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Biomedical subjects

Masataka Kuwana

Publications and source records attributed to Masataka Kuwana.

At least 55 records · Page 3Linked to original sources
PubMed2003

Anti-c-Mpl (thrombopoietin receptor) autoantibody-induced amegakaryocytic thrombocytopenia in a patient with systemic sclerosis.

Amegakaryocytic thrombocytopenia (AMT) associated with systemic sclerosis (SSc) has been described in several case reports, but the underlying mechanisms have not been identified. Here we describe a rare case of SSc accompanied by thrombocytopenia and megakaryocytic hypoplasia, in which autoantibody against thrombopoietin receptor (c-Mpl) was detected. A 61-year-old woman with limited SSc was admitted to our hospital because of severe thrombocytopenia (platelet count 0.2 x 10(4)/mm(3)) with gingival bleeding. Her bone marrow was hypocellular with absent megakaryocytes, consistent with AMT. Treatment with corticosteroids and intravenous immunoglobulin infusions resulted in an increased platelet count, and she sustained a remission over a 1-year period, with a platelet count averaging 10.0 x 10(4)/mm(3). Her serum was strongly positive for anti-c-Mpl antibody, and IgG fraction purified from her serum inhibited thrombopoietin-dependent cell proliferation in vitro. Our case report suggests that AMT in patients with SSc could be mediated by the anti-c-Mpl antibody, which functionally blocks an interaction between thrombopoietin and c-Mpl.

Autoantibodies↗
PubMed2003

Autoreactive T cells to the P3A+ isoform of AChR alpha subunit in myasthenia gravis.

In vitro T cell proliferative response to an alternative splicing variant of acetylcholine receptor alpha subunit (AChR alpha) with the P3A exon-encoded region was examined in peripheral blood samples from 28 myasthenia gravis (MG) patients and 14 healthy donors using recombinant fragments and synthetic peptides. T cells responsive to the P3A region-specific sequences were detected in five MG patients, all of whom were late-onset disease with thymoma, but in none of healthy donors. These autoreactive T cells may be involved in the pathogenic process in a subset of MG patients.

Adult↗
PubMed2003

Initial predictors of development of pure red cell aplasia in myasthenia gravis after thymectomy.

Pure red cell aplasia (PRCA) is well known to be concomitant with myasthenia gravis (MG), but it is difficult to predict the development of PRCA in patients with MG. Of 135 patients with MG, four (2.9%) had PRCA. All patients developed PRCA after thymectomy during a period when MG was in remission. The frequencies of thymoma, bulbar involvement and high anti-acetylcholine receptor (AChR) antibody levels were significantly higher in four patients with PRCA. Japanese MG patients with these characteristics at presentation were at significant risk for the development of PRCA after thymectomy.

Adult↗
PubMed2003

Autoreactive CD4(+) T cells to beta(2)-glycoprotein I in patients with antiphospholipid syndrome.

Antiphospholipid syndrome (APS) is characterized by recurrent thrombosis and intrauterine fetal loss in association with antiphospholipid antibodies (aPL). We have recently identified autoreactive CD4(+) T cells to beta(2)-glycoprotein I (beta(2)GPI) that promote aPL production in APS patients. beta(2)GPI-specific CD4(+) T cells preferentially recognize the antigenic peptide containing the major phospholipid-binding site in the context of DRB4*0103 (DR53). T-cell receptor beta chains of beta(2)GPI-specific T cells are highly restricted and mainly utilize rearranged Vbeta7 or Vbeta8 gene segments. T-cell helper activity that stimulates B cells to produce anti-beta(2)GPI antibodies is mediated through IL-6 and CD40-CD40 ligand engagement. beta(2)GPI-specific T cells respond to reduced beta(2)GPI and recombinant beta(2)GPI fragments produced in bacteria, but not to native beta(2)GPI, indicating that the epitopes recognized by beta(2)GPI-specific T cells are apparently cryptic. Activation of beta(2)GPI-specific T cells resulting in production of pathogenic anti-beta(2)GPI antibodies can be induced by the exposure to cryptic peptides of beta(2)GPI. Finally, beta(2)GPI-specific T cell is a reasonable target of potential therapeutic strategies that selectively suppress pathogenic aPL production in APS patients.

Antibody Formation↗
PubMed2003

A role of autoantibody-mediated platelet destruction in thrombocytopenia in patients with cirrhosis.

Thrombocytopenia is a common manifestation in patients with liver cirrhosis (LC), but its underlying mechanism remains controversial. This study examined the role of anti-platelet autoimmunity in cirrhotic thrombocytopenia by determining the autoantibody response to GPIIb-IIIa, a major platelet surface autoantigen recognized by anti-platelet antibodies in patients with idiopathic thrombocytopenic purpura (ITP). Circulating B cells producing anti-GPIIb-IIIa antibodies as well as platelet-associated and plasma anti-GPIIb-IIIa antibodies were examined in 72 patients with LC, 62 patients with ITP, and 52 healthy controls. In vitro anti-GPIIb-IIIa antibody production was induced in cultures of peripheral blood mononuclear cells (PBMCs) by stimulation with GPIIb-IIIa. The frequency of anti-GPIIb-IIIa antibody-producing B cells in patients with LC was significantly greater than in healthy controls (10.9 +/- 6.2 vs. 0.4 +/- 0.3/10(5) PBMCs; P <.0001) and was even higher than the frequency in patients with ITP (8.2 +/- 5.2; P =.007). Anti-GPIIb-IIIa antibodies in the patients with LC and ITP were mainly present on the surfaces of circulating platelets rather than in the plasma in an unbound form. Furthermore, PBMCs from patients with LC and ITP produced anti-GPIIb-IIIa antibodies on antigenic stimulation with GPIIb-IIIa in vitro, and the specific antibodies produced had the capacity to bind normal platelet surfaces. In conclusion, the similar profile of the anti-GPIIb-IIIa autoantibody response in patients with LC and ITP suggests that autoantibody-mediated platelet destruction may contribute at least in part to cirrhotic thrombocytopenia.

Aged↗
PubMed2003

Induction of T-cell tolerance in a patient with idiopathic thrombocytopenic purpura by single injection of humanized monoclonal antibody to CD40 ligand.

Normal B cells can be induced to express immune costimulatory molecules by activated T cells, and activated CD4 T cells can express CD40 ligand, a molecule that can engage CD40 on the B-cell surface. CD40-CD40 ligand interaction plays an important role in the pathology of certain autoimmune diseases. We report a patient with chronic idiopathic thrombocyopenic purpura (ITP) who was effectively treated with a single injection of humanized monoclonal antibody to CD40 ligand (E6040). The patient was refractory to steroid therapy, and had baseline platelet counts below 30 x 10(9)/l during the 3-month period before antibody treatment. The patient's platelet counts have increased to more than 100 x 10(9)/l long-term after E6040 administration. Platelet-associated IgG was decreased with thrombocytosis. Compared with the initial period of E6040 administration, the number of anti-GPIIb/IIIa antibody-producing B cells decreased, and proliferative response of autoreactive T cells to GPIIb/IIIa was also improved. A single injection of humanized monoclonal antibody to CD40 ligand may induce T-cell tolerance in patients with ITP.

Antibodies, Monoclonal↗
PubMed2003

Dry eye as a major complication associated with chronic graft-versus-host disease after hematopoietic stem cell transplantation.

PURPOSE: To review the condition of dry eye associated with chronic graft-versus-host disease (GVHD). METHODS: The immunopathogenic processes and therapeutic options for lacrimal gland chronic GVHD are discussed. RESULTS: Dry eye is the most frequent ocular complication after hematopoietic stem cell transplantation. The condition typically occurs around 6 months post-operation and is recognized as a complication of chronic GVHD. Lacrimal gland specimens from patients with dry eye show prominent fibrosis and an increase in CD34+ stromal fibroblasts in the glandular interstitium in addition to infiltration of T cells into the periductal areas. In periductal areas, CD4+ and CD8+ T cells colocalize with stromal fibroblasts that express the full component of surface molecules necessary for antigen presentation. These findings strongly suggest that periductal fibroblasts are involved in fibrogenic and immune processes by interacting with T cells in the lacrimal gland of patients with chronic GVHD, resulting in rapidly progressive dry eye. Current therapies for dry eye related to chronic GVHD include tear supplements and nonspecific immunosuppressants. CONCLUSION: We report a significant role for stromal fibroblasts in the pathogenic processes of dry eye related to chronic GVHD. Although several supportive therapies can reduce the symptoms, specific therapies that suppress fibrotic and immune processes in the lacrimal glands are necessary to control dry eye associated with chronic GVHD.

Chronic Disease↗
PubMed2003

Periductal area as the primary site for T-cell activation in lacrimal gland chronic graft-versus-host disease.

PURPOSE: To examine immune processes in the lacrimal gland of patients with chronic graft-versus-host disease (cGVHD) by evaluating the expression of surface molecules associated with T-cell activation. METHODS: Antibodies to CD4, CD8, CD34, CD40, CD54, CD80, CD86, CD154, and HLA-DR were used for immunohistochemical analysis of lacrimal gland biopsy specimens obtained from nine patients with cGVHD and five with Sjögren's syndrome (SS). The regions of interest were further assessed by transmission electron microscopy. RESULTS: CD4(+) and CD8(+) T cells were mainly detected in the periductal areas of the glands of patients with cGVHD, but were distributed throughout the acinar areas in patients with SS. In the periductal areas of patients with cGVHD, a subpopulation of CD4(+) and CD8(+) T cells expressed the activation marker CD154. In addition, CD4(+) and CD8(+) T cells were colocalized with mononuclear infiltrates and stromal fibroblasts expressing the full component of surface molecules necessary for antigen presentation, including HLA-DR, CD54, CD40, CD80, and CD86. Electron microscopy revealed activated fibroblasts that embraced lymphocytes and macrophages with their processes. Also, there were more CD8(+) T cells in the glandular epithelia of patients with cGVHD than in those with SS. Intraepithelial T cells were attached to epithelial cells by several primitive contacts and colocalized with dead cells. CONCLUSIONS: The results strongly suggest that CD4(+) and CD8(+) T cells in the lacrimal glands of patients with cGVHD are primarily activated in the periductal area through antigenic stimulation by potent antigen-presenting cells and stromal fibroblasts, and exert various effector functions, including cytotoxic effects on glandular epithelial cells.

Adult↗
PubMed2003

[Clinical significance of anti-phosphatidylserine-prothrombin complex antibodies in the diagnosis of anti-phospholipid syndrome].

In this study, we clarified the clinical significance of IgG anti-phosphatidylserine-prothrombin complex (PS-PT) antibodies in the diagnosis of antiphospholipid syndrome (APS). The study population consisted of 113 patients with SLE and lupus-like disease. IgG anti-PS-PT antibodies were examined by ELISA. These antibodies were detected in 31% of the population, and were significantly associated with thrombosis and fetal loss. The frequency was significantly higher in patients who did not satisfy the Sapporo criteria, but met the Harris and Hughes diagnostic criteria (36%) than in non-APS patients (14%). The above findings suggest that IgG anti-PS-PT antibodies should be listed in the diagnostic criteria for APS.

Antiphospholipid Syndrome↗
PubMed2003

[Advances in immunological aspects of idiopathic thrombocytopenic purpura].

Idiopathic thrombocytopenic purpura(ITP) is an autoimmune disease characterized by increased platelet destruction caused by anti-platelet autoantibodies, which mainly target a platelet surface antigen, GP IIb-IIIa. CD4+ T cells reactive with GP IIb-IIIa play a primary role in the disease process, since these autoreactive T cells are involved in the production of pathogenic anti-platelet autoantibodies. GP IIb-IIIa-reactive T cells mainly recognize 'cryptic' determinants on the amino-terminal extracellular domains of both GP IIb alpha and GP IIIa, and are activated primarily in the spleen. These findings are particularly useful for clarifying the pathogenic process in ITP patients and for developing a therapeutic approach that blocks pathogenic anti-platelet antibody production.

Autoantibodies↗
PubMed2003

Evaluation of functional disability using the health assessment questionnaire in Japanese patients with systemic sclerosis.

OBJECTIVE: To assess whether the functional disability in Japanese patients with systemic sclerosis (SSc) can be adequately evaluated by the Health Assessment Questionnaire (HAQ) developed in the United States. METHODS: The HAQ was completed by 121 Japanese patients with SSc, in whom SSc-specific physical examinations and laboratory tests were performed at the same time. Clinical findings associated with the disability index (DI) and individual components of the HAQ were examined using Student's t tests and Pearson's correlation tests. Logistic regression analysis was used to identify clinical findings that independently contributed to the increase in the HAQ-DI score. RESULTS: Japanese patients with SSc had significant functional disability, especially in the categories of eating and gripping, but the degree of disability was much less than was reported in previous studies carried out in the US. The increase in the HAQ-DI score was strongly correlated with increased total skin score, reduced oral aperture, reduced hand extension, increased finger flexion, subcutaneous calcinosis, flexion contractures, increased erythrocyte sedimentation rates, decreased percent vital capacity, and vascular involvement (p < 0.001 for all correlations). Multivariate logistic regression analysis showed that hand extension was the most important and an independent correlate of the HAQ-DI. CONCLUSION: Our multicenter, cross-sectional study has demonstrated that the self-administered HAQ is a valuable assessment tool of functional disability in Japanese SSc patients, who have social customs different from Americans, but functional disability measured by the HAQ is potentially influenced by ethnic variability.

Adult↗
PubMed2003

[Antiphospholipid antibodies].

The concept of antiphospholipid syndrome(APS) has been widely accepted. Antiphospholipid antibodies originally included anticardiolipin antibodies and lupus anticoagulants as serological marker of APS. However, recent advances have shown that most pathogenic antiphospholipid antibodies are directed to phospholipid binding proteins such as beta 2-glycoprotein I and prothrombin as well as phospholipids. The preliminary classification criteria for definite APS have been advocated as the "Sapporo criteria". Further prospective investigations are required to re-evaluate the clinical significance of so-called antiphospholipid antibodies.

Antibodies, Antiphospholipid↗
PubMed2003

HLA class II alleles in systemic sclerosis patients with anti-RNA polymerase I/III antibody: associations with subunit reactivities.

OBJECTIVE: To examine HLA class II gene associations with anti-RNA polymerase (RNAP) I/III antibody responses in patients with systemic sclerosis (SSc). METHODS: HLA-DRB1, DRB3, DRB4, and DQB1 alleles were determined using polymerase chain reaction-based methods in 257 SSc patients (129 Japanese and 128 Caucasians) and 271 race-matched regional controls (138 Japanese and 133 Caucasians). Anti-RNAP I/III antibodies were identified by immunoprecipitation assay, and reactivities to individual RNAP subunits were determined by immunoblots using affinity-purified RNAP I, II, and III. RESULTS: Serum anti-RNAP I/III antibody was detected in 10 (8%) Japanese and 24 (19%) Caucasian patients with SSc. The presence of anti-RNAP I/III antibodies was associated with DRB1*0405, DRB4*01, and DQB1*0401 in Japanese, and with DRB3*02 in Caucasians, but these associations were weak and inconsistent between these 2 ethnic groups. When anti-RNAP I/III-positive SSc patients were divided into 2 groups based on the presence or absence of reactivities to individual RNAP subunit proteins, significant associations of anti-IIa/IIo reactivity with DRB3*02, anti-Ia reactivity with DRB1*04, anti-43-kDa subunit reactivity with DRB4*01, and anti-34-kDa subunit reactivity with DRB1*15 were detected. These HLA associations with subunit reactivities were generally shared by Japanese and Caucasian patients with SSc. CONCLUSION: Our results suggest that in patients with SSc, anti-RNAP I/III antibodies are composed of subsets defined by combinations of reactivities to individual RNAP subunits having specific HLA class II correlations.

Alleles↗
PubMed2003

Effect of intermittent cyclical etidronate therapy on corticosteroid induced osteoporosis in Japanese patients with connective tissue disease: 3 year followup.

OBJECTIVE: A 3 year prospective randomized study was conducted to clarify the efficacy of intermittent cyclical etidronate therapy on corticosteroid induced osteoporosis. METHODS: A group of 102 Japanese patients were enrolled, each taking > 7.5 mg of prednisolone daily for at least 90 days. Patients were randomly divided into 2 treatment groups: Group E (etidronate) took 200 mg etidronate disodium per day for 2 weeks with 3.0 g calcium lactate and 0.75 microg alphacalcidol daily; Group C (control) took 3.0 g calcium lactate and 0.75 microg alphacalcidol daily. Outcome measurements included changes from baseline in bone mineral density (BMD) of the lumbar spine and the rate of new vertebral fractures at 48 and 144 weeks. RESULTS: The mean (+/- SD) lumbar spine BMD increased 3.7 +/- 5.6% (p < 0.01) and 1.5 +/- 4.1% (NS) from baseline at 48 weeks and 4.8 +/- 6.9% (p < 0.005) and 0.4 +/- 5.0% (NS) from baseline at 144 weeks in Group E and Group C, respectively. The improvement of BMD in Group E was significantly greater than in Group C at 144 weeks (p < 0.01). In 3 subgroups, men and premenopausal and postmenopausal women, the postmenopausal women showed the greatest improvement. Mean percentage change in this subgroup was 10.1 +/- 8.0% and 1.35 +/- 6.4% in Group E and Group C, respectively. We noted that 2 patients in Group C had new vertebral fractures, whereas no fractures were observed in Group E. CONCLUSION: These results indicate that intermittent cyclical etidronate therapy is effective for the prevention and treatment of corticosteroid induced osteoporosis in patients with connective tissue diseases.

Adult↗
PubMed2002

Suppression of autoreactive T-cell response to glycoprotein IIb/IIIa by blockade of CD40/CD154 interaction: implications for treatment of immune thrombocytopenic purpura.

The potential immunosuppressive effect of an anti-CD154 monoclonal antibody (mAb) on the pathogenic autoreactive T-cell response was evaluated using an in vitro culture system with glycoprotein IIb/IIIa (GPIIb/IIIa)-reactive T cells from patients with immune thrombocytopenic purpura (ITP). The anti-CD154 mAb did not inhibit T-cell proliferation, but suppressed anti-GPIIb/IIIa antibody production, in bulk peripheral blood mononuclear cell cultures stimulated with GPIIb/IIIa. Repeated antigenic stimulation of GPIIb/IIIa-reactive CD4(+) T-cell lines in the presence of anti-CD154 mAb resulted in the loss of proliferative capacity and helper function for promoting anti-GPIIb/IIIa antibody production. These anergic T-cell lines showed a cytokine profile of low interferon gamma and high interleukin 10 and suppressed anti-GPIIb/IIIa antibody production. Our results indicate that blockade of the CD40/CD154 interaction induces generation of autoantigen-specific anergic CD4(+) T cells with regulatory function and could be a therapeutic option for suppressing pathogenic autoimmune responses in patients with ITP.

Antibodies, Monoclonal↗