Immunology
Molecular Mimicry of Human Endothelial Cell Antigen by Autoantibodies to Nonstructural Protein 1 of Dengue Virus*

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The pathogenesis of dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS), both serious complications of dengue virus (DV) infection, remains unclear. In this study, we found that anti-DV NS1 (nonstructural protein 1) polyclonal antibodies cross-reacted with human umbilical vein endothelial cells (HUVECs). We further identified a complex-specific mAb, DB16-1, which could recognize DV NS1 and cross-react with HUVECs and human blood vessels. The target protein of DB16-1 was further purified by immunoaffinity chromatography. LC-MS/MS analysis and co-immunoprecipitation revealed that the target protein of DB16-1 was human LYRIC (lysine-rich CEACAM1 co-isolated). Our newly generated anti-LYRIC mAbs bound to HUVECs in a pattern similar to that of DB16-1. The B-cell epitope of DB16-1 displayed a consensus motif, Lys-X-Trp-Gly (KXWG), which corresponded to amino acid residues 116–119 of DV NS1 and mimicked amino acid residues 334–337 in LYRIC. Moreover, the binding activity of DB16-1 in NS1 of DV-2 and in LYRIC disappeared after the KXWG epitope was deleted in each. In conclusion, DB16-1 targeted the same epitope in DV NS1 and LYRIC protein on human endothelial cells, suggesting that it might play a role in the pathogenesis of DHF/DSS. Future studies on the role of the anti-NS1 antibody in causing vascular permeability will undoubtedly be performed on sera collected from individuals before, during, and after the endothelial cell malfunction phase of a dengue illness.

Antibodies
Endothelium
Flavi Viruses
Immunology
RNA Viruses
Dengue Fever (DF)
Dengue Hemorrhagic Fever and Dengue Shock Syndrome (DHF/DSS)
Lysine-rich CEACAM1 Co-isolated (LYRIC)
Molecular Mimicry
Nonstructural Protein 1 (NS1)

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*

This work was supported by Academia Sinica (to H.-C. W.) and National Science Council, Taiwan, Grants NSC-98-3111-B-001-004 and NSC-98-2323-B-001-001 (to H.-C. W.).

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.