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postgraduate thesis: The role of annexin II in the pathogenesis of lupus nephritis

TitleThe role of annexin II in the pathogenesis of lupus nephritis
Authors
Issue Date2012
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Citation
Cheung, K. S. [張國勛]. (2012). The role of annexin II in the pathogenesis of lupus nephritis. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b4786934
AbstractLupus nephritis is a severe organ manifestation of systemic lupus erythematosus (SLE), and is characterized by the production of anti-dsDNA antibodies. It is an important cause of renal failure. The mechanism through which anti-dsDNA antibodies bind to tissues and mediate kidney injury remains to be fully elucidated. Emerging evidence suggests that anti-dsDNA antibodies can bind to cells and extracellular antigens directly through cross-reactivity, independent of bridging chromatin material. Mesangial cells play an important role in normal kidney structure and functions, and its pathophysiology. Mesangial abnormalities in lupus nephritis precede more severe injuries such as lesions in the glomerular capillary loop. We previously demonstrated that the binding of human anti-dsDNA antibodies to mesangial cells (HMC) correlated with disease activity and induced inflammatory as well as fibrotic pathways. The aim of this project is to identify the cross-reactive antigen(s) on the mesangial cell surface that mediates anti-dsDNA antibody binding and the alterations in cell functions that result from this interaction. HMC plasma membrane proteins were purified. Using proteomic and biochemical approaches, we identified annexin II as the predominant cross-reactive antigen on the HMC surface that mediated human polyclonal anti-dsDNA antibody binding. Following this interaction, anti-dsDNA antibodies were internalized in a time- and temperature-dependent manner, and translocated to both the cytoplasm and nucleus within 30 min. This resulted in induction of annexin II synthesis, IL-6 secretion and cell proliferation, which was mediated through the activation of p38 MAPK, JNK and AKT. The binding activity to annexin II in the serum immunoglobulin fraction correlated with the titre of anti-dsDNA antibody. Binding activity of anti-dsDNA antibodies to annexin II correlated with clinical disease activity and circulating anti-dsDNA antibody levels. These correlations were more prominent in male patients with lupus nephritis. Glomerular annexin II expression was increased in patients with active lupus nephritis and co-localized with IgG and C3 deposition. Gene silencing of annexin II in HMC reduced anti-dsDNA antibody binding, which was accompanied by reduced IL-6 secretion and cell proliferation. Using female NZB/W F1 mice, an established murine model of lupus nephritis, we demonstrated that intra-glomerular annexin II expression increased with disease progression and was accompanied by an increase in the expression of p11, its cellular protein ligand. Our data suggest that annexin II may exist in the kidney as a heterotetramer and is involved in disease pathogenesis. At the ultrastructural level, annexin II was detected in the mesangial matrix, amongst electron dense deposits in the glomerular basement membrane, on the foot processes in podocytes and within the Bowman’s capsule. In conclusion, our data demonstrated that annexin II is the major cell surface antigen on HMC that mediates the cross-reactive binding of human anti-DNA antibodies. Through this interaction, cellular processes are triggered that contribute to the pathogenesis of lupus nephritis.
DegreeDoctor of Philosophy
SubjectLipocortins.
Lupus nephritis - Pathogenesis.
Dept/ProgramMedicine
Persistent Identifierhttp://hdl.handle.net/10722/182310

 

DC FieldValueLanguage
dc.contributor.authorCheung, Kwok-fan, Stephen-
dc.contributor.author張國勛-
dc.date.accessioned2013-04-21T11:20:22Z-
dc.date.available2013-04-21T11:20:22Z-
dc.date.issued2012-
dc.identifier.citationCheung, K. S. [張國勛]. (2012). The role of annexin II in the pathogenesis of lupus nephritis. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b4786934-
dc.identifier.urihttp://hdl.handle.net/10722/182310-
dc.description.abstractLupus nephritis is a severe organ manifestation of systemic lupus erythematosus (SLE), and is characterized by the production of anti-dsDNA antibodies. It is an important cause of renal failure. The mechanism through which anti-dsDNA antibodies bind to tissues and mediate kidney injury remains to be fully elucidated. Emerging evidence suggests that anti-dsDNA antibodies can bind to cells and extracellular antigens directly through cross-reactivity, independent of bridging chromatin material. Mesangial cells play an important role in normal kidney structure and functions, and its pathophysiology. Mesangial abnormalities in lupus nephritis precede more severe injuries such as lesions in the glomerular capillary loop. We previously demonstrated that the binding of human anti-dsDNA antibodies to mesangial cells (HMC) correlated with disease activity and induced inflammatory as well as fibrotic pathways. The aim of this project is to identify the cross-reactive antigen(s) on the mesangial cell surface that mediates anti-dsDNA antibody binding and the alterations in cell functions that result from this interaction. HMC plasma membrane proteins were purified. Using proteomic and biochemical approaches, we identified annexin II as the predominant cross-reactive antigen on the HMC surface that mediated human polyclonal anti-dsDNA antibody binding. Following this interaction, anti-dsDNA antibodies were internalized in a time- and temperature-dependent manner, and translocated to both the cytoplasm and nucleus within 30 min. This resulted in induction of annexin II synthesis, IL-6 secretion and cell proliferation, which was mediated through the activation of p38 MAPK, JNK and AKT. The binding activity to annexin II in the serum immunoglobulin fraction correlated with the titre of anti-dsDNA antibody. Binding activity of anti-dsDNA antibodies to annexin II correlated with clinical disease activity and circulating anti-dsDNA antibody levels. These correlations were more prominent in male patients with lupus nephritis. Glomerular annexin II expression was increased in patients with active lupus nephritis and co-localized with IgG and C3 deposition. Gene silencing of annexin II in HMC reduced anti-dsDNA antibody binding, which was accompanied by reduced IL-6 secretion and cell proliferation. Using female NZB/W F1 mice, an established murine model of lupus nephritis, we demonstrated that intra-glomerular annexin II expression increased with disease progression and was accompanied by an increase in the expression of p11, its cellular protein ligand. Our data suggest that annexin II may exist in the kidney as a heterotetramer and is involved in disease pathogenesis. At the ultrastructural level, annexin II was detected in the mesangial matrix, amongst electron dense deposits in the glomerular basement membrane, on the foot processes in podocytes and within the Bowman’s capsule. In conclusion, our data demonstrated that annexin II is the major cell surface antigen on HMC that mediates the cross-reactive binding of human anti-DNA antibodies. Through this interaction, cellular processes are triggered that contribute to the pathogenesis of lupus nephritis.-
dc.languageeng-
dc.publisherThe University of Hong Kong (Pokfulam, Hong Kong)-
dc.relation.ispartofHKU Theses Online (HKUTO)-
dc.rightsThe author retains all proprietary rights, (such as patent rights) and the right to use in future works.-
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.source.urihttp://hub.hku.hk/bib/B47869343-
dc.subject.lcshLipocortins.-
dc.subject.lcshLupus nephritis - Pathogenesis.-
dc.titleThe role of annexin II in the pathogenesis of lupus nephritis-
dc.typePG_Thesis-
dc.identifier.hkulb4786934-
dc.description.thesisnameDoctor of Philosophy-
dc.description.thesislevelDoctoral-
dc.description.thesisdisciplineMedicine-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.5353/th_b4786934-
dc.date.hkucongregation2012-

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