The Fifth Domain Of Beta 2 Glycoprotein I Protects From Natural Igm Mediated Cardiac Ischaemia Reperfusion Injury

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 (beta 2GPI) is a plasma protein that binds to neoepitopes on damaged cells including anionic phospholipids through its highly conserved Domain V. Domain I of beta 2GPI 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 beta 2GPI and its Domain V in cardiac IRI using wild-type (WT), Rag-1(-/-) and beta 2GPI deficient mice. Compared with control, treatment with Domain V prior to cardiac IRI prevented binding of endogenous beta 2GPI to post-ischemic myocardium and resulted in smaller myocardial infarction size in both WT and beta 2GPI 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.