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Liver injury caused by antibodies against dengue virus nonstructural protein 1 in a murine model.
Lab Invest. 2008 Oct; 88(10):1079-89.LI

Abstract

Clinical manifestations of severe dengue diseases include thrombocytopenia, vascular leakage, and liver damage. Evidence shows that hepatic injury is involved in the pathogenesis of dengue infection; however, the mechanisms are not fully resolved. Our previous in vitro studies suggested a mechanism of molecular mimicry in which antibodies directed against dengue virus (DV) nonstructural protein 1 (NS1) cross-reacted with endothelial cells and caused inflammatory activation and apoptosis. In this study, the pathogenic effects of anti-DV NS1 antibodies were further examined in a murine model. We found, in liver sections, that anti-DV NS1 antibodies bound to naive mouse vessel endothelium and the binding activity was inhibited by preabsorption of antibodies with DV NS1. Active immunization with DV NS1 resulted in antibody deposition to liver vessel endothelium, and also apoptotic cell death of liver endothelium. Liver tissue damage was observed in DV NS1-immunized mice by histological examination. The serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were increased in mice either actively immunized with DV NS1 protein or passively immunized with antibodies obtained from DV NS1-immunized mice. Furthermore, histological examination revealed mononuclear phagocyte infiltration and cell apoptosis in mice passively immunized with antibodies obtained from mice immunized with DV NS1. Increased AST and ALT levels were observed in mice passively immunized with purified immunoglobulin G (IgG) from dengue patients compared with normal control human IgG-immunized mice. The increased AST and ALT levels were inhibited when dengue patient serum IgG was preabsorbed with DV NS1. In conclusion, active immunization with DV NS1 protein causes immune-mediated liver injury in mice. Passive immunization provides additional evidence that anti-DV NS1 antibodies may play a role in liver damage, which is a pathologic manifestation in dengue virus disease.

Authors+Show Affiliations

Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan, Taiwan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18679379

Citation

Lin, Chiou-Feng, et al. "Liver Injury Caused By Antibodies Against Dengue Virus Nonstructural Protein 1 in a Murine Model." Laboratory Investigation; a Journal of Technical Methods and Pathology, vol. 88, no. 10, 2008, pp. 1079-89.
Lin CF, Wan SW, Chen MC, et al. Liver injury caused by antibodies against dengue virus nonstructural protein 1 in a murine model. Lab Invest. 2008;88(10):1079-89.
Lin, C. F., Wan, S. W., Chen, M. C., Lin, S. C., Cheng, C. C., Chiu, S. C., Hsiao, Y. L., Lei, H. Y., Liu, H. S., Yeh, T. M., & Lin, Y. S. (2008). Liver injury caused by antibodies against dengue virus nonstructural protein 1 in a murine model. Laboratory Investigation; a Journal of Technical Methods and Pathology, 88(10), 1079-89. https://doi.org/10.1038/labinvest.2008.70
Lin CF, et al. Liver Injury Caused By Antibodies Against Dengue Virus Nonstructural Protein 1 in a Murine Model. Lab Invest. 2008;88(10):1079-89. PubMed PMID: 18679379.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Liver injury caused by antibodies against dengue virus nonstructural protein 1 in a murine model. AU - Lin,Chiou-Feng, AU - Wan,Shu-Wen, AU - Chen,Mei-Chun, AU - Lin,Shin-Chao, AU - Cheng,Chu-Chen, AU - Chiu,Shu-Chen, AU - Hsiao,Yu-Ling, AU - Lei,Huan-Yao, AU - Liu,Hsiao-Sheng, AU - Yeh,Trai-Ming, AU - Lin,Yee-Shin, Y1 - 2008/08/04/ PY - 2008/8/6/pubmed PY - 2008/10/31/medline PY - 2008/8/6/entrez SP - 1079 EP - 89 JF - Laboratory investigation; a journal of technical methods and pathology JO - Lab Invest VL - 88 IS - 10 N2 - Clinical manifestations of severe dengue diseases include thrombocytopenia, vascular leakage, and liver damage. Evidence shows that hepatic injury is involved in the pathogenesis of dengue infection; however, the mechanisms are not fully resolved. Our previous in vitro studies suggested a mechanism of molecular mimicry in which antibodies directed against dengue virus (DV) nonstructural protein 1 (NS1) cross-reacted with endothelial cells and caused inflammatory activation and apoptosis. In this study, the pathogenic effects of anti-DV NS1 antibodies were further examined in a murine model. We found, in liver sections, that anti-DV NS1 antibodies bound to naive mouse vessel endothelium and the binding activity was inhibited by preabsorption of antibodies with DV NS1. Active immunization with DV NS1 resulted in antibody deposition to liver vessel endothelium, and also apoptotic cell death of liver endothelium. Liver tissue damage was observed in DV NS1-immunized mice by histological examination. The serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were increased in mice either actively immunized with DV NS1 protein or passively immunized with antibodies obtained from DV NS1-immunized mice. Furthermore, histological examination revealed mononuclear phagocyte infiltration and cell apoptosis in mice passively immunized with antibodies obtained from mice immunized with DV NS1. Increased AST and ALT levels were observed in mice passively immunized with purified immunoglobulin G (IgG) from dengue patients compared with normal control human IgG-immunized mice. The increased AST and ALT levels were inhibited when dengue patient serum IgG was preabsorbed with DV NS1. In conclusion, active immunization with DV NS1 protein causes immune-mediated liver injury in mice. Passive immunization provides additional evidence that anti-DV NS1 antibodies may play a role in liver damage, which is a pathologic manifestation in dengue virus disease. SN - 1530-0307 UR - https://www.unboundmedicine.com/medline/citation/18679379/Liver_injury_caused_by_antibodies_against_dengue_virus_nonstructural_protein_1_in_a_murine_model_ L2 - https://doi.org/10.1038/labinvest.2008.70 DB - PRIME DP - Unbound Medicine ER -