Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019163 (hepatitis B)
 38,309 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pathogenesis and perpetuation of hepatocellular injury in hepatitis C viral infection remains unclear. It has been proposed that a direct viropathic effect, the host immune response, or both mediate cell damage. To address this issue, the immunophenotype of the inflammatory infiltrate in the liver of 18 patients with abnormal liver function tests and serologically detectable hepatitis C virus antibodies was compared with seven control patients (three cases with hepatitis B virus infection, two with alcoholic hepatitis, and one patient each with primary biliary cirrhosis and autoimmune hepatitis). The immunohistochemical markers included UCHL1, L26, Ham-56, Mac-387, CD68, Leu-M1, and cathepsin B. We found that T cells represent the predominant cell type in both histopathologic patterns of hepatitis C, ie, chronic active hepatitis and chronic persistent hepatitis, but the intensity of the T-cell infiltrate displayed marked differences. B-cell infiltrates were only seen in the germinal centers of lymphoid follicles in portal tracts. Furthermore, significant numbers of CD68-positive macrophages/monocytes were seen in the more aggressive form of hepatitis C viral infection. These data suggest that the T-lymphocyte-mediated host immune response is similar in chronic active and chronic persistent hepatitis patterns of hepatitis C viral infection, but varies in its intensity. In addition, macrophages/monocytes may play a role in hepatocyte and bile duct injury in chronic hepatitis C.
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PMID:Chronic hepatitis C. Analysis of host immune response by immunohistochemistry. 753 56

Cellular and humoral immune responses to vaccines of hepatitis B and rabies as antigens were suppressed by specific inhibitors of cathepsin B, anti-cathepsin B antibody and the specific substrate of cathepsin B. The antigenic peptides of these vaccines are processed by cathepsin B and the fragments are capable of binding with the desetope of MHC class II, beta-chain, because one of the active sites of cathepsin B (14, 15) VN217-222 shares high homology with a part of the desetope, VN57-62, of MHC class II, beta-chain. Rechallenge of the synthesized antigenic peptides of these vaccine molecules shows a strong proliferative response to the splenocyte primed by these vaccines. However, the response to these antigenic peptides was not inhibited by cathepsin B inhibitors. These findings suggest that cathepsin B inhibitors do not inhibit any other processes of immune responses than the proteolytic processing of antigens. Some investigators reported recently that the Ii-chain is degraded by purified cathepsin B in vitro (23-25). However, we showed that the suppression of these immune responses by cathepsin B inhibitors is not due to the inhibition of invariant chain degradation. We found that the invariant chain shares about 40% homology with the cystatin family which are the endogenous inhibitors of cysteine proteases (23, 24). Therefore, the Ii-chain is one of the members of the cystatin superfamily and may participate in the regulation of presentation of antigenic peptides and also antigen processing by cathepsin B.
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PMID:Mechanism and regulation of antigen processing by cathepsin B. 794 72

Cellular and humoral immune responses to vaccines of hepatitis B type and rabies were inhibited by specific inhibitors of cathepsin B, specific synthetic substrates of cathepsin B and anti-cathepsin B antibody. Therefore the lysosomal cathepsin B of antigen presenting cells plays an essential role in processing of these antigens for presentation to MHC class II. One of the active sites of cathepsin B, VN217-222 shares highly homologous sequences with a part of the desetope, a binding domain of antigenic peptides, VN57-62 of MHC class II, beta-chain. This evidence suggests that the peptides processed by the substrate specificity of cathepsin B exhibit a common affinity to bind with the desetope of MHC class II, beta-chain.
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PMID:Participation of cathepsin B in processing of antigen presentation to MHC class II. 840 75

Eleven human cathepsins have been identified, however, the in vivo roles of individual cathepsins are still largely unknown. In this brief review we will summarize the functions of individual cathepsins in antigen processing and presentation, which are the initial steps of the immune response. Two general inhibitors of papain-like cysteine proteases, E-64 and pyridoxal phosphate, can completely suppress antigen presentation in vivo. To evaluate the contribution of individual cathepsins, specific inhibitors have been developed based on cathepsin tertiary structures: CA-074 for cathepsin B, CLIK-148 and -195 for cathepsin L, CLIK-60 for cathepsin S. Administration of CA-074, a cathepsin B inhibitor, suppresses the response to exogenous antigens, such as hepatitis B virus antigen, ovalbumin and Leishmania major antigen, and induces switching of the helper T cell responses from Th-2 to Th-1 of CD4+ T cells, thereby downregulating the production of IgE and IgG1. Administration of the cathepsin S inhibitor CLIK-60 impairs presentation of an autoantigen, alpha-fodrin, in Sjogren's syndrome and suppresses the Th-1 response and autoantibody production.
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PMID:Insights into the roles of cathepsins in antigen processing and presentation revealed by specific inhibitors. 1288 55

The hepatitis B virus (HBV) core particle serves as a protective capsid shell for the viral genome and is highly immunogenic. Recombinant capsid-like core particles are used as effective carriers of foreign T and B cell epitopes and as delivery vehicles for oligonucleotides. The core monomer contains an arginine-rich C terminus that directs core particle attachment to cells via membrane heparan sulfate proteoglycans. Here we investigated the mechanism of recombinant core particle uptake and its intracellular fate following heparan sulfate binding. We found that the core particles are internalized in an energy-dependent manner. Core particle uptake is inhibited by chlorpromazine and by cytosol acidification known to block clathrin-mediated endocytosis but not by nystatin, which blocks lipid raft endocytosis. Particle uptake is abolished by expression of dominant negative forms of eps15 and Rab5, adaptors involved in clathrin-mediated endocytosis and early endosome transport, respectively. Endocytosed particles are transported to lysosomes where the core monomer is endoproteolytically cleaved into its distinct domains. Using protease inhibitors, cathepsin B was identified as the enzyme responsible for core monomer cleavage. Finally we found that monomer cleavage promotes particle dissociation within cells. Together, our results show that HBV capsid-like core particles are internalized through clathrin-mediated endocytosis, leading to lysosomal cleavage of the core monomer and particle dissociation.
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PMID:Clathrin-mediated endocytosis and lysosomal cleavage of hepatitis B virus capsid-like core particles. 1661 2

Hepatitis B spliced protein (HBSP) is involved in the pathogenicity and/or persistence of hepatitis B virus (HBV). Chronic HBV infection is one of the most important risk factors for the development of hepatocellular carcinoma (HCC). However, whether or not HBSP contributes to the progression of HBV-associated HCC remains unknown. This study reports that overexpression of HBSP in human hepatoma cells increased cell invasion and motility. Conversely, small interfering RNA (siRNA)-mediated knockdown of HBSP expression inhibited migration and invasion. By glutathione S-transferase (GST) pulldown, coimmunoprecipitation, and a mammalian two-hybrid assay, HBSP was found to directly interact with cathepsin B (CTSB). Similar to HBSP knockdown, knocking down CTSB also reduced cell migration and invasion. Furthermore, the HBSP-overexpressing hepatoma cells were shown to have increased expression and activity of matrix metalloproteinase-9 (MMP-9) and urokinase-type plasminogen activator (uPA), and overexpression of HBSP significantly enhanced tumor-induced vascularization of endothelial cells. In contrast, knockdown of either HBSP or CTSB by siRNA resulted in inhibition of the two proteolytic enzymes and of the in vitro angiogenesis. Expression of HBSP in the hepatoma cells appeared to activate the mitogen-activated protein kinase (MAPK) and Akt signaling pathway, as evidenced by increases in phosphorylation of p38, Jun N-terminal protein kinase (JNK), extracellular signal-regulated kinase (ERK), and Akt. Taken together, these findings imply that interaction of HBSP with CTSB may promote hepatoma cell motility and invasion and highlight new molecular mechanisms for HBSP-induced HCC progression that involve the secretion and activation of proteolytic enzymes, increased tumor-induced angiogenesis, and activation of the MAPK/Akt signaling, thereby leading to the aggressiveness of hepatoma cells.
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PMID:Interaction of the hepatitis B spliced protein with cathepsin B promotes hepatoma cell migration and invasion. 2303 14