Search PubMed⌕ Search

Biomedical subjects

Minoru Hasegawa

Publications and source records attributed to Minoru Hasegawa.

At least 37 records · Page 2Linked to original sources
PubMed2005

Drug-induced hypersensitivity syndrome associated with human herpesvirus 6 and cytomegalovirus reactivation.

We describe a patient with drug-induced hypersensitivity syndrome (DIHS) associated with human herpesvirus 6 (HHV-6) and cytomegalovirus (CMV) infection induced by sulfasalazine. Two weeks after starting sulfasalazine to treat a rectal ulcer, the patient developed disseminated macular erythema accompanied by fever, liver injury, and lymphadenopathy. Seroconversion of antibodies to HHV-6 was observed. Systemic steroid treatment was not effective against the eruptions. Five months after the onset, he presented with an acute febrile disease. The detection of CMV antigen on peripheral blood leukocytes and positive staining for CMV on cutaneous endothelium indicated active CMV infection. Furthermore, he developed a bacteremia of methicillin resistant Staphylococcus aureus. An association the CMV reactivation with DIHS was suggested, although there remains the possibility that the systemic steroid treatment precipitated CMV reactivation. Recently, HHV-6 has been documented to have immunomodulating effects and to be associated with CMV reactivation. Therefore, we should pay attention to the possibility of CMV reactivation in patients with DIHS in whom the immunomodulating virus of HHV-6 has been reactivated.

Aged↗
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].

Explore the source record for details and available documents.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2005

[Effect of glucocorticoids on bone mineral density in patients with idiopathic thrombocytopenic purpura].

To elucidate the effects of glucocorticoid on bone mineral density in idiopathic thrombocytopenic purpura (ITP) patients, we retrospectively evaluated the relationship between bone mineral density (BMD) and the total dose of glucocorticoid or the mean daily dose given. We found decreased BMD in 66.7% of the patients with ITP to whom glucocorticoid was given, though rather normal bone BMD was observed in 28.6% of ITP patients treated without steroids. The mean level of BMD was markedly decreased in steroid-treated patients compared with steroid non-treated patients (p < 0.01). The relationship between BMD and the total dose of glucocorticoid (p = 0.023) or the mean daily dose revealed a negative correlation (p = 0.022). This study showed that glucocorticoid-induced osteoporosis was observed in patients with ITP, similar to other diseases already reported. When we think of this disease, many cases tend to be followed for a long time, and as the majority of ITP patients is female, we should pay particular attention in the prevention of glucocorticoid-induced osteoporosis.

Adult↗
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↗
PubMed2004

Altered blood B lymphocyte homeostasis in systemic sclerosis: expanded naive B cells and diminished but activated memory B cells.

OBJECTIVE: To determine phenotypic and functional abnormalities of blood B cell subsets in patients with systemic sclerosis (SSc). METHODS: Cell surface marker expression was determined by flow cytometry. Spontaneous apoptosis was evaluated by annexin V expression with flow cytometric analysis. IgG production by isolated IgD- memory B cells was examined by enzyme-linked immunosorbent assay. RESULTS: The numbers of blood CD27- naive B cells from SSc patients were increased compared with normal control cells, while memory B cells expressing medium levels of CD27 and plasmablasts expressing high levels of CD27 were reduced. In contrast, plasmablasts were the predominant population in patients with systemic lupus erythematosus (SLE). Memory B cells in SSc showed increased expression of activation markers, including CD80, CD86, and CD95, relative to normal controls. Consistent with CD95 up-regulation, SSc memory B cells exhibited augmented spontaneous apoptosis after 24-hour incubation; augmented apoptosis may explain the reduced memory B cell number. Nonetheless, isolated IgD- SSc memory B cells treated with stimuli had an enhanced ability to produce IgG. Furthermore, expression of CD19, a critical signal transduction molecule of B cells that regulates autoantibody production, was significantly increased in memory B cells as well as in naive B cells in SSc. In contrast, CD19 expression was decreased in SLE B cells. CONCLUSION: SSc patients have distinct abnormalities of blood homeostasis and B cell compartments, characterized by expanded naive B cells and activated but diminished memory B cells. Our results suggest that CD19 overexpression in SSc memory B cells is related to their hyperreactivity.

Adult↗
PubMed2004

Expression of fractalkine and its receptor, CX3CR1, in atopic dermatitis: possible contribution to skin inflammation.

BACKGROUND: Fractalkine (FKN) induces activation and adhesion of leukocytes expressing its receptor, CX(3)CR1. FKN is released from the cell surface through proteolytic cleavage as soluble FKN (sFKN). OBJECTIVE: We sought to assess FKN and CX(3)CR1 expression in the skin, serum sFKN levels, and CX(3)CR1 expression on blood leukocytes in patients with atopic dermatitis (AD). METHODS: FKN and CX(3)CR1 expression in the skin was examined immunohistochemically. mRNA expression of FKN, thymus and activation-regulated chemokine, and macrophage-derived chemokine in the skin was assessed by means of real-time RT-PCR. Serum sFKN levels were assessed by using ELISA. Blood leukocytes were stained for CX(3)CR1 by means of flow cytometric analysis. RESULTS: FKN was strongly expressed on endothelial cells in skin lesions of patients with AD and psoriasis but not in normal skin. FKN mRNA levels in AD lesional skin increased to a similar extent to thymus and activation-regulated chemokine and macrophage-derived chemokine mRNA levels. CX(3)CR1-expressing cells in the affected skin of patients with AD or psoriasis increased compared with those in normal skin. Serum sFKN levels were increased in patients with AD but not in patients with psoriasis relative to levels in healthy control subjects. Serum sFKN levels were associated with the disease severity and decreased with the improvement of skin lesions in patients with AD. CX(3)CR1(+) cell frequencies and CX(3)CR1 expression levels were decreased in CD8(+) T cells, monocytes, and natural killer cells from patients with AD, but this was not observed in patients with psoriasis. CONCLUSIONS: These results suggest that through functions in both membrane-bound and soluble forms, FKN plays an important role in the trafficking of CX(3)CR1(+) leukocytes during the inflammation caused by AD.

Adolescent↗
PubMed2004

Serum levels of a Th1 chemoattractant IP-10 and Th2 chemoattractants, TARC and MDC, are elevated in patients with systemic sclerosis.

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.

Adolescent↗
PubMed2004

Altered B lymphocyte function induces systemic autoimmunity in systemic sclerosis.

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 approximately 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.

Animals↗
PubMed2004

B Lymphocyte signaling established by the CD19/CD22 loop regulates autoimmunity in the tight-skin mouse.

Systemic sclerosis (SSc) is characterized by fibrosis and autoimmmunity. Peripheral blood B cells from SSc patients specifically overexpress CD19, a critical cell-surface signal transduction molecule in B cells. CD19 deficiency in B cells also attenuates skin fibrosis in the tight-skin (TSK/+) mouse, a genetic model for SSc. Herein we analyzed two transgenic mouse lines that overexpress CD19. Remarkably, 20% increase of CD19 expression in mice spontaneously induced SSc-specific anti-DNA topoisomerase I (topo I) antibody (Ab) production, which was further augmented by 200% overexpression. In TSK/+ mice overexpressing CD19, skin thickness did not increase, although anti-topo I Ab levels were significantly augmented, indicating that abnormal CD19 signaling influences autoimmunity in TSK/+ mice and also that anti-topo I Ab does not have a pathogenic role. The molecular mechanisms for abnormal CD19 signaling were further assessed. B-cell antigen receptor crosslinking induced exaggerated calcium responses and augmented activation of extracellular signal-regulated kinase in TSK/+ B cells. CD22 function was specifically impaired in TSK/+ B cells. Consistently, CD19, a major target of CD22-negative regulation, was hyperphosphorylated in TSK/+ B cells. These findings indicate that reduced inhibitory signal provided by CD22 results in abnormal activation of signaling pathways including CD19 in TSK/+ mice and also suggest that this disrupted B cell signaling contribute to specific autoantibody production.

Animals↗