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ABSTRACT: BACKGROUND: Patients with primary biliary cirrhosis (PBC) exhibit a variety of clinical manifestations and patterns of disease progression. The aim of this study was to identify genetic determinants of PBC progression. METHODS: A total of 52 tag single nucleotide polymorphisms (SNPs) of 11 candidate genes involved in regulating bile acid synthesis were analyzed by polymerase chain reaction (PCR)-restriction fragment length polymorphism, -high resolution melting curve analysis, or -direct DNA sequencing in 315 Japanese patients with PBC. RESULTS: In this study, four tag SNPs of CYP7A1 (rs1457043, rs8192870, rs3808607, and rs3824260), two tag SNPs of HNF4A (rs6017340 and 6031587), and one SNP of PPARGC1A (rs8192678) showed a significant association with PBC progression. In addition, a dual luciferase assay revealed that the polymorphism of rs3808607 in CYP7A1 altered the expression of CYP7A1 in HepG2. Specifically, the CYP7A1 promoter carrying the risk G allele for PBC progression induced higher expression of CYP7A1 under both the normal and cholestatic conditions in vitro as compared to another promoter carrying the non-risk T allele. CONCLUSION: These results suggested that the genetic variants of CYP7A1 and its transcriptional activators (HNF4A and PPARGC1A) may activate bile acid synthesis, resulting in the accumulation of bile acids in hepatocytes and eventually leading to the predisposition to PBC progression. Thus, the regulation of CYP7A1 expression may represent an attractive therapeutic target for cholestatic liver diseases including PBC.
Journal of Gastroenterology 01/2013; · 4.16 Impact Factor
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Kiyoshi Migita,
Kazunaga Agematsu,
Junya Masumoto,
Hiroaki Ida,
Seiyo Honda,
Yuka Jiuchi,
Yasumori Izumi,
Yumi Maeda,
Ritei Uehara,
Yoshikazu Nakamura,
Tomohiro Koga,
Atsushi Kawakami,
Munetoshi Nakashima,
Yuichiro Fujieda,
Fumiaki Nonaka,
Katsumi Eguchi,
Hiroshi Furukawa,
Tadashi Nakamura, Minoru Nakamura,
Michio Yasunami
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ABSTRACT: Familial Mediterranean Fever (FMF) has traditionally been considered to be an autosomal-recessive disease, however, it has been observed that substantial numbers of patients with FMF possess only 1 demonstrable MEFV mutation. The clinical profile of familial Mediterranean fever (FMF) may be influenced by MEFV allelic heterogeneity and other genetic and/or environmental factors.
In view of the inflammatory nature of FMF, we investigated whether serum amyloid A (SAA) and interleukin-1 beta (IL-1β) gene polymorphisms may affect the susceptibility of Japanese patients with FMF. The genotypes of the -13C/T SNP in the 5'-flanking region of the SAA1 gene and the two SNPs within exon 3 of SAA1 (2995C/T and 3010C/T polymorphisms) were determined in 83 Japanese patients with FMF and 200 healthy controls. The same samples were genotyped for IL-1β-511 (C/T) and IL-1 receptor antagonist (IL-1Ra) variable number of tandem repeat (VNTR) polymorphisms. There were no significant differences between FMF patients and healthy subjects in the genotypic distribution of IL-1β -511 (C/T), IL-1Ra VNTR and SAA2 polymorphisms. The frequencies of SAA1.1 allele were significantly lower (21.7% versus 34.0%), and inversely the frequencies of SAA1.3 allele were higher (48.8% versus 37.5%) in FMF patients compared with healthy subjects. The frequency of -13T alleles, associated with the SAA1.3 allele in the Japanese population, was significantly higher (56.0% versus 41.0%, p = 0.001) in FMF patients compared with healthy subjects.
Our data indicate that SAA1 gene polymorphisms, consisting of -13T/C SNP in the 5'-flanking region and SNPs within exon 3 (2995C/T and 3010C/T polymorphisms) of SAA1 gene, are associated with susceptibility to FMF in the Japanese population.
PLoS ONE 01/2013; 8(2):e55227. · 4.09 Impact Factor
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Sung Kwan Bae,
Hiroshi Yatsuhashi,
Satoru Hashimoto,
Yasuhide Motoyoshi,
Eisuke Ozawa,
Shinya Nagaoka,
Seigo Abiru,
Atsumasa Komori,
Kiyoshi Migita, Minoru Nakamura,
Masahiro Ito,
Yuzo Miyakawa,
Hiromi Ishibashi
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ABSTRACT: Background: Hepatitis B e antigen (HBeAg) seroconversion is an important hallmark in the natural course of chronic hepatitis B. This study was designed to predict early HBeAg seroconversion within 1 year, by not only biochemical and virological markers, but also pathological parameters in patients with chronic hepatitis B. Material/Methods: In a retrospective cohort study, 234 patients with HBeAg were reviewed for demographic, biochemical, virological and pathological data at the time of liver biopsy. Then, the patients who accomplished HBeAg seroconversion within 1 year thereafter were compared with those who did not, for sorting out factors predictive of early HBeAg seroconversion. Results: Early HBeAg seroconversion occurred in 58 (24.8%) patients. In univariate analysis, factors predictive of early HBeAg seroconversion were: alanine aminotransferase (ALT) (p=0.002), IP-10 (p=0.029), HBsAg (p=0.003), HBeAg (p<0.001), HBV DNA (p=0.001), HBcrAg (p=0.001), core-promoter mutations (p=0.040), fibrosis (p=0.033) and lobular inflammation (p=0.002). In multivariate analysis, only serum HBeAg levels <100 Paul Ehrlich Institute (PEI) U/ml and grades of lobular inflammation ≥2 were independent factors for early HBeAg seroconversion (odds ratio 8.430 [95% confidence interval 4.173-17.032], p<0.001; and 4.330 [2.009-9.331], p<0.001; respectively). Conclusions: HBeAg levels < 100 PEIU/ml combined with grades of lobular inflammation ≥2 are useful for predicting early HBeAg seroconversion. In patients without liver biopsies, high ALT levels (≥200 IU/L) can substitute for lobular inflammation (grades ≥2).
Medical science monitor: international medical journal of experimental and clinical research 12/2012; 18(12):CR698-705. · 1.70 Impact Factor
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Kiyoshi Migita,
Seigo Abiru,
Masashi Ohtani,
Yuka Jiuchi,
Yumi Maeda,
Sung Kwan Bae,
Shigemune Bekki,
Satoru Hashimoto,
Kakharman Yesmembetov,
Shinya Nagaoka, Minoru Nakamura,
Atsumasa Komori,
Tatsuki Ichikawa,
Kazuhiko Nakao,
Hiroshi Yatsuhashi,
Hiromi Ishibashi,
Michio Yasunami
Translational research : the journal of laboratory and clinical medicine. 06/2012;
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Kiyoshi Migita,
Tomohiro Koga,
Kenshi Satomura,
Masahiro Izumi,
Takafumi Torigoshi,
Yumi Maeda,
Yasumori Izumi,
Yuka Jiuchi,
Taiichiro Miyashita,
Satoshi Yamasaki,
Yoshihiro Aiba,
Atsumasa Komori, Minoru Nakamura,
Satoru Motokawa,
Atsushi Kawakami,
Tadashi Nakamura,
Hiromi Ishibashi
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ABSTRACT: Monosodium urate (MSU) has been shown to promote inflammasome activation and interleukin-1β (IL-1β) secretion in monocyte/macrophages, but the cellular pathway and nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation in synovial tissues, remain elusive. In this study, we investigated the effects of MSU on synovial fibroblasts to elucidate the process of MSU-mediated synovial inflammation.
Human synovial fibroblasts were stimulated with MSU in the presence or absence of serum amyloid A (SAA). The cellular supernatants were analyzed by immunoblotting using anti-IL-1β or anti-caspase-1 antibodies. IL-1β or NLRP3 mRNA expressions were analyzed by real-time PCR or reverse transcription-PCR (RT-PCR) method.
Neither SAA nor MSU stimulation resulted in IL-1β or interleukin-1α (IL-1α) secretions and pro-IL-1β processing in synovial fibroblasts. However, in SAA-primed synovial fibroblasts, MSU stimulation resulted in the activation of caspase-1 and production of active IL-1β and IL-1α. The effect of SAA on IL-1β induction was impaired in cells by silencing NLRP3 using siRNA or treating with caspase-1 inhibitor. In addition, SAA induced the secretion of cathepsin B and NLRP3 mRNA expression in synovial fibroblasts.
Our data demonstrate that exposure of human synovial fibroblasts to SAA promotes MSU-mediated caspase-1 activation and IL-1β secretion in the absence of microbial stimulation. These findings provide insight into the molecular processes underlying the synovial inflammatory condition of gout.
Arthritis research & therapy 05/2012; 14(3):R119. · 4.27 Impact Factor
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Kenshi Satomura,
Takafumi Torigoshi,
Tomohiro Koga,
Yumi Maeda,
Yasumori Izumi,
Yuka Jiuchi,
Taiichiro Miyashita,
Satoshi Yamasaki,
Atsushi Kawakami,
Yoshihiro Aiba, Minoru Nakamura,
Atsumasa Komori,
Junji Sato,
Hiromi Ishibashi,
Satoru Motokawa,
Kiyoshi Migita
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ABSTRACT: OBJECTIVE: Pentraxin 3 (PTX3) is an acute-phase reactant that is involved in amplification of the inflammatory response and innate immunity. In the present study, we evaluated the relationship between PTX3 and serum amyloid A (SAA), another acute-phase reactant, in rheumatoid synoviocytes. METHODS: PTX3 mRNA expression was examined by reverse transcription polymerase chain reaction, and PTX3 protein was measured by enzyme-linked immunosorbent assay. RESULTS: SAA induced PTX3 mRNA and PTX3 protein expression in rheumatoid synoviocytes. SAA-induced PTX3 expression was attenuated when rheumatoid synoviocytes were nucleofected with N-formyl peptide receptor ligand-1 (FPRL-1)-specific siRNA, suggesting the involvement of FPRL-1. Furthermore, SAA-induced PTX3 expression was inhibited by NF-κB or mitogen-activated protein kinase-specific inhibitors. Neither soluble TNF receptor (etanercept) nor recombinant IL-1 receptor antagonist affected PTX3 production by SAA-stimulated synoviocytes, suggesting that SAA directly induces PTX3. CONCLUSION: Our data suggest that SAA plays a role in the proinflammatory and immune responses in rheumatoid synovium by inducing PTX3. We provide the first evidence that the acute-phase reactant SAA, which is produced systemically by hepatocytes, perpetuates the rheumatoid inflammatory processes by inducing another proinflammatory molecule, PTX3, locally in rheumatoid synovial tissues.
Modern Rheumatology 03/2012; · 1.58 Impact Factor
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Kiyoshi Migita,
Yukio Watanabe,
Yuka Jiuchi,
Yoko Nakamura,
Akira Saito,
Michiyasu Yagura,
Hajime Ohta,
Masaaki Shimada,
Eiji Mita,
Taizo Hijioka, [......],
Eiichi Takezaki,
Toyokichi Muro,
Hironori Sakai,
Makoto Nakamuta,
Seigo Abiru,
Atsumasa Komori,
Masahiro Ito,
Hiroshi Yatsuhashi, Minoru Nakamura,
Hiromi Ishibashi
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ABSTRACT: Although the outcome of autoimmune hepatitis (AIH) is generally good, the natural course and likelihood of progression to cirrhosis or hepatocellular carcinoma (HCC) remain undefined, and may vary by region and population structure. Our aims were to evaluate risk factors that contribute to poor outcome and particularly development of HCC in a prospective multicentric cohort study of AIH.
The study group comprised 193 Japanese patients with AIH who were prospectively followed up at annual intervals between 1995 and 2008. The mean follow-up period was 8.0 ± 4.5 years.
Twenty-one (10.9%) patients had cirrhosis at presentation and a further 15 (7.8%) developed cirrhosis during the follow-up period. Survival rates were 94.2% at 10 years and 89.3% at 15 years. HCC was diagnosed in seven of the 193 patients. The presence of cirrhosis at presentation was a risk factor for HCC according to a Cox proportional hazard model, and the HCC-free survival rate was significantly lower in those with cirrhosis compared to those without cirrhosis according to Kaplan-Meier analysis.
Although the outcome of AIH is as good if not better among Japanese than for other populations, there was an increased risk of HCC in these patients. Cirrhosis at presentation was predictive of development of HCC in AIH in Japan.
Liver international: official journal of the International Association for the Study of the Liver 12/2011; 32(5):837-44. · 3.82 Impact Factor
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Kiyoshi Migita,
Taiichiro Miyashita,
Yasumori Izumi,
Tomohiro Koga,
Atsumasa Komori,
Yumi Maeda,
Yuka Jiuchi,
Yoshihiro Aiba,
Satoshi Yamasaki,
Atsushi Kawakami, Minoru Nakamura,
Hiromi Ishibashi
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ABSTRACT: The new JAK3 inhibitor, CP690,550, has shown efficacy in the treatment of rheumatoid arthritis. The present study was undertaken to assess the effects of CP690,550 on cytokine production and cellular signaling in human CD4(+) T cells.
CD4(+) T cells produced IL-2, IL-4, IL-17, IL-22 and IFN-γ in following stimulation with a CD3 antibody. At the optimal concentration, CP690,550 almost completely inhibited the production of IL-4, IL-17, IL-22 and IFN-γ from these activated CD4(+) T cells, but only had marginal effects on IL-2 production. Moreover CP690,550 inhibited anti-CD3-induced phosphorylation of STAT1, STAT3, STAT4, STAT5, and STAT6, but not the TCR-associated phosphorylation of ZAP-70.
Therefore, CP690,550-mediated modification of the JAK/STAT pathway may be a new immunosuppressive strategy in the treatment of autoimmune diseases.
BMC Immunology 08/2011; 12:51. · 2.53 Impact Factor
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Kiyoshi Migita,
Tomohiro Koga,
Atsumasa Komori,
Takafumi Torigoshi,
Yumi Maeda,
Yasumori Izumi,
Junji Sato,
Yuka Jiuchi,
Taiichiro Miyashita,
Satoshi Yamasaki,
Atsushi Kawakami, Minoru Nakamura,
Satoru Motokawa,
Hiromi Ishibashi
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ABSTRACT: Inhibition of intracellular signal transduction is considered to be a therapeutic target for chronic inflammation. The new Janus kinase (JAK)3 inhibitor CP690,550 has shown efficacy in the treatment of rheumatoid arthritis (RA). We investigated the influence of JAK/STAT inhibition using CP690,550 on the induction of acute-phase serum amyloid A (SAA), which is triggered by interleukin 6 (IL-6) stimulation in rheumatoid fibroblast-like synoviocytes (RA-FLS).
IL-6-stimulated gene expression of the acute-phase serum amyloid A genes (A-SAA; encoded by SAA1+SAA2) and SAA4 was analyzed by reverse transcriptase-polymerase chain reaction. The intracellular signaling pathway mediating the effects of CP690,550 on IL-6-stimulated JAK/STAT activation was assessed by measuring the phosphorylation levels using Western blots.
IL-6 trans-signaling induced A-SAA messenger RNA (mRNA) expression in RA-FLS. By contrast IL-6 stimulation did not affect SAA4 mRNA expression, which is expressed constitutively in RA-FLS. IL-6 stimulation elicited rapid phosphorylation of JAK2 and STAT3, which was blunted by CP690,550. CP690,550 abrogated IL-6-mediated A-SAA mRNA expression in RA-FLS. Similarly, CP690,550 inhibited IL-6-mediated A-SAA mRNA expression in human hepatocytes.
Our data indicated that CP690,550 blocked IL-6-induced JAK2/STAT3 activation, as well as the induction of A-SAA. Inhibition of IL-6-mediated proinflammatory signaling pathways by CP690,550 may represent a new antiinflammatory therapeutic strategy for RA and AA amyloidosis.
The Journal of Rheumatology 08/2011; 38(11):2309-17. · 3.69 Impact Factor
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Yoshihiro Aiba, Minoru Nakamura,
Satoru Joshita,
Tatsuo Inamine,
Atsumasa Komori,
Kaname Yoshizawa,
Takeji Umemura,
Hitomi Horie,
Kiyoshi Migita,
Hiroshi Yatsuhashi, [......],
Toshiki Komeda,
Masaaki Shimada,
Naohiko Masaki,
Tatsuji Komatsu,
Michiyasu Yagura,
Kazuhiro Sugi,
Michiaki Koga,
Kazuhiro Tsukamoto,
Eiji Tanaka,
Hiromi Ishibashi
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ABSTRACT: Anti-gp210 and anti-centromere antibodies are different risk factors for the progression of primary biliary cirrhosis (PBC). In order to dissect the genetic basis for the production of these autoantibodies, as well as the development and progression of PBC in Japanese patients, we examined single nucleotide polymorphisms (SNPs) in cytotoxic T-lymphocyte antigen 4 (CTLA4) and solute carrier family 4 anion exchanger, member 2 (SLC4A2), which have been associated with the pathogenesis of PBC in Caucasian patients.
Four SNPs for both CTLA4 and SLC4A2 were genotyped, using the polymerase chain reaction-restriction fragment length polymorphism method and TaqMan assay, in 450 Japanese PBC patients and 371 sex-matched healthy controls.
The CTLA4 rs231775, rs3087243, and rs231725 SNPs were significantly associated with PBC susceptibility. The CTLA4 rs231725 SNP was significantly associated with progression to late-stage disease. The CTLA-4 haplotype 1 (rs231775 G, rs231777 C, rs3087243 G, rs231725 A; GCGA) was a risk factor for PBC susceptibility but a protective factor for PBC progression. Conversely, the CTLA-4 haplotype 2 (ACAG) was a protective and risk factor, respectively, for PBC susceptibility and progression. In addition, the CTLA4 rs231777 SNP and haplotype 3 (ATGG) was significantly associated with anti-gp210 antibody production, while SLC4A2 haplotype 4 (rs2069443 A, rs2303933 G, rs2303937 A, rs2303941 T; AGAT) and haplotype 3 (AAGC) were significantly associated with PBC susceptibility and anti-centromere antibody production, respectively.
CTLA4 and SLC4A2 genetic polymorphisms are differentially associated with PBC development and progression, as well as anti-gp210 or anti-centromere antibody production, in Japanese PBC patients.
Journal of Gastroenterology 05/2011; 46(10):1203-12. · 4.16 Impact Factor
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ABSTRACT: Interleukin (IL)-6-type cytokines exert their effects through activation of the Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling cascade. The JAK/STAT pathways play an important role in rheumatoid arthritis, since JAK inhibitors have exhibited dramatic effects on rheumatoid arthritis (RA) in clinical trials. In this study, we investigated the molecular effects of a small molecule JAK inhibitor, CP690,550 on the JAK/STAT signaling pathways and examined the role of JAK kinases in rheumatoid synovitis.
Fibroblast-like synoviocytes (FLS) were isolated from RA patients and stimulated with recombinant oncostatin M (OSM). The cellular supernatants were analyzed using cytokine protein chips. IL-6 mRNA and protein expression were analyzed by real-time PCR method and ELISA, respectively. Protein phosphorylation of rheumatoid synoviocytes was assessed by Western blot using phospho-specific antibodies.
OSM was found to be a potent inducer of IL-6 in FLS. OSM stimulation elicited rapid phosphorylation of STATs suggesting activation of the JAK/STAT pathway in FLS. CP690,550 pretreatment completely abrogated the OSM-induced production of IL-6, as well as OSM-induced JAK/STAT, and activation of mitogen-activated kinases (MAPKs) in FLS.
These findings suggest that IL-6-type cytokines contribute to rheumatoid synovitis through activation of the JAK/STAT pathway in rheumatoid synoviocytes. Inhibition of these pro-inflammatory signaling pathways by CP690,550 could be important in the treatment of RA.
Arthritis research & therapy 05/2011; 13(3):R72. · 4.27 Impact Factor
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ABSTRACT: The natural history of the disease varies greatly among individual patients with primary biliary cirrhosis (PBC). Some patients live long without any symptoms while other patients present jaundice and develop hepatic failure in early phases of the disease. Previous studies showed that the natural course of PBC is altered by the use of ursodeoxy cholic acid (UDCA). In this review we discuss variation in the natural course of the disease and it's alteration by UDCA, and risk factors that predict disease progression. Based on clinical observations, there are three types of clinical evolution in PBC: 1) minimal to slow progression over several years; 2) rapid progression to jaundice and hepatic failure, and 3) progression to portal hypertension without developing deep jaundice. Notably, based on our analyses accelerated progression to jaundice and liver failure are reflected by a sustained serologic presence of anti-gp210 antibodies whereas patients with portal hypertension in the absence of jaundice have anti-centromere autoantibodies. These observations highlight the clinical importance of antinuclear antibody analysis in patients with PBC.
Internal Medicine 01/2011; 50(1):1-10. · 0.94 Impact Factor
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Masakuni Tateyama,
Hiroshi Yatsuhashi,
Naota Taura,
Yasuhide Motoyoshi,
Shinya Nagaoka,
Kenji Yanagi,
Seigo Abiru,
Koji Yano,
Atsumasa Komori,
Kiyoshi Migita, Minoru Nakamura,
Hiroyasu Nagahama,
Yutaka Sasaki,
Yuzo Miyakawa,
Hiromi Ishibashi
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ABSTRACT: Noninvasive risk factors are required for predicting the development of hepatocellular carcinoma (HCC) not only in patients with cirrhosis but also in those with chronic hepatitis who are infected with hepatitis C virus (HCV).
A total of 707 patients with chronic HCV infection without other risks were evaluated for the predictive value of noninvasive risk factors for HCC, including age, sex, viral load, genotype, fibrosis stage, aspartate and alanine aminotransferase levels, bilirubin, albumin, platelet count, and alpha-fetoprotein (AFP) at entry to the study, as well as interferon (IFN) therapy they received.
The ten-year cumulative incidence rates of HCC for patients with fibrosis stages F0/F1, F2, F3, and F4 were 2.5, 12.8, 19.3, and 55.9%, respectively. Multivariate analysis identified age ≥57 years [hazard ratio (HR) 2.026, P = 0.004], fibrosis stage F4 (HR 3.957, P < 0.001), and AFP 6-20 ng/mL (HR 1.942, P = 0.030) and ≥20 ng/mL (HR 3.884, P < 0.001), as well as the response to IFN [relative risk (RR) 0.099, P < 0.001], as independent risk factors for the development of HCC. The ten-year cumulative incidence rates of HCC in the patients with AFP levels of <6, 6-20, and ≥20 ng/mL at entry were 6.0, 24.6, and 47.3%, respectively.
Not only high (>20 ng/mL), but also even slightly elevated (6-20 ng/mL) AFP levels, could serve as a risk factor for HCC to complement the fibrosis stage. In contrast, AFP levels <6 ng/mL indicate a low risk of HCC development in patients infected with HCV, irrespective of the fibrosis stage.
Journal of Gastroenterology 01/2011; 46(1):92-100. · 4.16 Impact Factor
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Tatsuo Inamine, Minoru Nakamura,
Ayumi Kawauchi,
Yayoi Shirakawa,
Hisae Hashiguchi,
Yoshihiro Aiba,
Akinobu Taketomi,
Ken Shirabe,
Makoto Nakamuta,
Shigeki Hayashi,
Takeo Saoshiro,
Atsumasa Komori,
Hiroshi Yatsuhashi,
Shinji Kondo,
Katsuhisa Omagari,
Yoshihiko Maehara,
Hiromi Ishibashi,
Kazuhiro Tsukamoto
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ABSTRACT: Accumulating evidence indicates that multiple genetic factors are involved in the pathogenesis of primary biliary cirrhosis (PBC). The aim of this study was to investigate whether polymorphisms of the integrin αV subunit gene (ITGAV), a component of integrin αVβ6, which plays an important role in the process of fibrosis, are associated with susceptibility to the onset and/or progression of PBC.
In the primary study, eight tag single nucleotide polymorphisms (SNPs) in ITGAV were analyzed by polymerase chain reaction (PCR)-restriction fragment length polymorphism, direct DNA sequencing, or high-resolution melting curve analysis in 309 Japanese patients with PBC who were registered in the National Hospital Organization Study Group for Liver Disease in Japan (PBC cohort I) and 293 gender-matched healthy Japanese volunteers (control subjects). For the replication study, 35 PBC patients who progressed to end-stage hepatic failure and underwent liver transplantation (PBC cohort II) were also analyzed.
Three tag SNPs (rs3911238, rs10174098, and rs1448427) in ITGAV were significantly associated with the severe progression of PBC, but not with susceptibility to the onset of PBC, in the primary study (PBC cohort I). Among these SNPs, rs1448427 was also significantly associated with the severe progression to end-stage hepatic failure in the replication study of PBC patients who underwent liver transplantation (PBC cohort II).
ITGAV is a genetic determinant for the severe progression of PBC in Japanese patients. Genetic polymorphisms of ITGAV may be useful for identifying high-risk Japanese PBC patients, including those who will require liver transplantation, at the time of initial diagnosis.
Journal of Gastroenterology 12/2010; 46(5):676-86. · 4.16 Impact Factor
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Kiyoshi Migita,
Yukio Watanabe,
Yuka Jiuchi,
Yoko Nakamura,
Akira Saito,
Michiyasu Yagura,
Hideo Morimoto,
Masaaki Shimada,
Eiji Mita,
Taizo Hijioka, [......],
Eiichi Takezaki,
Toyokichi Muro,
Hironori Sakai,
Makoto Nakamuta,
Seigo Abiru,
Koji Yano,
Atsumasa Komori,
Hiroshi Yatsuhashi, Minoru Nakamura,
Hiromi Ishibashi
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ABSTRACT: Autoimmune hepatitis (AIH) is a chronic and progressive liver disease characterized by histological interface hepatitis and circulating autoantibodies. Our aims were to evaluate risk factors that contribute to the outcome and, particularly, the development of liver cirrhosis in a prospective multicenter cohort study of AIH. One hundred and seventy-four patients were enrolled. Histologically 21 (12.1%) had cirrhosis at the initial observation and the remaining 153 showed chronic or acute hepatitis at presentation. Among the latter 153 patients, 14 developed cirrhosis during the follow-up period (mean 8.0 years). Demographic, clinical, and laboratory indices associated with the development of cirrhosis were identified. Patients who developed cirrhosis differed in mean levels of alanine aminotransferase (ALT; 158 ± 182 vs. 441 ± 423 IU/ml) and platelet counts (14.7 ± 5.5 vs. 19.4 ± 6.9 × 10(4)/μl) at presentation and received lower doses of corticosteroid (13.9 ± 15.8 vs. 31.8 ± 85.5 mg/day). In a multivariate analysis, an independent predictor for progression to cirrhosis was an older age of onset (≥ 60 years). AIH patients with cirrhosis, or those who developed cirrhosis, had a worse survival. AIH patients with an older age of onset were likely to develop cirrhosis, and careful observation and aggressive treatments are necessary for such patients.
Journal of Gastroenterology 11/2010; 46 Suppl 1:56-62. · 4.16 Impact Factor
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ABSTRACT: Primary biliary cirrhosis (PBC) is an organ-specific autoimmune disease of still unidentified genetic etiology that is characterized by chronic inflammation of the liver. Since cytotoxic T-lymphocyte antigen 4 (CTLA4) polymorphisms have recently been linked with PBC susceptibility in studies on Caucasians, we investigated the genetic association between CTLA4 polymorphisms and PBC in a Japanese population.
Five single nucleotide polymorphisms (SNPs) in the CTLA4 gene (rs733618, rs5742909, rs231775, rs3087243, and rs231725) were genotyped in 308 patients with PBC and 268 healthy controls using a TaqMan assay.
One CTLA4 gene SNP (rs231725) was significantly associated with susceptibility to anti-mitochondrial antibody (AMA)-positive PBC, but clinical significance disappeared after correction for multiple testing. Moreover, CTLA4 gene SNPs did not influence AMA development or disease progression to orthotopic liver transplantation in our Japanese cohort. In haplotype analyses, one haplotype [haplotype 1 (CGGA)] at rs5742909, rs231775, rs3087243, and rs231725, was significantly associated with susceptibility to both AMA-positive PBC and overall PBC.
This study showed that CTLA4 gene polymorphisms had a modest, but significant association with susceptibility to PBC in the Japanese population. The connection between genetic variants and the function of the CTLA4 gene remains to be addressed in future investigations.
Journal of Hepatology 09/2010; 53(3):537-41. · 9.26 Impact Factor
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Minoru Nakamura,
Michio Yasunami,
Hisayoshi Kondo,
Hitomi Horie,
Yoshihiro Aiba,
Atsumasa Komori,
Kiyoshi Migita,
Hiroshi Yatsuhashi,
Masahiro Ito,
Shinji Shimoda,
Hiromi Ishibashi
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[hide abstract]
ABSTRACT: Aims: Anti-gp210 and anti-centromere antibodies are different risk factors for the progression of primary biliary cirrhosis (PBC). However, the association of human leukocyte antigen (HLA) polymorphisms with these risk factors is unknown. Methods: We determined the HLA-DRB1 genotype in 334 Japanese PBC patients and studied their serum antibodies to gp210 and centromere during the 1-452-month observation period. Results: Anti-gp210 (odds ratio [OR] 46.56, 95% confidence interval [CI], 9.20-850.1) and anti-centromere antibodies (OR, 2.36, 95% CI, 1.28-4.35) were significant risk factors for jaundice- and nonjaundice-type progression, respectively. HLA-DRB1*0405 and *0803 predisposed patients to anti-gp210 (OR, 1.61, 95% CI, 1.08-2.39) and anti-centromere (OR, 2.30, 95% CI, 1.41-3.73) antibody production, respectively. HLA-DRB1*1502 and *0901 patients were predisposed to nonjaundice-type progression (OR, 1.98, 95% CI, 1.13-3.40 and OR, 1.78, 95% CI, 1.02-3.03), while HLA-DRB1*0803 and *0405 patients were predisposed to disease development (OR, 2.24, 95% CI, 1.48-3.41 and OR, 1.53, 95% CI, 1.11-2.11, respectively). Stratifying patients by HLA-DRB1 alleles revealed that anti-gp210 antibodies was a strong risk factor, regardless of the HLA-DRB1 alleles for jaundice-type progression, while anti-centromere antibodies was a significant risk factor for nonjaundice-type progression in patients with HLA-DRB1*0405 (OR, 6.89, 95% CI, 2.18-26.56) and -DRB1*0803 (OR, 5.42, 95% CI, 1.47-24.62) but not other HLA-DRB1 alleles. Conclusions: HLA-DRB1 polymorphisms are significantly associated with not only disease development and progression but also antinuclear antibody production and the determination of the relative risk of antinuclear antibodies that contribute to PBC disease progression.
Hepatology Research 03/2010; 40(5):494-504. · 2.20 Impact Factor
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Kiyoshi Migita,
Bibigul Ilyassova,
Elena F Kovzel,
Alexander Nersesov,
Seigo Abiru,
Yumi Maeda,
Atsumasa Komori,
Masahiro Ito,
Koji Yano,
Hiroshi Yatsuhashi,
Shinji Shimoda,
Hiromi Ishibashi, Minoru Nakamura
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ABSTRACT: B-cell-activating factor belonging to the TNF family (BAFF) and a proliferation-inducing ligand (APRIL) are known to be involved in the occurrence of autoimmune diseases. We assessed serum levels of these cytokines in PBC patients. Serum BAFF levels were significantly higher in PBC patients than in healthy controls (1253.9+/-741.4 vs. 722.8+/-199.2 pg/ml; p<0.0001) and HCV-infected patients (1253.9+/-741.4 vs. 871.0+/-251.1 pg/ml; p=0.015). Whereas changes in serum APRIL levels were not significant among these groups, there was a significant correlation between BAFF and AST (R=0.278, p=0.003) or total bilirubin (R=0.363, p=0.0006) in PBC patients. Furthermore, serum BAFF levels were elevated in PBC patients with advanced interface hepatitis. Our data indicate that serum levels of BAFF and APRIL are differentially regulated and serum BAFF levels are significantly elevated in PBC patients. These findings suggest that BAFF may serve as a modulator of the clinical and/or serological manifestation in PBC patients.
Clinical Immunology 10/2009; 134(2):217-25. · 4.05 Impact Factor
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Kiyoshi Migita,
Tomohiro Koga,
Takafumi Torigoshi,
Yumi Maeda,
Taichiro Miyashita,
Yasumori Izumi,
Yoshihiro Aiba,
Atsumasa Komori, Minoru Nakamura,
Satoru Motokawa,
Hiromi Ishibashi
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ABSTRACT: Although serum amyloid A (SAA) has been used as a marker of inflammation, its role in leucocyte recruitment and angiogenesis has not been well established in RA. CCL20 is a chemokine involved in the migration of CCR6-expressing Th17 cells. To study the contribution of SAA to the recruitment of Th17 cells, we investigated the effects of SAA on CCL20 production by RA synoviotytes.
Synoviocytes isolated from RA patients were stimulated with recombinant SAA and cellular supernatants were analysed by CCL20-specific ELISA. CCL-20 mRNA expression was analysed by RT-PCR.
SAA is a most potent inducer of CCL20 secretion in RA synoviocytes compared with other inflammatory cytokines (IL-1beta, TNF-alpha and IL-17A). SAA stimulation induced CCL20 mRNA expression in RA synoviocytes, which was not affected by polymyxin B pre-treatment. SAA-induced CCL20 production was down-regulated by NF-kappaB inhibition and partially by c-jun N-terminal kinase (JNK) inhibition. SAA-induced CCL20 production was also suppressed by dexamethasone or FK506.
These findings suggest that SAA may be implicated in the recruitment of lymphocytes, including CCR6-expressing Th17 cells, in RA synovium by up-regulating CCL20 production in synoviocytes.
Rheumatology (Oxford, England) 06/2009; 48(7):741-7. · 4.24 Impact Factor
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ABSTRACT: The liver is an organ consisting of the largest reticulo-endothelial cell network in the body and playing an important role in host defense against invading microorganisms. The organ is comprised of parenchymal cells and many different types of non-parenchymal cells, all of which play a significant role. Even biliary epithelial cells are not only the target in autoimmune liver diseases but also have central role in orchestrating several immune cells involved in both innate and acquired immunity. Tissue damage caused by various agents results in inflammation, necrosis, fibrosis, and, eventually, distortion of normal hepatic architecture, cirrhosis, and functional deterioration.
Seminars in Immunopathology 06/2009; 31(3):399-409. · 6.27 Impact Factor
