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Biomedical subjects

Shoichi Ozaki

Publications and source records attributed to Shoichi Ozaki.

16 recordsLinked to original sources
PubMed2006

Association of killer cell immunoglobulin-like receptor genotypes with microscopic polyangiitis.

OBJECTIVE: Genetic background and infection have been implicated in the etiology of microscopic polyangiitis (MPA). Killer cell immunoglobulin-like receptors (KIRs) are a diverse family of activating and inhibitory receptors expressed on natural killer (NK) cells and T cells, the genes of which show extreme polymorphism. Some KIRs bind to HLA class I subgroups, and genetic interactions between KIR genes and their ligand HLA have been shown to be associated with several autoimmune and viral diseases. In this study, we examined possible associations of the presence or absence of KIR loci with a genetic predisposition to MPA. METHODS: The presence or absence of 14 KIR loci was determined in 57 myeloperoxidase antineutrophil cytoplasmic antibody-positive Japanese subjects (43 patients with MPA and 239 healthy controls). RESULTS: The carrier frequency of activating KIR2DS3 was significantly decreased among patients with MPA compared with healthy controls (4.7% versus 16.7%; P = 0.038, odds ratio [OR] 0.24, 95% confidence interval [95% CI] 0.06-0.94). When KIRs were analyzed in combination with their HLA ligands, the proportion of individuals carrying inhibitory KIR3DL1 and HLA-Bw4 but not activating receptor KIR3DS1, a combination presumed to be the most inhibitory of all KIR3DS1/3DL1/HLA-B combinations, was significantly increased in the MPA group compared with the control group (46.5% versus 27.0%; P = 0.014, OR 2.35, 95% CI 1.18-4.70). Furthermore, when subjects were classified according to KIR3DL1/3DS1/HLA-B and KIR2DL1/ HLA-C combinations, an increasing trend toward susceptibility was observed as combinations became more inhibitory. CONCLUSION: The decreased activation potential of NK and/or T cells associated with KIR/HLA genotypes may predispose to MPA, possibly through insufficient resistance against infections.

Aged↗
PubMed2006

Cutaneous manifestations in patients with microscopic polyangiitis: two case reports and a minireview.

Microscopic polyangiitis is a systemic small vessel vasculitis, which often has cutaneous and musculoskeletal features. Microscopic polyangiitis is a member of the family of anti-neutrophil cytoplasmic auto-antibody (ANCA)-associated vasculitides and is strongly associated with anti-myeloperoxidase (MPO)-ANCA. Titres of MPO-ANCA may reflect disease activity and play a pathogenic role. Patients with microscopic polyangiitis usually present with erythematous macules on the extremities as the first cutaneous manifestation. Skin biopsy specimens from the erythema reveal small-sized vessels that are infiltrated with neutrophils, consistent with leukocytoclastic vasculitis, in the deep dermis to the subcutaneous fat tissue. The cutaneous involvement is present at an early stage of microscopic polyangiitis with other non-specific symptoms, such as arthralgias and myalgias. The initial cutaneous manifestations are important in early diagnosis of possible ANCA-associated vasculitides with elevated ANCA titres.

Aged↗
PubMed2005

High-dose glucocorticoid treatment induces rapid loss of trabecular bone mineral density and lean body mass.

A recent large-scale study revealed that glucocorticoid treatment increased fracture risk, which occurred at a far smaller dose and by a shorter duration than previously thought. To study the underlying mechanism for the increased risk of fracture, we studied the early changes in bone mineral density (BMD) and body composition by dual energy X-ray absorptiometry (DXA) after initiating high-dose glucocorticoid treatment. High-dose glucocorticoid treatment was arbitrarily defined as daily doses of >or=40 mg of a predonisolone equivalent. The 33 patients enrolled in this study had not received glucocorticoid treatment before. Only 2 months of treatment resulted in substantial BMD loss, most markedly in the lumbar spine, followed by the femoral neck and total body, which suggests the preferential trabecular bone loss. Body composition was also greatly affected. Thus, 2-month treatment with glucocorticoid significantly reduced bone mineral content (BMC), lean body mass (LBM) and increased fat mass (FAT). Our results are likely to have some clinical relevance. First, BMD loss occurs quite rapidly after starting glucocorticoid treatment, and patients receiving glucocorticoid treatment should be more carefully monitored for their BMD. Second, LBM, which mainly represents muscle volume, decreases rapidly after initiating glucocorticoid treatment. Decreased LBM might be also responsible for the increased risk of fracture, since falling is a well-known risk factor for fracture, and patients receiving glucocorticoid treatment should also be evaluated for their body composition.

Absorptiometry, Photon↗
PubMed2005

The role of HMGB-1 on the development of necrosis during hepatic ischemia and hepatic ischemia/reperfusion injury in mice.

BACKGROUND: High-mobility group 1 (HMGB-1) is a late mediator of endotoxin lethality in mice. The release of HMGB-1 is delayed compared to other proinflammatory cytokines that mediate shock and tissue injury. The purpose of this study was to investigate the role of HMGB-1 levels in response to hepatic ischemia, hepatic I/R injury, and the relationship between changes in HMGB-1 and other cytokines. MATERIALS AND METHODS: Three murine models were employed: our robust model of segmental hepatic warm ischemia (SHWI), a model of partial hepatic ischemia/reperfusion injury (PHIRI), and a model of total hepatic ischemia/reperfusion injury (THIRI). Over a 48-h period following ischemic insult and reperfusion using these models, serum HMGB-1 concentrations, concentrations of HMGB-1 in ischemic and nonischemic lobes, and serum concentrations of TNF-alpha and IL-6 levels were determined in mice. An anti-HMGB-1 antibody treatment was used in SHWI and THIRI to evaluate what aspects of response to ischemia and reperfusion were potentially mediated by HMGB-1. RESULTS: Hepatic HMGB-1 tissue concentrations exhibited biphasic changes in SHWI mice, which were increased in the ischemic lobes relative to nonischemic lobes at 12 h but decreased relative to nonischemic lobes at 24 h after ischemic insult. These results suggested that HMGB-1 was released into the systemic circulation by necrotic cells over the first 12 h but this process may be complete by 24 h postischemia. By 6 to 12 h after SHWI, serum TNF-alpha began to increase significantly and continued to increase for 18 h, followed by a sudden decline. Similarly, serum IL-6 increased over 1-3 h after SHWI and then decreased over the next 6 h. Treatment with an anti-HMGB-1 antibody significantly prolonged survival time in SHWI and THIRI. CONCLUSIONS: HMGB-1 plays a significant role in the response to hepatic ischemia and hepatic ischemia/reperfusion injury. The present study demonstrated a time-dependent production of HMGB-1 following hepatic warm ischemia in mice. The inherent HMGB-1 in ischemic areas was exhausted and HMGB-1 may be released by necrotic cells. HMGB-1 activation is involved in immediate proinflammatory stress response to I/R and anti-HMGB-1 antibody treatment remarkably improved survival. We demonstrated that systemic HMGB-1 accumulation was measured at an earlier phase of the hepatic ischemia and ischemia/reperfusion injury model than LPS-induced endotoxemia.

Animals↗
PubMed2005

Autoantibodies to peroxiredoxin I and IV in patients with systemic autoimmune diseases.

Anti-oxidative enzymes protect living bodies from various oxidative stresses. In the systemic autoimmune diseases, autoantibodies to oxidized molecules and to anti-oxidative enzymes have been reported. To promote understanding of the relationships between autoimmunity and oxidative stress, we here investigate whether autoimmunity to the anti-oxidative peroxiredoxin (Prxs) enzymes exists in patients with systemic autoimmune diseases. Specifically, we detected autoantibodies to recombinant Prx I and Prx IV respectively by ELISA and western blotting. Next, clinical parameters were compared between the anti-Prx I or IV-positive and-negative patients. We found that 33% of the 92 patients with autoimmune diseases tested possessed autoantibodies to Prx I (57% in systemic lupus erythematosus (SLE), 19% in rheumatoid arthritis (RA), 5% in Behçet disease, and 46% in primary vasculitis syndrome). In contrast, autoantibodies to Prx IV were detected in only 17% of the same patients. No significant correlation was found between occurrence of the two autoantibodies. Clinically, possession of anti-Prx I autoantibodies correlated with lower serum levels of CH50, C3, and C4. Taken together, our data demonstrate the existence of autoantibodies to Prxs for the first time. The autoantibodies to Prx I may be involved in the pathophysiology of systemic autoimmune diseases such as SLE and vasculitis.

Arthritis, Rheumatoid↗
PubMed2004

Ameliorative effects of follistatin-related protein/TSC-36/FSTL1 on joint inflammation in a mouse model of arthritis.

OBJECTIVE: To clarify the in vivo function of follistatin-related protein (FRP)/TSC-36/FSTL1 in rheumatoid arthritis (RA), we investigated the roles of FRP in a mouse model of arthritis. METHODS: Arthritis was induced in BALB/c mice by injecting anti-type II collagen monoclonal antibody and lipopolysaccharide. Mice were treated with daily intraperitoneal injections of 20 microg of recombinant FRP. Development of arthritis was assessed by the clinical score and footpad swelling. Histologic examination of affected paws was performed on day 21 after the onset of arthritis. The gene expression profiles of affected paws in FRP-treated and untreated mice were compared using commercially available complementary DNA (cDNA) arrays. The difference in gene expression was confirmed by real-time quantitative reverse transcription-polymerase chain reaction. RESULTS: Treatment with recombinant FRP showed significant amelioration of the arthritis severity. Histologic analyses confirmed this finding and revealed the alleviation of cellular infiltration into the synovium as well as cartilage damage. The significant decrease in the amount of urinary deoxypyridinoline also indicated the ameliorative effect of FRP on joint destruction. Moreover, cDNA array analysis of the gene expression profile in FRP-treated arthritic lesions revealed a reduced expression of the c-fos, ets-2, IL6, MMP3, and MMP9 genes, some of which are thought to be associated with synovial inflammation and joint destruction. CONCLUSION: These findings from in vivo experiments suggest that FRP could be one of the key molecules in the treatment of inflammatory joint diseases such as RA.

Animals↗
PubMed2004

Intravenous cyclophosphamide therapy in a case with refractory thrombotic microangiopathic hemolytic anemia and SLE.

The case of a 27-year-old woman who simultaneously presented with SLE and severe refractory thrombotic microangiopathic hemolytic anemia (TMHA) is reported. She had extremely high levels of platelet-associated IgG (PAIgG), and her TMHA was refractory to plasma exchange and corticosteroid therapy. However, the TMHA was effectively controlled by i.v. cyclophosphamide therapy. ITP and TTP are generally considered distinct diseases; however, TMHA may occur secondary to platelet aggregation via autoimmune mechanisms in certain cases. Immunosuppressive therapy at an early stage of the disease may be beneficial in refractory cases of TMHA with autoimmune features.

Adult↗
PubMed2004

N-acetyltransferase 2 genotype-related efficacy of sulfasalazine in patients with rheumatoid arthritis.

PURPOSE: For the individual optimization of drug therapy with sulfasalazine (SASP), we studied the influence of the N-acetyltransferase 2 (NAT2) genotype on the pharmacokinetics, efficacy, and incidence of adverse reactions of SASP in patients. METHODS: Ninety-six rheumatoid arthritis (RA) patients were treated or had been treated with 0.5 and/or 1.0 g/day of SASP. The wild-type allele (NAT2*4) and three variant alleles (NAT2*5B, *6A, and *7B) of NAT2 were determined by the polymerase chain reaction-restriction fragment length polymorphism method. Plasma concentrations of SASP and its two metabolites, sulfapyridine (SP) and N-acetylsulfapyridine (AcSP), were estimated by HPLC. Therapeutic efficacy and incidence of adverse reactions were also monitored as recommended by the American College of Rheumatology. RESULTS: Patients were classified into three groups by NAT2 genotyping: Rapid Type (homozygote for NAT2*4), Intermediate Type (heterozygote for NAT2*4 and variant alleles), and Slow Type (homozygote for variant alleles). There was no clear difference in the genotype frequencies between RA patients and healthy subjects. NAT2 genotypes significantly affected both the plasma concentration ratios of SP to AcSP (SP/AcSP) and the efficacy of SASP (p < 0.05). Adverse reactions to SASP were found in 26 (27.1%) out of 96 patients, and there was no difference among the three genotype groups. CONCLUSIONS: NAT2 gene polymorphism is related to the plasma SP/AcSP ratio and the efficacy of SASP.

Antirheumatic Agents↗
PubMed2004

Conformational difference in HMGB1 proteins of human neutrophils and lymphocytes revealed by epitope mapping of a monoclonal antibody.

HMGB1 and HMGB2 are abundant nonhistone chromosomal proteins in eukaryotic organisms. Their respective primary sequences are highly conserved. Our previous studies showed that these proteins are novel autoantigens of anti-neutrophil cytoplasmic antibodies in sera from patients with ulcerative colitis (UC), rheumatic disease and autoimmune hepatitis (AIH). In the present paper, we showed that anti-HMGB1 and HMGB2 antibodies in sera of patients with UC do not recognize HMGB1 in neutrophils while they recognize the protein in lymphocytes. Anti-HMGB2 monoclonal antibody FBH7, recognizing HMGB1 in lymphocytes, showed a similar profile to the antibodies in the patients' sera. In order to elucidate the difference in immunoreactivity to HMGB1 between neutrophils and lymphocytes, we mapped the epitope for FBH7 by means of several methods. The results showed that FBH7 recognizes the intact conformation composed of 52-56 residues of HMGB1 in lymphocytes. This suggested that HMGB1 in neutrophils is conformationally changed in the epitope or the peripheral structure of the epitope from the protein in lymphocytes. The apparent conformational change of HMGB1 between neutrophils and lymphocytes will be important for understanding the functional difference of HMGB1 in these cells.

Amino Acid Sequence↗
PubMed2003

Potential preventive effects of follistatin-related protein/TSC-36 on joint destruction and antagonistic modulation of its autoantibodies in rheumatoid arthritis.

We previously reported that follistatin-related protein (FRP)/TSC-36 was one of the target antigens of autoantibodies in rheumatoid arthritis (RA) and that the appearance of serum autoantibodies to FRP correlated to disease activity in RA. However, the significance of FRP in autoimmunity remained to be explained due to the unknown function of FRP. Here, we disclose in part the function of FRP. Transforming growth factor (TGF)-beta augmented FRP gene expression in synovial cells. FRP reduced synovial production of matrix metalloproteinase (MMP)-1, MMP-3 and prostaglandin E(2), potent agonists of joint destruction in RA. In contrast, autoantibodies to FRP from patients with RA increased their production by blocking FRP activity, probably in the autocrine system. Moreover, FRP down-regulated synovial expression of FOS (c-fos), which seemed responsible for the reduction in MMP-1 and MMP-3 caused by FRP. Therefore, FRP and its autoantibody can be regarded as defensive and offensive factors respectively in rheumatoid arthropathy. The major epitope of autoantibodies to FRP was mapped to the sequence LKFVEQNE (residues 169-176) and homologous sequences were found in proteins from Escherichia coli, Epstein-Barr virus, etc. FRP and its autoantibody may provide some clues to elucidate the process of disease development and a new approach to the design of therapeutics in RA.

Animals↗
PubMed2003

[Beneficial effect of high-dose etidronate on periarticular calcinosis associated with arterial and periarticular basic calcium phosphate (BCP) crystal deposition disease].

Basic calcium phosphate (BCP) deposition disease is a crystal-induced inflammation syndrome. We report a beneficial effect of high-dose etidronate, one of the bisphosphonates, on periarticular calcinosis in a case of arterial and periarticular BCP crystal deposition disease. A 55-year-old woman was referred to St. Marianna University Hospital because of a 30-year history of recurrent acute periarthritis. The X-ray photographs revealed periarticular calcinosis of the hand and foot, wrist, and knee joints without bony erosions and the calcification of carotid and popliteal arteries. The biopsied specimen from periarticular tissue showed Alizalin-red and von Kossa staining-positive crystals. With the diagnosis of BCP crystal-induced periarthritis, she has been treated with colchicine and probenecid. This regimen was partially effective in terms of a decrease in the frequency of periarthritic attack. Despite the treatment, periarticular calcinosis increased in size and number. She was treated with 800 mg of etidronate 3 months after the etidronate therapy; periarticular calcinosis was diminished although arterial calcification was unchanged. This case suggests that high-dose etidronate might be useful for heterotopic calcification associated with rheumatic diseases.

Calcinosis↗
PubMed2002

Autoantibodies to the transcriptional factor SOX13 in primary biliary cirrhosis compared with other diseases.

The molecule SOX13 was initially identified as an autoantigen (ICA12) in Type 1 diabetes. SOX13 is a member of the SOX family of transcriptional regulatory proteins that contain a high mobility group (HMG) motif with structural similarity to HMG proteins 1 and 2. Antibodies to HMG 1 and 2 occur in autoimmune diseases of the liver and in ulcerative colitis. We measured the occurrence and levels of anti-SOX13 by radioimmunoprecipitation in primary biliary cirrhosis (PBC) and other diseases, and compared frequencies with anti-HMG measured by ELISA. Anti-SOX13 was detected in 18% of patients with PBC, 13% with autoimmune hepatitis, 18% with Type 1 diabetes, at lower frequencies in other conditions including the multisystem autoimmune diseases, systemic lupus erythematosus and rheumatoid arthritis, and in 1% of normal sera. Anti-HMG1 and anti-HMG2 occurred at frequencies of 30% and 35% respectively in PBC. Serum levels of anti-SOX13 and anti-HMG correlated significantly for PBC although not for Type 1 diabetes. Anti-SOX13 in PBC may occur merely as an immune response to products of damage to parenchymal tissue, or may be illustrative of a general proclivity of transcriptional regulatory proteins to elicit autoimmune responses.

Antigens, Nuclear↗