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The Fifth Domain of Beta 2 Glycoprotein I Protects from Natural IgM Mediated Cardiac Ischaemia Reperfusion Injury.

Zhang P, Weaver JC, Chen G, Beretov J, Atsumi T, Qi M, Bhindi R, Qi JC, Madigan MC, Giannakopoulos B, Krilis SA - PLoS ONE (2016)

Bottom Line: Beta 2 Glycoprotein I (β2GPI) is a plasma protein that binds to neoepitopes on damaged cells including anionic phospholipids through its highly conserved Domain V.Domain V treatment in WT mice also resulted in less neutrophil infiltration, less apoptosis and improved ejection fraction at 24 h.Domain V remained equally effective when delivered at the time of reperfusion which has therapeutic clinical relevance.Based upon this study Domain V may function as a universal inhibitor of IgM NAb binding in the setting of cardiac IRI, which offers promise as a new therapeutic strategy in the treatment of cardiac IRI.

View Article: PubMed Central - PubMed

Affiliation: Department of Infectious Diseases, Immunology and Sexual Health, St George Hospital, Sydney, Australia.

ABSTRACT
Reperfusion after a period of ischemia results in reperfusion injury (IRI) which involves activation of the inflammatory cascade. In cardiac IRI, IgM natural antibodies (NAb) play a prominent role through binding to altered neoepitopes expressed on damaged cells. Beta 2 Glycoprotein I (β2GPI) is a plasma protein that binds to neoepitopes on damaged cells including anionic phospholipids through its highly conserved Domain V. Domain I of β2GPI binds circulating IgM NAbs and may provide a link between the innate immune system, IgM NAb binding and cardiac IRI. This study was undertaken to investigate the role of Β2GPI and its Domain V in cardiac IRI using wild-type (WT), Rag-1 -/- and β2GPI deficient mice. Compared with control, treatment with Domain V prior to cardiac IRI prevented binding of endogenous β2GPI to post-ischemic myocardium and resulted in smaller myocardial infarction size in both WT and β2GPI deficient mice. Domain V treatment in WT mice also resulted in less neutrophil infiltration, less apoptosis and improved ejection fraction at 24 h. Rag-1 -/- antibody deficient mice reconstituted with IgM NAbs confirmed that Domain V prevented IgM NAb induced cardiac IRI. Domain V remained equally effective when delivered at the time of reperfusion which has therapeutic clinical relevance.Based upon this study Domain V may function as a universal inhibitor of IgM NAb binding in the setting of cardiac IRI, which offers promise as a new therapeutic strategy in the treatment of cardiac IRI.

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Serum β2GPI levels after cardiac IRI. Serum total β2GPI levels in mice 24 h after cardiac IRI.NT = No treatment. rhβ2GPI = recombinant human β2GPI. Domain V = recombinant human Domain V. Horizontal line for each group represents mean.
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pone.0152681.g004: Serum β2GPI levels after cardiac IRI. Serum total β2GPI levels in mice 24 h after cardiac IRI.NT = No treatment. rhβ2GPI = recombinant human β2GPI. Domain V = recombinant human Domain V. Horizontal line for each group represents mean.

Mentions: In mice undergoing sham procedure the mean serum β2GPI was 104.1 ± 21 μg/ml (n = 7) and this was significantly reduced to 80.5 ± 16 μg/ml in the control group (n = 10) 24 h after IRI (Fig 4). In the groups treated with rhDomain V (n = 17) and rhβ2GPI (n = 11) there was no fall in serum β2GPI levels which remained comparable to sham treated mice. This fall in native serum β2GPI during cardiac IRI was taken to represent consumption of circulating β2GPI due to tissue binding which was prevented by rhDomain V and rhβ2GPI.


The Fifth Domain of Beta 2 Glycoprotein I Protects from Natural IgM Mediated Cardiac Ischaemia Reperfusion Injury.

Zhang P, Weaver JC, Chen G, Beretov J, Atsumi T, Qi M, Bhindi R, Qi JC, Madigan MC, Giannakopoulos B, Krilis SA - PLoS ONE (2016)

Serum β2GPI levels after cardiac IRI. Serum total β2GPI levels in mice 24 h after cardiac IRI.NT = No treatment. rhβ2GPI = recombinant human β2GPI. Domain V = recombinant human Domain V. Horizontal line for each group represents mean.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4816326&req=5

pone.0152681.g004: Serum β2GPI levels after cardiac IRI. Serum total β2GPI levels in mice 24 h after cardiac IRI.NT = No treatment. rhβ2GPI = recombinant human β2GPI. Domain V = recombinant human Domain V. Horizontal line for each group represents mean.
Mentions: In mice undergoing sham procedure the mean serum β2GPI was 104.1 ± 21 μg/ml (n = 7) and this was significantly reduced to 80.5 ± 16 μg/ml in the control group (n = 10) 24 h after IRI (Fig 4). In the groups treated with rhDomain V (n = 17) and rhβ2GPI (n = 11) there was no fall in serum β2GPI levels which remained comparable to sham treated mice. This fall in native serum β2GPI during cardiac IRI was taken to represent consumption of circulating β2GPI due to tissue binding which was prevented by rhDomain V and rhβ2GPI.

Bottom Line: Beta 2 Glycoprotein I (β2GPI) is a plasma protein that binds to neoepitopes on damaged cells including anionic phospholipids through its highly conserved Domain V.Domain V treatment in WT mice also resulted in less neutrophil infiltration, less apoptosis and improved ejection fraction at 24 h.Domain V remained equally effective when delivered at the time of reperfusion which has therapeutic clinical relevance.Based upon this study Domain V may function as a universal inhibitor of IgM NAb binding in the setting of cardiac IRI, which offers promise as a new therapeutic strategy in the treatment of cardiac IRI.

View Article: PubMed Central - PubMed

Affiliation: Department of Infectious Diseases, Immunology and Sexual Health, St George Hospital, Sydney, Australia.

ABSTRACT
Reperfusion after a period of ischemia results in reperfusion injury (IRI) which involves activation of the inflammatory cascade. In cardiac IRI, IgM natural antibodies (NAb) play a prominent role through binding to altered neoepitopes expressed on damaged cells. Beta 2 Glycoprotein I (β2GPI) is a plasma protein that binds to neoepitopes on damaged cells including anionic phospholipids through its highly conserved Domain V. Domain I of β2GPI binds circulating IgM NAbs and may provide a link between the innate immune system, IgM NAb binding and cardiac IRI. This study was undertaken to investigate the role of Β2GPI and its Domain V in cardiac IRI using wild-type (WT), Rag-1 -/- and β2GPI deficient mice. Compared with control, treatment with Domain V prior to cardiac IRI prevented binding of endogenous β2GPI to post-ischemic myocardium and resulted in smaller myocardial infarction size in both WT and β2GPI deficient mice. Domain V treatment in WT mice also resulted in less neutrophil infiltration, less apoptosis and improved ejection fraction at 24 h. Rag-1 -/- antibody deficient mice reconstituted with IgM NAbs confirmed that Domain V prevented IgM NAb induced cardiac IRI. Domain V remained equally effective when delivered at the time of reperfusion which has therapeutic clinical relevance.Based upon this study Domain V may function as a universal inhibitor of IgM NAb binding in the setting of cardiac IRI, which offers promise as a new therapeutic strategy in the treatment of cardiac IRI.

Show MeSH
Related in: MedlinePlus