期刊
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
卷 21, 期 11, 页码 1912-1927出版社
AMER SOC NEPHROLOGY
DOI: 10.1681/ASN.2009080805
关键词
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资金
- Hong Kong Research Grants Council [HKU 7374/03M, HKU 7603/09M]
- Committee on Research and Conference [10203476, 10400647]
- Outstanding Researcher Award [10207175]
- University Grants Committee [20730358]
- Wai Hung Charitable Foundation Limited
Production of anti-dsDNA antibodies is a hallmark of lupus nephritis, but how these antibodies deposit in organs and elicit inflammatory damage remains unknown In this study, we sought to identify antigens on the surface of human mesangial cells (HMC) that mediate the binding of human anti-dsDNA antibodies and the subsequent pathogenic processes We isolated anti-dsDNA antibodies from patients with lupus nephritis by affinity chromatography We used multiple methods to identify and characterize antigens from the plasma membrane fraction of mesangial cells that crossreacted with the anti-dsDNA antibodies We found that annexin II mediated the binding of anti-dsDNA antibodies to HMC After binding to the mesangial cell surface anti dsDNA antibodies were internalized into the cytoplasm and nucleus This also led to induction of IL-6 secretion and annexin II synthesis mediated through activation of p38 MAPK, JNK, and AKT Binding of anti dsDNA antibodies to annexin II correlated with disease activity in human lupus nephritis Glomerular expression of annexin II correlated with the severity of nephritis and annexin II colocalized with IgG and C3 deposits in both human and murine lupus nephritis Gene silencing of annexin II in HMC reduced binding of anti dsDNA antibody and partially decreased IL-6 secretion In summary, our data demonstrate that annexin II mediates the binding of anti-dsDNA antibodies to mesangial cells contributing to the pathogenesis of lupus nephritis This interaction provides a potential target for therapeutic intervention
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