role in autoimmunity and disease expression through various functions, including autoantibody production, cytokine secretion, antigen presentation, and co-stimulatory effect. Selective targeting of B cells has been recently achieved using a chimeric monoclonal antibody against CD20 (Rituximab). Significant clinical efficacy has been demonstrated in several autoimmune diseases including rheumatoid arthritis and systemic lupus erythematosus by the infusion of this antibody. Rituxumab significantly improves the symptoms during the long period of complete B cell depletion. Understanding the dynamics of B cell involvement in autoimmune diseases will be crucial to the development of B cell-targeted strategies. Conversely, the findings derived from studies of anti-B cell therapy provide us a lot of important clues to clarify the pathogenesis of autoimmune diseases. This review focuses on recent data demonstrating the roles of B cells in autoimmune diseases as well as the current studies concerning the treatment of autoimmune diseases by Rituximab.

Animals↗
PubMed2005

Anti-lipoprotein lipase antibody in systemic sclerosis: association with elevated serum triglyceride concentrations.

OBJECTIVE: The vascular damage systemic sclerosis (SSc) consists mainly of microvascular changes, but recently macrovascular changes with dyslipidemia were recognized. In systemic lupus erythematosus (SLE), autoantibody to lipoprotein lipase (LPL), a key enzyme that hydrolyzes triglycerides, suggested a role of autoimmunity for elevated serum triglyceride levels and atherosclerosis. We investigated the prevalence and levels of anti-LPL antibodies, their clinical correlation, and their functional significance in patients with SSc. METHODS: Serum samples from patients with diffuse cutaneous SSc (dSSc; n = 55), limited cutaneous SSc (lSSc; n = 75), SLE (n = 21), and dermatomyositis (DM; n = 21) and healthy controls (n = 41) were examined by ELISA. The presence of anti-LPL antibody was evaluated by immunoblotting analysis using purified LPL. To determine the functional relevance of anti-LPL antibody in vivo, we assessed whether anti-LPL autoantibody was able to inhibit LPL activity using the LPL activity kit. RESULTS: ELISA revealed that IgG or IgM anti-LPL antibodies were detected in 35% of SSc patients, while they were also positive in 67% of SLE patients and 43% of DM patients. The presence of IgG anti-LPL antibody was associated with elevated serum triglyceride levels, greater extent of skin fibrosis, and more frequent presence of lung fibrosis, heart involvement, and anti-topoisomerase I antibodies. The presence of anti-LPL autoantibody was confirmed by immunoblotting analysis. LPL activity was inhibited by IgG anti-LPL antibodies in sera from SSc patients with elevated serum triglyceride levels. CONCLUSION: Our results suggest that anti-LPL autoantibody contributes to elevated serum triglyceride levels by inhibiting LPL enzyme activity in patients with SSc.

Autoantibodies↗
PubMed2005

[Scleroderma].

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Angiotensin-Converting Enzyme Inhibitors↗
PubMed2004

Alpha-beta chimeric oligo-DNA bearing intercalator-conjugated nucleobase inside the linker sequence remarkably improves thermal stability of an alternate-stranded triple helix.

Novel alpha-beta chimeric oligodeoxynucleotides bearing an intercalator-conjugated nucleobase located at the internal 4-nt linker region were synthesized, and their triplex-stabilizing property was examined. The triple helical DNA formed between the modified chimera DNA and double-stranded DNA exhibited remarkable thermal stability; however, the position of the intercalator-conjugated nucleobase had little influence on the stability. Among the examined, modified chimera DNA bearing the two intercalator-conjugated nucleobases at adjacent positions exhibited the highest stability.

Chimera↗
PubMed2004

CD22 regulates B lymphocyte function in vivo through both ligand-dependent and ligand-independent mechanisms.

The interaction of CD22 with alpha2,6-linked sialic acid ligands has been widely proposed to regulate B lymphocyte function and migration. Here, we generated gene-targeted mice that express mutant CD22 molecules that do not interact with these ligands. CD22 ligand binding regulated the expression of cell surface CD22, immunoglobulin M and major histocompatibility complex class II on mature B cells, maintenance of the marginal zone B cell population, optimal B cell antigen receptor-induced proliferation, and B cell turnover rates. However, CD22 negative regulation of calcium mobilization after B cell antigen receptor ligation, CD22 phosphorylation, recruitment of SHP-1 to CD22 and B cell migration did not require CD22 ligand engagement. These observations resolve longstanding questions regarding the physiological importance of CD22 ligand binding in the regulation of B cell function in vivo.

Animals↗
PubMed2004

Augmented production of transforming growth factor-beta by cultured peripheral blood mononuclear cells from patients with systemic sclerosis.

We sought to determine whether the spontaneous production of transforming growth factor-beta (TGF-beta) by peripheral blood mononuclear cells (PBMC) is increased in patients with systemic sclerosis (SSc). Culture supernatants of PBMC from SSc patients (n = 88) and healthy controls (n = 44) were analyzed by enzyme-linked immunosorbent assay. The production of active TGF-beta1 and total (active and latent) TGF-beta1 by PBMC from patients with limited cutaneous SSc (lSSc) and by PBMC from patients with diffuse cutaneous SSc (dSSc) was significantly elevated compared to the production by PBMC from normal controls. Production of active TGF-beta1 by dSSc PBMC was higher than that by lSSc PBMC, although not significantly. Patients with PBMC with increased active or total TGF-beta1 production showed significantly shorter disease duration than patients with PBMC with normal production levels. PBMC from patients without anticentromere antibody showed enhanced active TGF-beta1 production more frequently than those from patients with anticentromere antibody. PBMC from SSc patients more frequently showed enhanced total TGF-beta2 production than PBMC from normal controls. Among each leukocyte subset, spontaneous production of total TGF-beta1 was significantly higher in cultured peripheral monocytes/macrophages, but not in T cells, B cells, or NK cells, from patients than from normal controls. Thus, the enhanced production of TGF-beta by PBMC may contribute to the disease process in SSc

Adult↗
PubMed2004

A case of scleroderma spectrum disorder with anticentriole antibody and pulmonary hypertension.

We describe the case of a patient with anticentriole antibody-positive scleroderma spectrum disorder (SSD) who developed pulmonary hypertension. A 54-year-old woman had noticed Raynaud's phenomenon and digital ulcers during the winter for the past 10 years. Although sclerodactyly was not present, digital ulcers, swelling of her hands, and phalangeal contracture were observed. An indirect immunofluorescence test revealed anticentriole antibody. Other SSc-specific antoantibodies were negative. An echocardiogram demonstrated that the estimated right ventricular systolic pressure was increased to 51 mmHg. She was diagnosed as SSD with pulmonary hypertension. This is the first case of SSD with anticentriole antibody to develop pulmonary hypertension.

Autoantibodies↗
PubMed2004

Improvement of skin sclerosis after occurrence of anticentromere antibody in a patient with diffuse cutaneous systemic sclerosis.

A 38-year-old woman had noticed sclerodactylia and Raynaud's phenomenon 10 months before consultation. She was diagnosed as having systemic sclerosis (SSc) based on the skin sclerosis of her arms, chest, and face. Antinuclear antibody (ANA) level was 1:1280 with a speckled pattern, but specific autoantibodies were negative. Following the treatment with oral prednisolone and D-penicillamine, her skin sclerosis gradually improved. Three months after initiation of prednisolone, she presented Pneumocystis carinii pneumonia. About 1 year after the first admission, the pattern of indirect immunofluorescence staining changed from the speckled pattern to the discrete speckled pattern, and simultaneously anticentromere antibody (ACA) was detected by enzyme-linked immunosorbent assay. Her skin sclerosis rapidly and remarkably improved after appearance of ACA. It is generally considered that once certain SSc-specific autoantibody occurs, it does not disappear and change into other specificity of autoantibody thereafter. This case suggests that the presence of ACA closely correlates with clinical features and also suggests that clinical features may change during the clinical course with the appearance of another specific ANA. This case is very rare because such a case was not reported previously.

Administration, Oral↗
PubMed2004

Regulation of the circadian oscillator in Xenopus retinal photoreceptors by protein kinases sensitive to the stress-activated protein kinase inhibitor, SB 203580.

Circadian rhythms are generated by transcriptional and translational feedback loops. Stress-activated protein kinases (SAPKs) are known to regulate transcription factors in response to a variety of extracellular stimuli. In the present study, we examined whether the SAPKs play a role in the circadian system in cultured Xenopus retinal photoreceptor layers. A 6-h pulse of SB 203580, an inhibitor of SAPKs, reset the circadian rhythm of melatonin in a phase-dependent manner similar to dark pulses. This phase-shifting effect was dose-dependent over the range of 1-100 microm. Treatment with SB 203580 also affected light-induced phase shifts, and light had no effect on the circadian oscillator in the presence of 100 microm SB 203580. In-gel kinase assays showed that SB 203580 selectively inhibited a small group of protein kinases in the photoreceptor cells. These SB 203580-sensitive kinases correspond to two isoforms of phosphorylated p38 MAPK and three isoforms of c-Jun N-terminal kinase (JNK). Further in vitro study demonstrated that SB 203580 also inhibited casein kinase Iepsilon (CKIepsilon), which has been shown to regulate circadian rhythms in several organisms. However, a pharmacological inhibition of CKI reset the circadian oscillator in a phase-dependent manner distinct from that of SB 203580. This argues against a primary role of CKI in the phase-shifting effects of SB 203580. These results suggest that SB 203580 affects the circadian system by inhibiting p38 MAPKs or JNKs and that these protein kinases are candidate cellular signals in the regulation of the circadian oscillator in the Xenopus retinal photoreceptors.

Animals↗
PubMed2004

Anti-DNA topoisomerase IIalpha autoantibodies in localized scleroderma.

OBJECTIVE: To determine the prevalence and clinical correlation of anti-DNA topoisomerase IIalpha (anti-topo IIalpha) antibody in patients with localized scleroderma. METHODS: Anti-topo IIalpha antibodies or anti-DNA topoisomerase I (topo I) antibodies were determined by enzyme-linked immunosorbent assay (ELISA) and immunoblotting. Inhibition of topo IIalpha enzymatic activity by the antibodies was evaluated by decatenation assays using kinetoplast DNA as a substrate. RESULTS: IgG or IgM anti-topo IIalpha antibody was detected in 76% (35 of 46) of patients with localized scleroderma, and in 85% (11 of 13) of patients with generalized morphea, the severest form of localized scleroderma. This prevalence of the antibody in patients with localized scleroderma was much higher than that found in patients with systemic sclerosis (SSc) (5 of 37 [14%]), systemic lupus erythematosus (2 of 26 [8%]), dermatomyositis (2 of 20 [10%]), and in healthy controls (3 of 42 [7%]). Immunoblotting confirmed the presence of IgG anti-topo IIalpha antibody in sera from patients with localized scleroderma and showed no cross-reactivity of anti-topo IIalpha antibody with topo I. Anti-topo I antibody was not detected by ELISA in any sera from patients with localized scleroderma. In addition, anti-topo I antibody from SSc patients did not cross-react with topo IIalpha. The presence of anti-topo IIalpha antibody was associated with a greater total number of sclerotic lesions and number of plaque lesions in patients with localized scleroderma. Furthermore, anti-topo IIalpha antibody was able to inhibit topo IIalpha enzymatic activity. CONCLUSION: The results of the present study indicate that anti-topo IIalpha is a major autoantibody in localized scleroderma, and is distinct from anti-topo I antibody in SSc.

Adolescent↗