Collagen degradation and in the pathogenesis of dieseases

組織のコラーゲン沈着にはコラーゲン合成系と分解系の不均衡によって生ずる｡従来,主としてコラーゲン合成系が注目されていたが,最近の研究の進歩により,コラーゲン分解系が重要な役割を演ずることが明らかになってきた｡コラーゲンの分解系には細胞内と細胞外の二つの経路が存在する｡それぞれcollagenolytic cathepsinおよびmatrix metalloproteinases( MMP)がコラーゲン分解能を有する重要な酵素である｡その調節因子については細胞外の経路についての解明か進んでいる｡MMPの遺伝子の発現にはサイトカインや成長因子が関与し,IL-1やTNF-αは強力な誘導因子である｡一旦,遺伝子か発現すれば,MMPは合成され,細胞外に不活性型(latent form)で分泌される｡不活性型のMMPが活性化する過程にはplasminogen activator inhibitorやtissue inhibitors of metalloproteinases(TIMP)などの阻害因子が存在し,MMP活性を調節する｡TIMPの遺伝子の発現にもサイトカインや成長因子が関与する｡MMPがTIMPを上回るような病態では組織破壊が,逆にTIMPがMMPを上回るような病態では綿維化が生ずる｡コラーゲン分解能の障害が線維化の維持や不可逆性に関与することが推察される。Fibrosis is the result of net accumulation of collagen in the organ. This may occur as a consequence of alterations in the synthesis of collagen, their degradation, or both. Recent investigations revealed that a decrease in collagen degradation plays a crucial role in fibrogenesis. Two pathways exist in collagen degradation : extracellular and intracellular. Each pathway has an important enzyme; that is, matrix metalloproteinases (MMP) and collagenolytic cathepsin, respectively. Collagenolytic activity is regulated at several levels. Expression of MMP and tissue inhibitors of metalloproteinase (TIMP), which act as inhibitors of MMP, is regulated independently by a number of cytokines and growth factors. MMP, which is synthesized in the cell, is secreted in a latent form. Activation of the latent MMP is controlled by TIMP and plasminogen activator inhibitor. TIMP also inhibits activated MMP which can degrade connective tissue matrices including collagens. In the condition where TIMP is predominant over MMP, activity of collagen breakdown is reduced, and consequently collagen deposition occurrs

HLA-DRB1 and DQB1 alleles in Japanese type 1 autoimmune hepatitis: The predisposing role of the DR4/DR8 heterozygous genotype

ObjectiveAutoimmune hepatitis (AIH) is a chronic progressive liver disease. AIH is composed predominantly of type 1 in Japanese populations. The genetic and environmental factors are associated with the pathogenesis of AIH. HLA-DRB1*03:01 and *04:01 are associated with type 1 AIH in European and *04:05 in Japanese populations. Here, we conducted an HLA association study in order to find HLA alleles or haplotypes predisposing or protective for Japanese AIH.MethodsHLA-DRB1 and DQB1 genotyping of 360 type 1 AIH patients and 1026 healthy controls was performed.ResultsThe predisposing association of DRB1*04:01 (P = 0.0006, corrected P [Pc] = 0.0193, odds ratio [OR] 2.97, 95% confidence interval [CI] 1.62–5.43), DRB1*04:05 (P = 1.89×10−21, Pc = 5.86×10−20, OR 3.41, 95% CI 2.65–4.38), and DQB1*04:01 (P = 4.66×10−18, Pc = 6.99×10−17, OR 3.89, 95% CI 2.84–5.33) and the protective association of DRB1*13:02 (P = 0.0003, Pc = 0.0080, OR 0.48, 95% CI 0.32–0.72) with Japanese type 1 AIH were observed. An association of the DR4/DR8 heterozygous genotype with Japanese AIH was identified for the first time (P = 3.12×10−9, OR 3.52, 95% CI 2.34–5.29). Susceptible diplotypes were DRB1*04:05-DQB1*04:01/DRB1*08:02-DQB1*03:02 (P = 0.0004, OR 24.77, 95% CI 1.45–424.31) and DRB1*04:05-DQB1*04:01/DRB1*08:03-DQB1*06:01 (P = 1.18×10−6, OR 10.64, 95% CI 3.19–35.46). Serum levels of Immunoglobulin G and Immunoglobulin M, International Autoimmune Hepatitis Group score, positive rate of anti-smooth muscle antibodies, and the rate of definite AIH were higher in AIH patients with DRB1*04:05 than without.ConclusionsThe important roles of specific combinations of DRB1 and DQB1 alleles or haplotypes in the pathogenesis of type 1 AIH were suggested. The association of DR4/DR8 heterozygous genotype suggested the pathologic importance of trans-complementing DQα-β heterodimer molecules encoded by DQA1 allele of one haplotype and the DQB1 allele of the other haplotype, as it was proposed in the HLA association studies of Type 1 diabetes

Lack of association between the CARD10 rs6000782 polymorphism and type 1 autoimmune hepatitis in a Japanese population

Background: Previous genome-wide association studies have evaluated the impact of common genetic variants and identified several non-HLA risk loci associated with autoimmune liver diseases. More recent genome-wide association studies and replication analyses reported an association between variants of the CARD10 polymorphism rs6000782 and risk of type 1 autoimmune hepatitis (AIH). In this case-control study, we genotyped 326 Japanese AIH patients and 214 control subjects. Results: Genomic DNA from 540 individuals of Japanese origin, including 326 patients with type-1 AIH and 214 healthy controls, was analyzed for two single nucleotide polymorphisms (SNPs) in the CARD10 gene. We selected CARD10 rs6000782 SNPs and genotyped these using PCR-RFLP method and direct sequencing. The Chi square test revealed that the rs6000782 variant alle (c) was not associated with the susceptibility for AIH in a Japanese population [p = 0.376, odds ratio (OR) 1.271, 95 % confidence interval (CI) 0.747-2.161] in an allele model. Our data also showed that CARD10 rs6000782 variants were not associated with AIH or with the clinical parameters of AIH. Conclusions: In this study we examined an association between rs6000782 SNPs in the CARD10 gene and type-1 AIH. Results showed no significant association of rs62000782 with type-1 AIH in a Japanese population. This study demonstrated no association between CARD10 rs6000782 variants and AIH in a Japanese population

Probing subpicosecond dynamics using pulsed laser combined scanning tunneling microscopy

Time-resolved tunneling current measurement in the subpicosecond range was realized by ultrashort-pulse laser combined scanning tunneling microscopy, using the shaken-pulse-pair method. A low-temperature-grown GaN_[x]As_[1-x] (x=0.36%) sample exhibited two ultrafast transient processes in the time-resolved tunnel current signal, whose lifetimes were determined to be 0.653±0.025 and 55.1±5.0 ps. These values are of the same order of magnitude as those measured in the conventional pump-probe reflectivity measurement

Stability and nuclear formation of Si(111)-7 x 7 structure as determined from charge redistribution in surface layers

Abstract By considering the charge transfer from adatoms to rest atoms, the structure of the dimer and stacking-fault (DS) layers in the Si(111) dimer-adatom-stacking-fault (DAS ) structure was analyzed at a subunit level on a quenched surface. In comparison with the modified model of Vanderbilt, corner holes with a completed DS structure in the second layer, completed corner holes, were confirmed to play a key role not only in the mechanism to stabilize the DAS structure, but also in its formation process. The formation of the completed corner hole works as a rate-limiting process for the growth of the DAS structure. This mechanism was shown to be quite consistent with the experimental results obtained using scanning tunneling microscopy on the quenched Si(111) surface

Data from: New endoscopic finding of esophageal achalasia with ST Hood short type: corona appearance

Background and Study Aims: Detecting esophageal achalasia remains a challenge. We describe the diagnostic utility of corona appearance, a novel endoscopic finding specific to esophageal achalasia. Patients and Methods: Corona appearance and seven conventional endoscopic findings were compared for sensitivity and consistency (-value) among 53 untreated esophageal achalasia patients who underwent endoscopy at our hospital. The following criteria had to be met during lower esophageal sphincter examination using the attached ST Hood short-type for positive corona appearance: A) congestion inside the hood, B) ischemic change around the hood, and C) palisade vessels outside the hood. Results: Corona appearance had the highest sensitivity (91%; -value, 0.71). Other findings in descending order of sensitivity included 1) functional stenosis of the esophagogastric junction (EGJ; 86%; -value, 0.58), 2) mucosal thickening and whitish change (71%; -value, 0.27), 3) abnormal contraction of the esophageal body (59%; -value, 0.32), 4) dilation of the esophageal lumen (58%; -value, 0.53), 5) liquid remnant (57%; -value, 0.51), 6) Wrapping around EGJ (49%; -value, 0.14), and 7) food remnant (30%; -value, 0.88). Even in 22 patients with poor (grade 1) intraluminal expansion, corona appearance had highest sensitivity (88%) compared to other endoscopic findings (-value, 0.63). Conclusions: Among endoscopic findings using a ST Hood short-type to diagnose esophageal achalasia, corona appearance had the highest sensitivity and its consistency (-value) among endoscopists was substantial compared to other endoscopic findings. Similar results were obtained for esophageal achalasia cases with poor expansion. Endoscopic diagnosis of esophageal achalasia with hood attached is useful