34 results on '"Ikuko Haruta"'
Search Results
2. Potential role of bacterial components in the pathogenesis of autoimmune pancreatitis
- Author
-
Kyoko Shimizu, Katsutoshi Tokushige, Yoshihiro Abe, Naoko Yanagisawa, Junji Yagi, Ikuko Haruta, and Tomoaki Higuchi
- Subjects
Pathogenesis ,business.industry ,Immunology ,medicine ,medicine.disease ,business ,Autoimmune pancreatitis - Published
- 2018
3. Flagellar filament structural protein induces Sjögren's syndrome-like sialadenitis in mice
- Author
-
Junji Yagi, Ikuko Haruta, Naoko Yanagisawa, Noriyuki Shibata, and Tomoaki Higuchi
- Subjects
0301 basic medicine ,Chemokine ,medicine.medical_treatment ,medicine.disease_cause ,Sialadenitis ,Immunoglobulin G ,Autoimmunity ,Mice ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,General Dentistry ,Autoantibodies ,030203 arthritis & rheumatology ,biology ,business.industry ,Escherichia coli Proteins ,Interleukins ,Autoantibody ,Interleukin ,medicine.disease ,Sjogren's Syndrome ,030104 developmental biology ,Cytokine ,Ribonucleoproteins ,Otorhinolaryngology ,Immunology ,biology.protein ,bacteria ,Female ,business ,Flagellin - Abstract
Objective Sjogren's syndrome (SS) is a systemic autoimmune disease that primarily affects lacrimal and salivary glands. We previously reported that FliC derived from Escherichia coli could induce autoimmune pancreatitis-like lesions. From these results, we speculated that FliC could also induce SS-like exocrinopathy. In this study, we investigated the effects of chronic exposure to FliC on lacrimal and salivary glands and the possibility that it might lead to an autoimmune response. Methods C57BL/6 mice were repeatedly injected with FliC and histological changes, serum levels of cytokine/chemokines and autoantibodies were evaluated at different time points after the final injection. The presence of sialadenitis was diagnosed by histological methods. Results In FliC-treated groups, 57% of subjects developed inflammatory cell infiltrates around ducts in mandibular salivary glands, but not lacrimal glands. In addition, serum levels of total IgG, IgG1, and IgG2a were significantly higher in FliC-treated groups. Intriguingly, serum anti-SSA/Ro levels were also significantly higher in FliC-treated groups. Cytokine analysis revealed that serum levels of IL-1β, IL-12p70, IL-13, IFN-γ, IL-15, and IL-23 seemed to be higher in FliC-treated mice. Conclusions Our data suggest that FliC-treated mice develop an SS-like phenotype. Our model may elucidate the relationship between commensal bacteria and SS.
- Published
- 2017
4. Autoimmune pancreatitis and commensal flora
- Author
-
Kyoko Shimizu, Toru Furukawa, Junji Yagi, Naoko Yanagisawa, Keiko Shiratori, and Ikuko Haruta
- Subjects
Flora ,business.industry ,Immunology ,medicine ,medicine.disease ,business ,Autoimmune pancreatitis - Published
- 2014
5. Clinical profile of primary biliary cirrhosis with features of autoimmune hepatitis: Importance of corticosteroid therapy
- Author
-
Etsuko Hashimoto, Ikuko Haruta, Keiko Shiratori, Makiko Taniai, and Youko Yoshioka
- Subjects
Hepatitis ,medicine.medical_specialty ,Hepatology ,Anti-nuclear antibody ,biology ,business.industry ,Overlap syndrome ,Autoimmune hepatitis ,medicine.disease ,Gastroenterology ,digestive system diseases ,Ursodeoxycholic acid ,Immunoglobulin G ,Infectious Diseases ,Primary biliary cirrhosis ,Internal medicine ,Immunology ,medicine ,biology.protein ,Antibody ,business ,medicine.drug - Abstract
Aim The aim of this study was to elucidate the clinical and histological features, response to corticosteroid therapy and long-term outcome of primary biliary cirrhosis (PBC) with features of autoimmune hepatitis (AIH). Methods Among 280 PBC patients under ursodeoxycholic acid administration, we identified 28 patients with AIH features fulfilling the following criteria: sustained high levels of serum aminotransferases and high immunoglobulin G levels with positivity for antinuclear antibodies or anti-smooth muscle antibodies (ASMA) and/or histological features of moderate to severe interface hepatitis or moderate to severe lobular hepatitis. We analyzed PBC patients with AIH features, focusing mainly on therapeutic responses to corticosteroids. Results Patients with PBC with AIH features included 26 women (93%). Their median age was 55 years, and the median follow-up period was 7.5 years. Eight of these 28 patients were not actually treated with corticosteroids due to medical conditions. Among the 20 patients receiving corticosteroid therapy, 15 were responders and five were non-responders. A high alkaline phosphatase (ALP) level, negativity for ASMA and positivity for gp210 were identified as risk factors for lack of a response to corticosteroid therapy. Among 28 PBC patients with AIH features, the responders to corticosteroids had an excellent prognosis, while those who could not be treated with corticosteroids and non-responders to corticosteroids had a poor outcome. Conclusion Patients with PBC with AIH features benefit from corticosteroid therapy. Features of PBC such as high ALP level, negativity for ASMA and positivity for gp210 appear to predict a poor response to corticosteroids.
- Published
- 2013
6. Mouse Monoclonal Antibody Specific for Outer Membrane Protein A ofEscherichia coli
- Author
-
Ikuko Haruta, Yoshihiro Abe, Junji Yagi, and Naoko Yanagisawa
- Subjects
medicine.drug_class ,Confocal ,Immunoblotting ,Immunology ,Enzyme-Linked Immunosorbent Assay ,Biology ,medicine.disease_cause ,Monoclonal antibody ,Pathogenesis ,Antibodies, Monoclonal, Murine-Derived ,Mice ,Mouse monoclonal antibody ,medicine ,Animals ,Immunology and Allergy ,Escherichia coli ,Microscopy, Confocal ,Outer membrane protein A ,Original Articles ,respiratory system ,bacterial infections and mycoses ,Molecular biology ,bacteria ,Bacterial outer membrane ,Function (biology) ,Bacterial Outer Membrane Proteins - Abstract
Outer membrane protein A (OmpA) is a major outer membrane protein of Escherichia coli and other Enterobacteriaeae. Although the structural features of OmpA have been well studied, its roles in the pathogenesis of various bacterial infections have not been fully elucidated. Here, we report the generation of mouse monoclonal antibody (MAb) 49.4-15, which specifically recognizes OmpA of E. coli, using immunoblot and confocal microscopic examinations. MAb 49.4-15 might be a useful tool for studying the expression and function of E. coli OmpA.
- Published
- 2013
7. Engulfment of Gram-Positive Bacteria by Pancreatic Stellate Cells in Pancreatic Fibrosis
- Author
-
Keiichi Morishita, Kyoko Shimizu, Keiko Shiratori, Shunji Kawamura, Ikuko Haruta, and Makio Kobayashi
- Subjects
Lipopolysaccharides ,Male ,Endocrinology, Diabetes and Metabolism ,Gram-positive bacteria ,Phagocytosis ,Gram-Positive Bacteria ,Pathogenesis ,Endocrinology ,Fibrosis ,Internal Medicine ,medicine ,Animals ,Rats, Wistar ,Pancreas ,Cells, Cultured ,Hepatology ,biology ,Pancreatic Stellate Cells ,biology.organism_classification ,medicine.disease ,Toll-Like Receptor 2 ,Rats ,Teichoic Acids ,Cancer research ,Hepatic stellate cell ,Pancreatic fibrosis ,Bacteria ,Function (biology) - Abstract
We previously reported the finding that pancreatic stellate cells (PSCs) have a phagocytic function. The aim of the present study was to investigate whether engulfment of gram-positive bacteria by PSCs plays any role in the pathogenesis of pancreatic fibrosis.Rat PSCs were cultured with lipoteichoic acid (LTA) or bacteria and analyzed for α-smooth muscle actin expression and collagen secretion. Human pancreata were obtained from routine autopsies of 20 cases; a diagnosis of gram-positive sepsis was made in 10 of the cases (sepsis group), but sepsis had not been diagnosed in the other 10 cases (control group). Pancreatic tissue was stained with anti-LTA antibody, and the severity of pancreatic fibrosis was evaluated by histological scoring.Bacteria and LTA were internalized into the cytoplasm of cultured PSCs. Exposure to LTA or bacteria significantly increased α-smooth muscle actin expression and collagen secretion. Blockade of toll-like receptor 2 significantly inhibited the increase in collagen secretion in response to LTA. There was no significant difference in the severity of pancreatic fibrosis between the sepsis group and the control group.The fibrogenic action of PSCs seems to be more strongly associated with activation of the toll-like receptor-dependent pathway than it is with phagocytosis of bacteria by PSCs.
- Published
- 2010
8. A possible role of histone-like DNA-binding protein of Streptococcus intermedius in the pathogenesis of bile duct damage in primary biliary cirrhosis
- Author
-
Katsuhiko Hirota, Yoichiro Miyake, Makio Kobayashi, Hidehito Kato, Keiko Shiratori, Etsuko Hashimoto, Takehiko Uchiyama, Junji Yagi, Ikuko Haruta, and Ken Kikuchi
- Subjects
Adult ,Male ,Biopsy ,Hepatitis C virus ,Immunology ,Enzyme-Linked Immunosorbent Assay ,Streptococcus intermedius ,medicine.disease_cause ,digestive system ,Microbiology ,Pathogenesis ,Primary biliary cirrhosis ,Streptococcal Infections ,medicine ,Humans ,Immunology and Allergy ,skin and connective tissue diseases ,Aged ,biology ,Liver Cirrhosis, Biliary ,Bile duct ,Autoantibody ,Middle Aged ,medicine.disease ,biology.organism_classification ,Streptococcaceae ,Antibodies, Bacterial ,Immunohistochemistry ,digestive system diseases ,DNA-Binding Proteins ,medicine.anatomical_structure ,Biliary tract ,Female - Abstract
Bacterial infection has become a focus of attention in the pathogenesis of primary biliary cirrhosis (PBC). It was reported that anti-histone autoantibody was detected in PBC, suggesting that bacterial histone-like DNA-binding protein (HLP) may be involved in the pathogenesis of PBC. To identify bacterial species in PBC to confirm this possibility, serum reactivity to bacterial cells was studied by ELISA. The IgM class Streptococcus intermedius titers were significantly higher in PBC than chronic hepatitis due to hepatitis C virus (CH-C) and healthy subjects. Among the streptococci, S. intermedius was selected for further study. The antigenic peptide of S. intermedius of HLP was synthesized to examine the serum reactivity to Si-HLP. IgM class anti-Si-HLP peptide titers were significantly higher in PBC. Immunoreactivity to anti-Si-HLP was detected in the cytoplasm of biliary epithelial cells and inflammatory cells in the portal area in PBC patients' livers. Streptococci, especially S. intermedius, might play a key role in the pathogenesis of PBC, possibly involving HLP.
- Published
- 2008
9. Spur cell anemia associated with a cirrhotic non-alcoholic steatohepatitis patient
- Author
-
Ayae Kabutake, Katsutoshi Tokushige, Ikuko Haruta, Makiko Taniai, Etsuko Hashimoto, and Keiko Shiratori
- Subjects
Hemolytic anemia ,medicine.medical_specialty ,Alcoholic liver disease ,Cirrhosis ,Hepatology ,business.industry ,Acquired hemolytic anemia ,nutritional and metabolic diseases ,Alcoholic hepatitis ,Jaundice ,medicine.disease ,digestive system ,Gastroenterology ,digestive system diseases ,Infectious Diseases ,hemic and lymphatic diseases ,Internal medicine ,Spur cell anemia ,medicine ,medicine.symptom ,Steatohepatitis ,business - Abstract
Spur cell anemia is an acquired hemolytic anemia, which may occur in patients with severe liver dysfunction, especially in those with alcoholic cirrhosis. Recently, non-alcoholic steatohepatitis (NASH) has been highlighted as one of the causes of chronic liver diseases, which could progress to cirrhosis. Histological features of NASH are indistinguishable from those of alcoholic hepatitis. We report on a cirrhotic NASH patient who developed progressive indirect dominant jaundice and intractable hemolytic anemia during his follow-up. This report shows the first case of a cirrhotic NASH patient who died as a result of spur cell anemia.
- Published
- 2007
10. Lipoteichoic acid may affect the pathogenesis of PBC-like bile duct damage and might be involved in systemic multifocal epithelial inflammations in chronic colitis-harboring TCRα−/−×AIM−/−mice
- Author
-
Ikuko Haruta, Etsuko Hashimoto, Noriyuki Shibata, Yoichiro Kato, Makio Kobayashi, and Keiko Shiratori
- Subjects
Lipopolysaccharides ,medicine.medical_specialty ,Immunology ,Biology ,Gram-Positive Bacteria ,Kidney ,Gastroenterology ,Article ,Epithelium ,Primary sclerosing cholangitis ,Pathogenesis ,Mice ,Primary biliary cirrhosis ,Internal medicine ,Intestine, Small ,medicine ,Animals ,Immunology and Allergy ,TCRα−/− mice ,Pancreas ,Inflammation ,Gastrointestinal tract ,Liver Cirrhosis, Biliary ,Bile duct ,Stomach ,primary sclerosing cholangitis ,Colitis ,medicine.disease ,Small intestine ,primary biliary cirrhosis ,Teichoic Acids ,multiple organ dysfunction syndrome (MODS) ,Bile Ducts, Intrahepatic ,medicine.anatomical_structure ,Liver ,LTA ,Chronic Disease ,Female ,Spleen - Abstract
Chronic colitis-harboring TCRalpha(- / - ) x AIM(- / - ) mice showed PBC-like bile duct damage in the liver. Bacterial infection is one of the candidates for the pathogenesis of PBC. We demonstrated that the bacterial cell wall component lipotheicoic acid (LTA) was detected at sites of inflammation around damaged bile ducts in PBC patients. The aim of this study was to investigate the pathophysiology of the liver and other organs in TCRalpha(- / - ) x AIM(- / - ) mice.Thirteen female TCRalpha(- / - ) x AIM(- / - ) mice were sacrificed at 24 weeks of age. The liver, stomach, small intestine, colon, pancreas, kidney and spleen were studied for pathological examination. Using anti-LTA antibody as the primary antibody, an immunohistochemical study was carried out.In the liver, LTA was mainly detected in the portal area with inflammation, and some of the cytoplasm of hepatocytes. Inflammations were also observed in the stomach, intestine, pancreas and kidney. Throughout the gastrointestinal tract, from the stomach to the colon, LTA was detected in the epithelium at sites of inflammation. Furthermore, LTA was detected around both pancreatic ducts with inflammation and distal renal tubules with inflammation.The development of inflammations in the liver as well as extensive organs, strongly suggests a close relationship between bile duct damage and systemic multifocal epithelial inflammations, perhaps involving bacterial LTA, in TCRalpha(- / - ) x AIM(- / - ) mice.
- Published
- 2007
11. Effect of Lipopolysaccharide on the Progression of Non-Alcoholic Fatty Liver Disease in High Caloric Diet-Fed Mice
- Author
-
Kayoko Saito, Miyuki Omori-Miyake, Noriko Matsushita, Hidehiro Ueshiba, Ikuko Haruta, Satoshi Tsuneda, Junji Yagi, Katsutoshi Tokushige, Naoko Yanagisawa, Etsuko Hashimoto, Noriyuki Shibata, and Toshifumi Osaka
- Subjects
0301 basic medicine ,Lipopolysaccharides ,Male ,medicine.medical_specialty ,Lipopolysaccharide ,Colon ,Immunology ,Proinflammatory cytokine ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Non-alcoholic Fatty Liver Disease ,Internal medicine ,RNA, Ribosomal, 16S ,medicine ,Animals ,RNA, Messenger ,Bacteroidaceae ,biology ,Fatty liver ,General Medicine ,medicine.disease ,biology.organism_classification ,Diet ,Gastrointestinal Microbiome ,Cellular infiltration ,Mice, Inbred C57BL ,Disease Models, Animal ,RNA, Bacterial ,030104 developmental biology ,Endocrinology ,chemistry ,Liver ,Disease Progression ,Cytokines ,030211 gastroenterology & hepatology ,Steatosis ,Metabolic syndrome ,Steatohepatitis ,Energy Intake - Abstract
The incidence of non-alcoholic steatohepatitis (NASH) is increasing. Because gut microbiota have been highlighted as one of the key factors in the pathogenesis of metabolic syndrome, we investigated the involvement of the bacterial component in the progression of non-alcoholic fatty liver (NAFL) to NASH. C57BL/6 mice were fed with maintenance food (MF, groups A and B) or a high caloric diet (HCD, groups C and D) for 1 month. Mice were then divided into four groups: Groups A and C were inoculated with PBS, while groups B and D were inoculated with lipopolysaccharide (LPS) plus complete Freund's adjuvant (CFA). The inoculations were performed a total of 3 times over 3 months. At 6 months, while hepatic steatosis was observed in groups C and D, cellular infiltration and fibrosis were less evident in group C than in group D. Inflammatory cytokines were upregulated in groups B and D. 16S rRNA pyrosequencing of whole colon homogenates containing faeces showed that certain bacterial groups, such as Bacteroidaceae, Peptostreptococcaceae and Erysipelotrichaceae, were increased in groups C and D. Although loading of bacterial components (LPS) resulted in hepatic inflammation in both MF- and HCD-fed mice, HCD feeding was more crucial in the progression of NAFL during the triggering phase.
- Published
- 2015
12. Intrahepatic biliary epithelial cell damage and inflammation in portal tract in association with chronic colitis-harboring TCRα−/− mice
- Author
-
Ikuko Haruta, Makio Kobayashi, Hiroshi Miyakawa, Yoichiro Kato, Noriyuki Shibata, Etsuko Hashimoto, and Keiko Shiratori
- Subjects
medicine.medical_specialty ,Pathology ,Hepatology ,T-cell receptor ,Intrahepatic bile ducts ,Inflammation ,Biology ,medicine.disease ,Ulcerative colitis ,Gastroenterology ,Epithelium ,Primary sclerosing cholangitis ,Cellular infiltration ,Infectious Diseases ,Primary biliary cirrhosis ,medicine.anatomical_structure ,Internal medicine ,medicine ,medicine.symptom - Abstract
Background Intrahepatic bile ducts are the target for inflammation in both primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). The mechanisms of biliary epithelial cell damage in both diseases are not clearly understood. Ulcerative colitis (UC) is one of the known complications in PSC. In this study, we assessed the possible influence of apoptosis inhibitor expressed by macrophages (AIM) on intrahepatic bile ducts in the chronic colitis-harboring condition by generating T cell receptor α-deficient (TCRα−/−) × AIM-deficient (AIM−/−) double-knockout mice. Methods TCRα−/− × AIM−/− mice were generated by crossbreeding TCRα−/− mice with AIM−/− mice. At 24 weeks of age, mice were sacrificed to obtain liver tissues for pathological examinations, and blood was collected to study the serum levels of IgG, IgM and IgA. Results In female TCRα−/− × AIM−/− mouse livers, mixed cellular infiltration in the portal area and epithelial cell damage in bile ducts were observed, when compared with female TCRα−/− × AIM+/− and male TCRα−/− × AIM−/− mice. Inflammation in hepatic parenchyma was mild to none in all mice. In the female mouse group, the serum IgA level was relatively increased in TCRα−/− × AIM−/− mice compared to TCRα−/− × AIM+/− mice. Conclusion The defect of AIM might be involved not only in colonic mucosal inflammation but also in portal inflammation, as well as in biliary epithelial cell damage in the livers of female TCRα−/− × AIM−/− mice.
- Published
- 2006
13. Analysis of adhesion molecules in patients with idiopathic portal hypertension
- Author
-
Naoko Yamaguchi, Katsutoshi Tokushige, Katsumi Yamauchi, Naoaki Hayashi, and Ikuko Haruta
- Subjects
Pathology ,medicine.medical_specialty ,Hepatology ,Vascular disease ,Cell adhesion molecule ,business.industry ,Intercellular Adhesion Molecule-1 ,Fatty liver ,Gastroenterology ,Hepatitis C ,medicine.disease ,Intercellular adhesion molecule ,medicine ,Portal hypertension ,Cell adhesion ,business - Abstract
Background: The aetiology of idiopathic portal hypertension (IPH) is unknown. However, some evidence of immunological abnormalities in IPH patients has been reported. Methods: As adhesion molecules are important in the interaction between lymphocytes and accessory and target cells, the expression and release of the soluble form of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule (ICAM-1) were examined in this study. Results: In IPH patients, the serum level of soluble VCAM-1 was found to be increased, compared with that of healthy subjects, fatty liver patients and chronic hepatitis patients. The level of soluble ICAM-1 of IPH patients was found to be slightly increased, compared with that of healthy subjects; however, it was not different from the level in patients with other diseases. The expression of VCAM-1 was observed in the sinusoidal lining cells and endothelial cells around the liver vessels of several IPH patients. In contrast, ICAM-1 was weakly expressed in sinusoidal lining cells and hepatocytes in the liver tissue of only one of four IPH patients. Conclusions: This differential pattern of VCAM-1 and ICAM-1 was found in IPH patients and it was suggested that VCAM-1 might be an important molecule in the occurrence of IPH.
- Published
- 2002
14. Characterization of a Conformationally Sensitive Murine Monoclonal Antibody Directed to the Metal Ion-Dependent Adhesion Site Face of Integrin CD11b
- Author
-
Rui Li, M. Amin Arnaout, Ikuko Haruta, Takashi Sugimori, Jian-Ping Xiong, and Philippe Rieu
- Subjects
Integrins ,Cations, Divalent ,Protein Conformation ,Immunology ,Integrin ,Antibody Affinity ,Macrophage-1 Antigen ,CHO Cells ,Ligands ,Binding, Competitive ,Divalent ,Mice ,Protein structure ,Cricetinae ,Animals ,Humans ,Immunology and Allergy ,Binding site ,Antibodies, Blocking ,Integrin binding ,chemistry.chemical_classification ,Mice, Inbred BALB C ,biology ,Chemistry ,Ligand ,Antibodies, Monoclonal ,Biochemistry ,Integrin alpha M ,Metals ,CD18 Antigens ,COS Cells ,biology.protein ,Biophysics ,Integrin, beta 6 ,Binding Sites, Antibody - Abstract
Integrin binding to physiologic ligands requires divalent cations and an inside-out-driven switch of the integrin to a high-affinity state. Divalent cations at the metal ion-dependent adhesion site (MIDAS) face of the α subunit-derived A domain provide a direct bridge between ligands and the integrin, and it has been proposed that activation dependency is caused by reorientation of the surrounding residues relative to the metal ion, forming an optimal binding interface. To gain more insight into the functional significance of the protein movements on the MIDAS face, we raised and characterized a murine mAb 107 directed against the MIDAS face of the A domain from integrin CD11b. We find that mAb 107 behaves as a ligand mimic. It binds in a divalent-cation-dependent manner to solvent-exposed residues on the MIDAS face of CD11b, blocks interaction of 11bA or the holoreceptor with ligands, and inhibits spreading and phagocytosis by human neutrophils. However, in contrast to physiologic ligands, mAb 107 preferentially binds to the inactive low-affinity form of the integrin, suggesting that its antagonistic effects are exerted in part by stabilizing the receptor in the low-affinity state. These data support a functional relevance of the protein movements on the MIDAS face and suggest that stabilizing the A domain in the low-affinity state may have therapeutic benefit.
- Published
- 2002
15. Association of AIM, a Novel Apoptosis Inhibitory Factor, with Hepatitis via Supporting Macrophage Survival and Enhancing Phagocytotic Function of Macrophages
- Author
-
Sei-ichi Yusa, Naoaki Hayashi, Yoichiro Kato, Ikuko Haruta, Christina Minjares, Makio Kobayashi, Katsumi Yamauchi, Etsuko Hashimoto, Hirofumi Uto, Toru Miyazaki, Urs Müller, and Shawna Kennedy
- Subjects
Cell Survival ,Phagocytosis ,Adipose tissue macrophages ,Apoptosis ,Mice, Transgenic ,Inflammation ,Biology ,Biochemistry ,Mice ,Downregulation and upregulation ,medicine ,Animals ,Macrophage ,Autocrine signalling ,Molecular Biology ,Macrophages ,Proteins ,Cell Biology ,Up-Regulation ,Mice, Inbred C57BL ,Haematopoiesis ,Liver ,Hepatitis, Viral, Animal ,Immunology ,medicine.symptom - Abstract
A hallmark of many inflammatory diseases is the destruction of tissue cells by infiltrating hematopoietic cells including lymphocytes, neutrophils, and macrophages. The regulation of apoptosis of both target tissue cells and the infiltrating cells is one of the key events that defines the initiation and the progression of inflammation. However, the precise picture of the apoptosis regulation of the cells at the inflammatory sites is still unclear. We recently isolated a novel apoptosis inhibitory factor, termed AIM, which is secreted exclusively by tissue macrophages. In this report, we present unique characteristics of AIM associated with liver inflammation (hepatitis), identified by introducing an experimental hepatitis in both AIM-transgenic mice, which overexpress AIM in the body, and normal mice. First, endogenous AIM expression in macrophages is rapidly increased in response to inflammatory stimuli. Second, AIM appears to inhibit the death of macrophages in the inflammatory regions, judging by the remarkably increased number of macrophages observed in the liver from transgenic mice. In addition, we show that AIM also enhances the phagocytosis by macrophages, which emphasizes the multifunctional character of AIM. All these findings strongly provoke an idea that AIM may play an important role in hepatitis pathogenesis in a sequential manner; first AIM expression is up-regulated by inflammatory stimuli, and then in an autocrine fashion, AIM supports the survival of infiltrating macrophages as well as enhances phagocytosis by macrophages, which may result in an efficient clearance of dead cells and infectious or toxic reagents.
- Published
- 2001
16. Identification of commensal flora-associated antigen as a pathogenetic factor of autoimmune pancreatitis
- Author
-
Toru Furukawa, Noriyuki Shibata, Ikuko Haruta, Tomoaki Higuchi, Naoko Yanagisawa, Keiko Shiratori, Junji Yagi, and Kyoko Shimizu
- Subjects
Adult ,Male ,Endocrinology, Diabetes and Metabolism ,Molecular Sequence Data ,medicine.disease_cause ,Autoimmunity ,law.invention ,Microbiology ,Autoimmune Diseases ,Mice ,Antigen ,law ,medicine ,Escherichia coli ,Animals ,Humans ,Amino Acid Sequence ,Pancreas ,Autoimmune pancreatitis ,Aged ,Autoantibodies ,Aged, 80 and over ,Antigens, Bacterial ,Hepatology ,business.industry ,Gastroenterology ,Antibody titer ,Middle Aged ,medicine.disease ,Recombinant Proteins ,Mice, Inbred C57BL ,Titer ,medicine.anatomical_structure ,Pancreatitis ,Immunology ,Recombinant DNA ,Female ,business ,Bacterial Outer Membrane Proteins - Abstract
Objectives Autoimmune pancreatitis (AIP) is a chronic fibro-inflammatory disease of the pancreas constituting, in part, a recently defined nosological entity of IgG4-related systemic sclerosing diseases. The pathogenetic factors of AIP have not been fully elucidated. We previously established a mouse model of AIP using chronic exposure to a commensal bacteria, Escherichia coli . Methods To determine the pathogenetically relevant antigen of E. coli , the outer membrane fractions of E. coli were subjected to two-dimensional gel electrophoresis followed by immunoblotting against sera from the AIP model. Immunoreactive spots were determined using MALDI TOF/MS and Mascot search. The recombinant protein of the identified antigen was examined for their ability to induce AIP-like disorder in C57BL/6 mice. Furthermore, the antibody titer against that antigen was determined in AIP patients. Results One representative spot reacting with sera from E. coli -inoculated mice was identified as FliC from E. coli , based on the results of TOF/MS. The repeated inoculation of recombinant FliC in C57BL/6 mice induced AIP-like pancreatitis and higher titers of anti-lactoferrin and anti-carbonic anhydrase II. Sera from patients with AIP had the highest antibody titer, while those from patients with pancreatic diseases other than AIP had a higher antibody titer against E. coli and FliC, compared with pancreatic disease-free controls. Conclusions FliC from E. coli may pathogenetically generate an AIP-like inflammation status. A reconsideration of the importance of commensal bacteria as an environmental factor(s) capable of inducing autoimmunity could provide insight to overcoming AIP.
- Published
- 2013
17. Clinical Implication of Vascular Cell Adhesion Molecule-1 and Very Late Activation Antigen-4 Interaction, and Matrix Metalloproteinase-2 Production in Patients with Liver Disease
- Author
-
Katsutoshi Tokushige, Naoaki Hayashi, Ikuko Haruta, Tatsuji Komatsu, Katsumi Yamauchi, and Ikuo Ikeda
- Subjects
Male ,Integrins ,Pathology ,medicine.medical_specialty ,Cirrhosis ,genetic structures ,Receptors, Lymphocyte Homing ,Vascular Cell Adhesion Molecule-1 ,Integrin alpha4beta1 ,Chronic liver disease ,Hepatitis ,Liver disease ,Antigen ,Humans ,Medicine ,lcsh:RC799-869 ,Cell adhesion ,Cell adhesion molecule ,business.industry ,Liver Diseases ,Liver cell ,Gastroenterology ,General Medicine ,Middle Aged ,medicine.disease ,Immunohistochemistry ,medicine.anatomical_structure ,Hepatocyte ,Acute Disease ,Chronic Disease ,Disease Progression ,Cancer research ,Matrix Metalloproteinase 2 ,lcsh:Diseases of the digestive system. Gastroenterology ,Female ,business - Abstract
OBJECTIVES: To clarify the role of adhesion molecule in liver cell injury.PATIENTS AND METHODS: The serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1), and the expression of VCAM-1 and its ligand, very late activation antigen-4 (VLA-4), were examined in patients with various liver diseases. In addition, the presence of matrix metalloproteinase-2 (MMP-2) was investigated because the release of MMP-2 is thought to be mediated by VLA-4-positive cells. sVCAM-1 and MMP-2 were measured by ELISA assay, and VCAM-1 and VLA-4 were studied by immunohistological methods.RESULTS: In acute hepatitis (AH) patients, the serum level of sVCAM-1 was significantly elevated compared with that in other cohorts. VCAM-1 was expressed on sinusoidal lining cells but not on hepatocytes. In patients with chronic liver disease, sVCAM-1 levels rose in concert with the progression of chronic hepatitis (CH), and VCAM-1 was also expressed. VLA-4 was detected in both mononuclear cells and Kupffer cells in AH livers, but mainly in Kupffer cells in patients with CH. In AH patients, MMP-2 levels were similar to those in control subjects, but in CH and liver cirrhosis patients, MMP-2 level was elevated in association with CH progression.CONCLUSIONS: The immune response through the VCAM-1 and VLA-4 pathways is important in hepatocyte injury, especially in AH patients, to attach VLA-4-positive mononuclear cells to VCAM-1-positive sinusoidal lining cells. The distribution of VLA-4-positive cells differs between AH and CH patients. VLA-4-positive Kupffer cells in chronic liver diseases might be involved in the progression of CH, perhaps through the mechanism of upregulation of MMP-2 production.
- Published
- 1999
18. Antibody dependent cell-mediated cytotoxicity using hepatocellular carcinoma reactive monoclonal antibody
- Author
-
Naoaki Hayashi, Tomo Kuwata, Katsumi Yamauchi, Ikuko Haruta, and Kiyoshi Hasegawa
- Subjects
Carcinoma, Hepatocellular ,medicine.drug_class ,Monoclonal antibody ,Peripheral blood mononuclear cell ,Mice ,Antigen ,Tumor Cells, Cultured ,Animals ,Humans ,Medicine ,Cytotoxicity ,Antibody-dependent cell-mediated cytotoxicity ,Mice, Inbred BALB C ,Hepatology ,biology ,business.industry ,Liver Neoplasms ,Antibody-Dependent Cell Cytotoxicity ,Gastroenterology ,Antibodies, Monoclonal ,Flow Cytometry ,medicine.disease ,Pancreatic Neoplasms ,Hepatocellular carcinoma ,Colonic Neoplasms ,Immunology ,biology.protein ,Cancer research ,Immunohistochemistry ,Antibody ,business - Abstract
We have established monoclonal antibodies from mice immunized with the human hepatocellular carcinoma cell line, hu-H2. One of the antibodies, designated 523(KY-3), was reactive with this hepatocellular carcinoma cell line as well as with the human pancreatic cancer cell line, MIA. Another monoclonal antibody, 512(KY-2), only reacted with the hepato-cellular carcinoma cell lines. Neither antibody reacted with the colon cancer cell line CW3. Pretreatment of peripheral blood mononuclear cells with 523 resulted in enhancement of their natural cytotoxicity to hu-H2 (9.0 vs 18.4% in subject 1, 3.5 vs 14.7% in subject 2, and 14.2 vs 31.0% in subject 3). In contrast, such antibody mediated enhanced natural cytotoxicity was not found by pretreatment of the same peripheral blood mononuclear cell with 512. With the similarity in reactivity of 523, this antibody dependent enhancement was found in natural cytotoxicity to hu-H2 and MIA but not to CW3. Based on the facts that 523 did not have a direct cytopathic effect on these tumours and that this 523-mediated enhanced natural cytotoxicity was inhibited by anti-FcgammaRIII antibody, we concluded that the 523-mediated enhanced cytotoxicity reflects its activity to induce antibody dependent cytotoxic cells. Thus, these results demonstrate that several distinct tumour-specific antigens exist in hepatocellular carcinoma (HCC) and that one of them represents a potentially useful target for immunotherapy of human hepatocellular carcinoma.
- Published
- 1998
19. Clinical profile of primary biliary cirrhosis with features of autoimmune hepatitis: Importance of corticosteroid therapy
- Author
-
Youko, Yoshioka, Makiko, Taniai, Etsuko, Hashimoto, Ikuko, Haruta, and Keiko, Shiratori
- Abstract
The aim of this study was to elucidate the clinical and histological features, response to corticosteroid therapy and long-term outcome of primary biliary cirrhosis (PBC) with features of autoimmune hepatitis (AIH).Among 280 PBC patients under ursodeoxycholic acid administration, we identified 28 patients with AIH features fulfilling the following criteria: sustained high levels of serum aminotransferases and high immunoglobulin G levels with positivity for antinuclear antibodies or anti-smooth muscle antibodies (ASMA) and/or histological features of moderate to severe interface hepatitis or moderate to severe lobular hepatitis. We analyzed PBC patients with AIH features, focusing mainly on therapeutic responses to corticosteroids.Patients with PBC with AIH features included 26 women (93%). Their median age was 55 years, and the median follow-up period was 7.5 years. Eight of these 28 patients were not actually treated with corticosteroids due to medical conditions. Among the 20 patients receiving corticosteroid therapy, 15 were responders and five were non-responders. A high alkaline phosphatase (ALP) level, negativity for ASMA and positivity for gp210 were identified as risk factors for lack of a response to corticosteroid therapy. Among 28 PBC patients with AIH features, the responders to corticosteroids had an excellent prognosis, while those who could not be treated with corticosteroids and non-responders to corticosteroids had a poor outcome.Patients with PBC with AIH features benefit from corticosteroid therapy. Features of PBC such as high ALP level, negativity for ASMA and positivity for gp210 appear to predict a poor response to corticosteroids.
- Published
- 2013
20. Commensal Flora, is it an Unwelcomed Companion as a Triggering Factor of Autoimmune Pancreatitis?
- Author
-
Naoko Yanagisawa, Junji Yagi, Keiko Shiratori, Ikuko Haruta, and Kyoko Shimizu
- Subjects
Autoimmune disease ,Innate immune system ,Bacteria ,lcsh:QP1-981 ,Physiology ,business.industry ,autoimmune disease ,Review Article ,medicine.disease ,autoimmune pancreatitis ,AIP (autoimmune pancreatitis) ,lcsh:Physiology ,Pathogenesis ,Physiology (medical) ,Flora (microbiology) ,Immunology ,medicine ,business ,innate immunity ,commensal flora ,Autoimmune pancreatitis - Abstract
The etiopathogenesis of many autoimmune disorders has not been identified. The aim of this paper is to focus on the involvement of bacterial exposure, as an environmental factor, in the pathogenesis of autoimmune pancreatitis (AIP), which is broadly categorized as autoimmune disorders involving pancreatic lesions. Avirulent and/or commensal bacteria, which may have an important role(s) as initiating/progressing factors in the pathogenesis of autoimmune disorder AIP, will be emphasized.
- Published
- 2012
21. Are Dysregulated Inflammatory Responses to Commensal Bacteria Involved in the Pathogenesis of Hepatobiliary-Pancreatic Autoimmune Disease? An Analysis Using Mice Models of Primary Biliary Cirrhosis and Autoimmune Pancreatitis
- Author
-
Junji Yagi, Noriyuki Shibata, Naoko Yanagisawa, Ikuko Haruta, and Ken Kikuchi
- Subjects
Pathogenesis ,Autoimmune disease ,Primary biliary cirrhosis ,business.industry ,Immunology ,medicine ,Review Article ,medicine.disease ,Commensalism ,business ,digestive system diseases ,Autoimmune pancreatitis - Abstract
The etiopathogenesis of many autoimmune disorders has not been identified. The aim of this paper is to focus on the involvement of bacterial exposure in the pathogenesis of primary biliary cirrhosis (PBC) and autoimmune pancreatitis (AIP), both of which are broadly categorized as autoimmune disorders involving hepatobiliary-pancreatic lesions. Avirulent and/or commensal bacteria, which may have important role(s) as initiating factors in the pathogenesis of autoimmune disorders such as PBC and AIP, will be emphasized.
- Published
- 2011
22. A mouse model of autoimmune pancreatitis with salivary gland involvement triggered by innate immunity via persistent exposure to avirulent bacteria
- Author
-
Toru Furukawa, Naoko Yanagisawa, Ikuko Haruta, Kyoko Shimizu, Makio Kobayashi, Hidehito Kato, Junji Yagi, Keiko Shiratori, and Shunji Kawamura
- Subjects
Salivary Gland Diseases ,Biology ,Salivary Glands ,Pathology and Forensic Medicine ,Autoimmune Diseases ,Pathogenesis ,Mice ,Immune system ,Antigen ,Immunity ,medicine ,Escherichia coli ,Animals ,Molecular Biology ,Autoimmune pancreatitis ,Inflammation ,Innate immune system ,Salivary gland ,Cell Biology ,medicine.disease ,Immunity, Innate ,Pancreas, Exocrine ,Mice, Inbred C57BL ,Disease Models, Animal ,medicine.anatomical_structure ,Pancreatitis ,Antibodies, Antinuclear ,Immunology ,Female - Abstract
The pathogenesis of autoimmune pancreatitis (AIP) remains unknown. Here, we investigated the possible involvement of chronic, persistent exposure to avirulent bacteria in the pathogenesis of AIP. C57BL/6 mice were inoculated with heat-killed Escherichia coli weekly for 8 weeks. At 1 week and up to 12 months after the final inoculation, the mice were killed to obtain samples. At 1 week after the final E. coli inoculation, marked cellular infiltration with fibrosis was observed in the exocrine pancreas. Cellular infiltration in the exocrine pancreas was still observed up to 12 months after the completion of E. coli inoculation. At 10 months after the final inoculation, duct-centric fibrosis became obvious. Inflammation around the ducts in the salivary glands was also observed. Furthermore, sera from heat-killed E. coli-inoculated mice possessed anti-carbonic anhydrase, anti-lactoferrin, and antinuclear antibodies. Exposure to E. coli-triggered AIP-like pancreatitis in C57BL/6 mice. We propose a hypothetical mechanism for AIP pathogenesis. During the initiation phase, silently infiltrating pathogen-associated molecular patterns (PAMP) and/or antigen(s) such as avirulent bacteria might trigger and upregulate the innate immune system. Subsequently, the persistence of such PAMP attacks or stimulation by molecular mimicry upregulates the host immune response to the target antigen. These slowly progressive steps may lead to the establishment of AIP and associated extrapancreatic lesions. Our model might be useful for clarifying the pathogenesis of AIP.
- Published
- 2010
23. Possible role of LECT2 as an intrinsic regulatory factor in SEA-induced toxicity in d-galactosamine-sensitized mice
- Author
-
Yutaka Arimura, Miyuki Omori-Miyake, Makoto Ozaki, Tohru Kotani, Satoshi Yamagoe, Takehiko Uchiyama, Minh Hung Dang, Ikuko Haruta, Junji Yagi, Hidehiro Ueshiba, Hidehito Kato, Kazuyoshi Ando, Kazuo Suzuki, and Ken'ichi Imanishi
- Subjects
medicine.medical_specialty ,Time Factors ,Ratón ,medicine.medical_treatment ,T-Lymphocytes ,Immunology ,Down-Regulation ,Inflammation ,Apoptosis ,Galactosamine ,Hemorrhage ,medicine.disease_cause ,chemistry.chemical_compound ,Enterotoxins ,Mice ,Internal medicine ,medicine ,In Situ Nick-End Labeling ,Immunology and Allergy ,Animals ,Lung ,Sensitization ,Intrinsic factor ,business.industry ,Toxin ,Interleukin-6 ,Tumor Necrosis Factor-alpha ,Flow Cytometry ,Shock, Septic ,Mice, Inbred C57BL ,Disease Models, Animal ,medicine.anatomical_structure ,Endocrinology ,Cytokine ,chemistry ,Liver ,Toxicity ,Intercellular Signaling Peptides and Proteins ,Female ,medicine.symptom ,Chemical and Drug Induced Liver Injury ,business - Abstract
To elucidate whether leukocyte cell-derived chemotaxin 2 (LECT2) controls the progression of staphylococcal enterotoxin A (SEA)-induced toxicity, we examined the role of LECT2 in a mouse model. Almost all the C57BL/6 J (B6) mice survived for 72 h after the injection of 0.1 μg of SEA and 20 mg of d -galactosamine ( d -GalN). However, the same treatment protocol in LECT2−/− mice produced a high lethality (~ 90%), severe hepatic apoptosis, and massive hepatic and pulmonary hemorrhage, similar to the situation observed in B6 mice treated with 1.0 μg SEA/ d -GalN. The plasma LECT2 levels in B6 mice treated with 1.0 μg SEA/ d -GalN were inversely correlated with the plasma cytokine levels and were associated with prognosis. LECT2 administration increased the survival of B6 mice and down-regulated TNF-α and IL-6. These results suggest the involvement of LECT2 in the regulation of fatal SEA-induced toxicity in d -GalN-sensitized mice.
- Published
- 2010
24. Long-term bacterial exposure can trigger nonsuppurative destructive cholangitis associated with multifocal epithelial inflammation
- Author
-
Takehiko Uchiyama, Noriyuki Shibata, Minoru Nakamura, Makio Kobayashi, Hidehito Kato, Ken Kikuchi, Keiko Shiratori, Hideaki Nagamune, Katsuhiko Hirota, Yutaka Arimura, Junji Yagi, Yoichiro Kato, Yoichiro Miyake, Hiroshi Miyakawa, Etsuko Hashimoto, and Ikuko Haruta
- Subjects
Pathology ,medicine.medical_specialty ,Inflammation ,Streptococcus intermedius ,Pathology and Forensic Medicine ,Pathogenesis ,Mice ,Primary biliary cirrhosis ,Parenchyma ,medicine ,Animals ,Molecular Biology ,Mice, Inbred BALB C ,biology ,business.industry ,Liver Cirrhosis, Biliary ,Epithelial Cells ,Cell Biology ,medicine.disease ,biology.organism_classification ,Immunity, Innate ,Cellular infiltration ,Nuclear Pore Complex Proteins ,Disease Models, Animal ,Antibodies, Antinuclear ,biology.protein ,Lipoteichoic acid ,medicine.symptom ,Antibody ,business - Abstract
Bacterial infection has become a focus of attention in the pathogenesis of primary biliary cirrhosis (PBC). We earlier reported that the bacterial lipoteichoic acid was detected at the sites of inflammation around damaged bile ducts in the livers of PBC, and PBC patients' sera showed high titers against streptococcal histone-like protein. Here, we investigated whether chronic bacterial exposure could trigger PBC-like epithelial cell damage in normal mouse. BALB/c mice were repeatedly inoculated with various bacteria for 8 weeks. At 1 week (Group 1) and 3, 4, or 20 months (long term; Group 2) after the final inoculation, mice were killed to obtain samples. In the livers of the Streptococcus intermedius (S.i.)-inoculated mice in Group 1, cellular infiltration was predominantly observed around the bile ducts over the hepatic parenchyma. In the S.i.-inoculated mice in Group 2, portal but not parenchymal inflammation was observed in the livers, and periductal cellular infiltrates were detected in the salivary glands. Both S.i.-inoculated Groups 1 and 2 BALB/c mice sera had antibodies against HuCCT1 biliary epithelial cells, anti-nuclear antibodies, and anti-gp210 antibodies, but not anti-mitochondrial antibodies. Immunoreactivity to histone-like DNA-binding protein of S.i. (S.i.-HLP) was detectable around the sites of chronic nonsuppurative destructive cholangitis in the portal area in the livers of both S.i.-inoculated Groups 1 and 2 BALB/c mice. Furthermore, anti-S.i.-HLP antibody bound to synthetic gp210 peptide, as well. Bacteria triggered PBC-like cholangitis, multifocal epithelial inflammation, and autoantibody production. Bacteria are likely involved in the pathogenesis of PBC and of associated multifocal epithelial inflammation.
- Published
- 2010
25. Treatment of nonalcoholic steatohepatitis with colestimide
- Author
-
Makiko Taniai, Maki Tobari, Etsuko Hashimoto, Keiko Shiratori, Satoru Yatsuji, Katsutoshi Tokushige, and Ikuko Haruta
- Subjects
medicine.medical_specialty ,Hepatology ,business.industry ,Fatty liver ,nutritional and metabolic diseases ,Adipokine ,Abdominal distension ,medicine.disease ,Gastroenterology ,law.invention ,Infectious Diseases ,Endocrinology ,Insulin resistance ,Randomized controlled trial ,law ,Internal medicine ,Hyperlipidemia ,medicine ,medicine.symptom ,Steatosis ,business ,Adverse effect - Abstract
Aim: To clarify the usefulness of colestimide in patients with nonalcoholic steatohepatitis (NASH) with hyperlipidemia. Methods: In an open-label randomized controlled trial, 17 NASH patients with hyperlipidemia received colestimide (3 g/day) for 24 weeks. There were 21 control patients. All patients received lifestyle modification therapy. Efficacy was assessed based on metabolic profile, insulin resistance, transaminases, serum hepatic fibrosis markers, adipokine levels, visceral fat on computed tomography (CT), and the fatty liver grade on CT. NASH patients with moderate to severe steatosis by histology were also evaluated separately. Results: Baseline clinical characteristics of the two groups were similar. Both groups experienced a significant decrease of BMI with no difference between them. However, visceral fat decreased significantly more in the colestimide group (P = 0.046). Aspartate aminotransferase (AST) showed a significantly greater decrease in the colestimide group compared with the control group (P = 0.042). In patients with moderate to severe histological steatosis, there were significant differences between the two groups regard to HbA1c, transaminases, and hyaluronic acid (P = 0.018 for HbA1c, P = 0.003 for AST, P = 0.042 for alanine aminotransferase, and P = 0.042 for hyaluronic acid). Steatosis significantly improved in patients in the colestimide group who had fatty liver on CT (P = 0.049). In the colestimide group, abdominal distension and/or constipation were seen, but mostly tolerable, no other clinical or laboratory adverse events associated with the use of this medicine were not observed. Conclusions: Colestimide seems to increase the efficacy of lifestyle modification in NASH patients with hyperlipidemia. Its beneficial effects were more prominent in NASH patients with moderate to severe histological steatosis.
- Published
- 2009
26. Systemic multifocal epithelial inflammations associated with PBC-like bile duct damage in chronic colitis harboring TCR alpha -/- x AIM -/- mice: does lipoteichoic acid affect the pathogenesis of epithelial inflammation followed by fibrosis?
- Author
-
Keiko Shiratori, Etsuko Hashimoto, Ikuko Haruta, and Makio Kobayashi
- Subjects
Lipopolysaccharides ,Pathology ,medicine.medical_specialty ,Receptors, Antigen, T-Cell, alpha-beta ,Inflammation ,General Biochemistry, Genetics and Molecular Biology ,Epithelium ,Pathogenesis ,Mice ,Primary biliary cirrhosis ,History and Philosophy of Science ,Fibrosis ,medicine ,Animals ,Colitis ,Receptors, Immunologic ,Mice, Knockout ,Receptors, Scavenger ,Bile duct ,business.industry ,Liver Cirrhosis, Biliary ,General Neuroscience ,medicine.disease ,Teichoic Acids ,medicine.anatomical_structure ,Lipoteichoic acid ,medicine.symptom ,business ,Pancreas ,Apoptosis Regulatory Proteins - Abstract
Autoimmune disorder and associated multifocal organ inflammations such as dry gland syndrome are occasionally observed; however, their etiologies are not clearly understood. We previously reported that chronic colitis-harboring TCR alpha(-/-) x AIM(-/-) mice show primary biliary cirrhosis (PBC)-like bile duct damage in the liver. Gram-positive bacterial infection is one of the candidates for the pathogenesis of PBC. We also reported that the bacterial cell wall component lipoteichoic acid (LTA) was detected at the sites of inflammation around damaged bile ducts in PBC patients. On the basis of these facts, we hypothesized that LTA might affect the pathogenesis of bile duct damage in the livers of TCR alpha(-/-) x AIM(-/-) mice. LTA was detected not only in the portal area with inflammation in the liver but also throughout the gastrointestinal tract, from the stomach to the colon, and especially in the epithelium at sites of inflammation. In addition, LTA was detected around both pancreatic ducts with inflammation and at the distal renal tubules with inflammation in TCR alpha(-/-) x AIM(-/-) mice. Furthermore, in the liver, pancreas, kidney, and colon, fibrous stroma were detected at the sites of LTA-positive inflammation foci. Bacterial LTA might affect the pathogenesis of epithelial inflammation followed by fibrosis in systemic multifocal epithelial inflammations in chronic colitis-harboring TCR alpha(-/-) x AIM(-/-) mice with PBC-like bile duct damage.
- Published
- 2007
27. Lipoteichoic acid may affect the pathogenesis of bile duct damage in primary biliary cirrhosis
- Author
-
Ikuko Haruta, Etsuko Hashimoto, Yoichiro Kato, Ken Kikuchi, Hidehito Kato, Jyunji Yagi, Takehiko Uchiyama, Makio Kobayash, and Keiko Shiratori
- Subjects
Adult ,Lipopolysaccharides ,medicine.medical_specialty ,Pathology ,Hepatitis C virus ,Immunology ,Intrahepatic bile ducts ,medicine.disease_cause ,Gram-Positive Bacteria ,digestive system ,Gastroenterology ,Pathogenesis ,Primary biliary cirrhosis ,Internal medicine ,medicine ,Immunology and Allergy ,Humans ,Aged ,biology ,Bile duct ,Liver Cirrhosis, Biliary ,Hepatitis C, Chronic ,Middle Aged ,medicine.disease ,Antibodies, Bacterial ,digestive system diseases ,Teichoic Acids ,medicine.anatomical_structure ,Bile Ducts, Intrahepatic ,Biliary tract ,biology.protein ,Female ,Lipoteichoic acid ,Antibody - Abstract
Intrahepatic bile ducts are the targets for inflammation in primary biliary cirrhosis (PBC), but their pathogenesis is not known. Gram-positive bacterial DNA was detected recently in gallbladder bile of PBC patients. In the present study, we assessed the possible pathological role of lipoteichoic acid (LTA), the gram-positive bacterial cell wall component, in PBC.Liver samples, obtained from 20 patients with PBC (stage 1-2 with CNSDC: stage 3-4 with loss of bile ducts = 10:10) and from 13 patients with chronic hepatitis due to hepatitis C virus (CH-C) with lymphocytic cholangitis, were subjected to immunohistochemical staining with polyclonal rabbit anti-LTA as the primary antibody. Serum reactivities to LTA were studied by ELISA. After 1 microg of purified LTA was placed in a 96-well microplate as an antigen, an antibody capture assay was carried out using serum samples from PBC (n = 20), CH-C (n = 13) and healthy subjects (n = 11).LTA was localized around the sites of chronic non-suppurative destructive cholangitis (CNSDC) in the portal area in stage 1-2 PBC but was not detected in the portal area in CH-C. In stage 3-4 PBC, LTA was localized around sites of ductular proliferation at the periphery of portal tracts. IgM class anti-LTA serum titers were significantly higher in PBC than in CH-C. IgA class anti-LTA serum titers were significantly higher in PBC than in healthy subjects.In the PBC livers, the profile of immunoreactivity to LTA changed markedly as the disease progressed. Sera from PBC showed higher levels of anti-LTA titers than CH-C (IgM) or from healthy subjects (IgA). The LTA-mediated immune system might affect the initiation and/or progression of PBC.
- Published
- 2006
28. Fatal propionic acidemia in mice lacking propionyl-CoA carboxylase and its rescue by postnatal, liver-specific supplementation via a transgene
- Author
-
Urs Müller, Hirofumi Uto, Ikue Hata, Makio Kobayashi, Toshihiro Ohura, Xue Yang, Toru Miyazaki, Christina Minjares, Yoichi Suzuki, Seiji Yamaguchi, Ikuko Haruta, Yosuke Shigematsu, Yuriko Ito, and Yoko Aoki
- Subjects
medicine.medical_specialty ,Methylmalonyl-CoA Decarboxylase ,Carboxy-Lyases ,Transgene ,Period (gene) ,Propionyl-CoA carboxylase ,Biology ,Biochemistry ,Mice ,Internal medicine ,medicine ,Animals ,Transgenes ,Propionic acidemia ,Molecular Biology ,Mice, Knockout ,Cell Biology ,medicine.disease ,Ketoacidosis ,Pyruvate carboxylase ,Endocrinology ,Liver ,Inborn error of metabolism ,Propionates ,Metabolism, Inborn Errors - Abstract
Propionic acidemia (PA) is an inborn error of metabolism caused by the genetic deficiency of propionyl-CoA carboxylase (PCC). By disrupting the alpha-subunit gene of PCC, we created a mouse model of PA (PCCA(-/-)), which died in 24-36 h after birth due to accelerated ketoacidosis. A postnatal, liver-specific PCC expression via a transgene in a far lower level than that in wild-type liver, allowed PCCA(-/-) mice to survive the newborn and early infant periods, preventing a lethal fit of ketoacidosis (SAP(+)PCCA(-/-) mice). Interestingly, SAP(+)PCCA(-/-) mice, in which the transgene expression increased after the late infant period, continued to grow normally while mice harboring a persistent low level of PCC died in the late infant period due to severe ketoacidosis, clearly suggesting the requirement of increased PCC supplementation in proportion to the animal growth. Based on these results, we propose a two-step strategy to achieve an efficient PA prevention in human patients: a partial PCC supplementation in the liver during the newborn and early infant periods, followed by a larger amount of supplementation in the late infant period.
- Published
- 2001
29. Environmental factors affecting autoimmunity (WS-019)
- Author
-
Karl Skriner, P. S. Leung, K. Tsuneyama, K. Tamakoshi, A. Holownia, Jordan D. Dimitrov, M. E. Gershwin, Srinivas V. Kaveri, Jonatan Tuncel, Guenter Steiner, Mahavir Singh, Yoshinao Muro, Rasmus Iversen, Markus H. Hoffmann, K. Shiratori, S. Wu, Kei Hoshino, Y. Yang, Y. Chuang, S Herman, R. Di Niro, Sébastien Lacroix-Desmazes, Kyoko Shimizu, S. Kawamura, Ikuko Haruta, Christoph Baumann, K. Sugiura, Junji Yagi, Nobuo Yanagisawa, Caroline Ospelt, Carl-Walter Steiner, A. Dubaniewicz, Ludvig M. Sollid, T. Furukawa, M. Kobayashi, and Cyril Planchais
- Subjects
business.industry ,Immunology ,Immunology and Allergy ,Medicine ,General Medicine ,business ,medicine.disease_cause ,Autoimmunity - Published
- 2010
30. Environmental factors affecting autoimmunity (PP-019)
- Author
-
M. Maeda, Y. Miura, David J. Steffen, Y. Lai, Chandirasegaran Massilamany, Hidehito Kato, P. Tsai, Miyuki Omori-Miyake, L. W. Christiansen, N. Kumagai, K. Shiratori, J. C. Wei, Ikuko Haruta, H. Hayashi, T. Othuki, Nobuo Yanagisawa, Jay Reddy, Arunakumar Gangaplara, H. Lu, T. Shen, Y. Hsia, H. Ueshiba, Y. Nishimura, M. Jan, and Junji Yagi
- Subjects
business.industry ,Immunology ,Immunology and Allergy ,Medicine ,General Medicine ,business ,medicine.disease_cause ,Autoimmunity - Published
- 2010
31. Commensal flora as possible pathogens of autoimmune pancreatitis
- Author
-
Y. Abe, Miyuki Omori-Miyake, Naoko Yanagisawa, Junji Yagi, Kyoko Shimizu, Keiko Shiratori, and Ikuko Haruta
- Subjects
medicine.medical_specialty ,endocrine system diseases ,Hepatology ,business.industry ,Endocrinology, Diabetes and Metabolism ,Gastroenterology ,Perioperative ,medicine.disease ,Malignancy ,digestive system diseases ,Internal medicine ,Pancreatic cancer ,medicine ,Adjuvant therapy ,Adenocarcinoma ,Pancreatitis ,Stage (cooking) ,business ,Autoimmune pancreatitis - Abstract
Department of General Surgery, University of Heidelberg, Germany Background: In pancreatic cancer, genetic markers to aid clinical decision making are still lacking. The present study aimed to determine the prognostic role of perioperative CA19-9 in pancreatic adenocarcinoma, with a focus on implications for preand postoperative therapeutic consequences. Patients and methods: Of a total of 1627 consecutive patients who underwent surgery for primary pancreatic adenocarcinoma, data from 1543 patients with preoperative serum levels of CA19-9 were evaluated for tumor stage, resectability, and prognosis. Pre-to-postoperative CA19-9 changes were analyzed for long-term survival. A control cohort of 706 patients with chronic pancreatitis was used to assess the predictability of malignancy by CA19-9 and the effects of hyperbilirubinemia on CA19-9 levels. A treatment algorithm including surgical, neoadjuvant, and adjuvant therapy was derived. Results: The more that preoperative CA19-9 increased, the lower were tumor resectability and survival rates. Resectability and 5-year survival varied from 80% to 38% and from 27% to 0% for CA19-9 4000U/ ml, respectively. CA19-9 increased with the stage of the disease and was highest in AJCC stage IV. Patients with postoperatively normal CA19-9 levels or a postoperative CA19-9 decrease of 75% had a superior prognosis (median survival 36.8 and 26months). CA19-9 levels >1000U/ml or postoperatively increasing levelswere associatedwith a dismal R0 resection rate and prognosis. Hyperbilirubinemia did not critically affect CA19-9 levels. Conclusion: In patients with pancreatic adenocarcinoma, perioperative CA19-9 predicts resectability, stage of disease, as well as prognosis, and was not critically affected by hyperbilirubinemia. Highly increased preoperative or increasing postoperative CA19-9 levels are associated with low respectability and poor survival rates, and demand the adaptation of operative and perioperative therapy.
- Published
- 2013
32. Effect of alpha-interferon on hepatitis B virus-specific cytotoxic T cells
- Author
-
Yumiko Kamogawa, Ikuko Haruta, Naoaki Hayashi, Katsumi Yamauchi, and Etsuko Isono
- Subjects
Adult ,HBsAg ,Hepatitis B virus ,Fluorescent Antibody Technique ,medicine.disease_cause ,Transfection ,Peripheral blood mononuclear cell ,Antigen ,medicine ,Tumor Cells, Cultured ,Cytotoxic T cell ,Humans ,Antigen-presenting cell ,Hepatology ,business.industry ,Gastroenterology ,Interferon-alpha ,Alanine Transaminase ,Hepatitis B ,Virology ,Molecular biology ,HBcAg ,CTL ,Chronic Disease ,DNA, Viral ,business ,T-Lymphocytes, Cytotoxic - Abstract
To study the mechanism of the effects of alpha-interferon (alpha-IFN) on chronic hepatitis B, we examined its effect on hepatitis B virus (HBV)-specific cytotoxic T cells (CTL). Using two different HBV-DNA transfected human myeloma cell lines, one expressing hepatitis B core antigen (HBcAg; C4) and the other expressing hepatitis B surface antigen (HBsAg; S6) as targets in cytotoxic tests in vitro, peripheral blood mononuclear cells obtained from chronic hepatitis B patients who were treated with alpha-IFN were examined for their cytotoxic activity against these transfectants. During the treatment with alpha-IFN, in association with a decline of serum alanine amino transferase levels, CTL activities were significantly reduced. An inhibition study in vitro revealed that alpha-IFN did not directly inhibit these CTL activities, indicating that alpha-IFN may inhibit the induction of CTL, and thereby may be related to the reduction of hepatocyte injury.
- Published
- 1995
33. 1295 UP-REGULATION OF INNATE IMMUNITY TRIGGERED BY AVIRULENT BACTERIA COULD BE A POSSIBLE PATHOGENESIS OF PRIMARY BILIARY CIRRHOSIS
- Author
-
N. Yanagisawa, Junji Yagi, Ikuko Haruta, Keiko Shiratori, N. Matsushita, and Etsuko Hashimoto
- Subjects
Pathogenesis ,Primary biliary cirrhosis ,Innate immune system ,Hepatology ,Downregulation and upregulation ,biology ,business.industry ,Immunology ,medicine ,medicine.disease ,biology.organism_classification ,business ,Bacteria - Published
- 2011
34. T1896 Gram-Positive Infection Provokes Pancreatic Fibrogenesis
- Author
-
Ikuko Haruta, Keiko Shiratori, Kyoko Shimizu, Makio Kobayashi, and Keiichi Morishita
- Subjects
Hepatology ,business.industry ,Gastroenterology ,Medicine ,business ,Gram ,Microbiology - Published
- 2008
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.