Hydrolysis of Coagulation Factors by Circulating IgG Is Associated with a Reduced Risk for Chronic Allograft Nephropathy in Renal Transplanted Patients

Centre de Recherche des Cordeliers, Université Pierre et Marie Curie-Paris 6, Unité Mixte de Recherche S 872, Université Paris Descartes, Unité Mixte de Recherche S 872, Institut National de la Santé et de la Recherche Médicale, Unité 872, Paris, France.
The Journal of Immunology (Impact Factor: 4.92). 06/2008; 180(12):8455-60. DOI: 10.4049/jimmunol.180.12.8455
Source: PubMed


Chronic allograft nephropathy (CAN), a major cause of late allograft failure, is characterized by a progressive decline in graft function correlated with tissue destruction. Uncontrolled activation of the coagulation cascade by the stressed endothelium of the graft is thought to play an important role in the pathophysiology of CAN. In this study, we demonstrate that circulating IgG from renal-transplanted patients are endowed with hydrolytic properties toward coagulation factors VIII and IX, but fail to hydrolyze factor VII and prothrombin. The hydrolytic activity of IgG was reliably quantified by the measure of the hydrolysis of a fluorescent synthetic substrate for serine proteases: proline-phenylalanine-arginine-methylcoumarinamide (PFR-MCA). A retrospective case-control study indicated that an elevated hydrolysis rate of PFR-MCA by circulating IgG correlated with the absence of CAN lesions on protocol graft biopsy performed 2 years posttransplantation. We propose that circulating hydrolytic IgG may counterbalance the procoagulation state conferred by the activated endothelium by disrupting the amplification loop of thrombin generation which is dependent on factors VIII and IX. Interestingly, low rates of PFR-MCA hydrolysis, measured 3 mo posttransplantation, were predictive of CAN at 2 years down the lane. These data suggest that PFR-MCA hydrolysis may be used as a prognosis marker for CAN in renal-transplanted patients.

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    • "It is here worth mentioning that Abs may in some instances be protective. The finding that catalytic antibodies able to disrupt the amplification loop of the coagulation cascade (67) with anti-inflammatory properties (68) may instead pave the way for the selective use of IVIG (69) or immune complexes. "
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    • "However, in other cases the pathophysiological relevance of catalytic antibodies remains unclear [13]. Moreover, the reports of Lacroix-Desmazes et al. have recently demonstrated that a high hydrolytic activity of circulating IgG is associated with a higher survival rate in severe sepsis patients [14] as well as with a slight activation of the coagulation cascade within rejected allografts that prevents the development of chronic allograft nephropathy in renal transplant patients [15]. These observations suggest that hydrolytic IgG may improve patient health by an as yet unknown mechanism. "
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