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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 B2GPI 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.

J Thromb Haemost. 2010 Aug;8(8):1754-62. doi: 10.1111/j.1538-7836.2010.03944.x.Redox control of â2-glycoprotein I-von Willebrand factor interaction by thioredoxin-1.Passam FH, Rahgozar S, Qi M, Raftery MJ, Wong JW, Tanaka K, Ioannou Y, Zhang JY, Gemmell R, Qi JC, Giannakopoulos B, Hughes WE, Hogg PJ, Krilis SA.Department of Immunology, Allergy and Infectious Diseases, University of New South Wales, St George Hospital, Sydney, Australia.AbstractBACKGROUND: â(2) -Glycoprotein I (â(2) GPI) is an abundant plasma protein that is closely linked to blood clotting, as it interacts with various protein and cellular components of the coagulation system. However, the role of â(2) GPI in thrombus formation is unknown. We have recently shown that â(2) GPI is susceptible to reduction by the thiol oxidoreductases thioredoxin-1 and protein disulfide isomerase, and that reduction of â(2) GPI can take place on the platelet surface.METHODS: â(2) GPI, reduced by thioredoxin-1, was labeled with the selective sulfhydryl probe N(a)-(3-maleimidylpropionyl)biocytin and subjected to mass spectrometry to identify the specific cysteines involved in the thiol exchange reaction. Binding assays were used to examine the affinity of reduced â(2) GPI for von Willebrand factor (VWF) and the effect of reduced â2GPI on glycoprotein (GP)Ibá binding to VWF. Platelet adhesion to ristocetin-activated VWF was studied in the presence of reduced â(2) GPI.RESULTS: We demonstrate that the Cys288-Cys326 disulfide in domain V of â(2) GPI is the predominant disulfide reduced by thioredoxin-1. Reduced â(2) GPI in vitro displays increased binding to VWF that is dependent on disulfide bond formation. â(2) GPI reduced by thioredoxin-1, in comparison with non-reduced â(2) GPI, leads to increased binding of GPIbá to VWF and increased platelet adhesion to activated VWF.CONCLUSIONS: Given the importance of thiol oxidoreductases in thrombus formation, we provide preliminary evidence that the thiol-dependent i