High levels of catalytic antibodies correlate with favorable outcome in sepsis

doi:10.1073/pnas.0500586102

High levels of catalytic antibodies correlate with favorable outcome in sepsis

^*Institut National de la Santé et de la Recherche Médicale, Unite 681, Université Paris VI, Institut des Cordeliers, 15 Rue de l'Ecole de Médecine, 75006 Paris, France; ^‡Department of Medical Intensive Care, Hôpital Universitaire Cochin-Port Royal, Assistance Publique-Hôpitaux de Paris, Université Paris V, 27 Rue du Faubourg Saint Jacques, 75014 Paris, France; ^§Institut National de la Santé et de la Recherche Médicale, Unite 567, Institut Cochin, 27 Rue du Faubourg Saint Jacques, 75014 Paris, France; and ^¶Indian Institute of Science, Bangalore 560 012, India

Communicated by Michael Sela, Weizmann Institute of Science, Rehovot, Israel, January 24, 2005 (received for review October 24, 2004)

Abstract

Sepsis is the leading cause of death in intensive care units and results from a deleterious systemic host response to infection. Although initially perceived as potentially deleterious, catalytic antibodies have been proposed to participate in removal of metabolic wastes and protection against infection. Here we show that the presence in plasma of IgG endowed with serine protease-like hydrolytic activity strongly correlates with survival from sepsis. Variances of catalytic rates of IgG were greater in the case of patients with severe sepsis than healthy donors (P < 0.001), indicating that sepsis is associated with alterations in plasma levels of hydrolytic IgG. The catalytic rates of IgG from patients who survived were significantly greater than those of IgG from deceased patients (P < 0.05). The cumulative rate of survival was higher among patients exhibiting high rates of IgG-mediated hydrolysis as compared with patients with low hydrolytic rates (P < 0.05). An inverse correlation was also observed between the markers of severity of disseminated intravascular coagulation and rates of hydrolysis of patients' IgG. Furthermore, IgG from three surviving patients hydrolyzed factor VIII, one of which also hydrolyzed factor IX, suggesting that, in some patients, catalytic IgG may participate in the control of disseminated microvascular thrombosis. Our observations provide the first evidence that hydrolytic antibodies might play a role in recovery from a disease.

Footnotes

↵ † To whom correspondence should be addressed. E-mail: sebastien.lacroix-desmazes{at}u430.bhdc.jussieu.fr.
Author contributions: S.L.-D., S.V.K., D.H.-S., J.C., C.-E.L., M.D.K., J.-F.D., and V.O.M. designed research; S.L.-D., J.B., and N.T. performed research; D.H.-S., J.C., C.-E.L., J.-P.M., J.-F.D., and V.O.M. contributed new reagents/analytic tools; S.L.-D., J.B., S.V.K., D.H.-S., N.T., J.C., C.-E.L., J.-P.M., V.N., M.D.K., J.-F.D., and V.O.M. analyzed data; and S.L.-D., J.B., S.V.K., J.-P.M., M.D.K., J.-F.D., and V.O.M. wrote the paper.
Abbreviations: SAPS II, simplified acute physiology score II; SOFA, sequential organ failure assessment; PT, prothrombin time; aPTT, activated partial thromboplastin time; PFR-MCA, proline-phenylalanine-arginine-methylcoumarinamide; IVIg, i.v. immunoglobulins; DIC, disseminated intravascular coagulation.