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J. Biol. Chem., Vol. 282, Issue 37, 26696-26706, September 14, 2007

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Antibodies Use Heme as a Cofactor to Extend Their Pathogen Elimination Activity and to Acquire New Effector Functions^*

Jordan D. Dimitrov^¶||12, Lubka T. Roumenina^**1, Virjinia R. Doltchinkova, Nikolina M. Mihaylova, Sebastien Lacroix-Desmazes^¶||, Srinivas V. Kaveri^¶||, and Tchavdar L. Vassilev³

From the Department of Immunology, Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria, the ^**Department of Biochemistry, Sofia University, St. Kliment Ohridsky, 1164 Sofia, Bulgaria, the Department of Biophysics and Radiobiology, Sofia University, St. Kliment Ohridski, 1164 Sofia, Bulgaria, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie-Paris 6, UMR S 872, F-75006 Paris, France, ^¶Université Paris Descartes, UMR S 872, F-75006 Paris, France, and ^||INSERM, U872, F-75006 Paris, France

Various pathological processes are accompanied by release of high amounts of free heme into the circulation. We demonstrated by kinetic, thermodynamic, and spectroscopic analyses that antibodies have an intrinsic ability to bind heme. This binding resulted in a decrease in the conformational freedom of the antibody paratopes and in a change in the nature of the noncovalent forces responsible for the antigen binding. The antibodies use the molecular imprint of the heme molecule to interact with an enlarged panel of structurally unrelated epitopes. Upon heme binding, monoclonal as well as pooled immunoglobulin G gained an ability to interact with previously unrecognized bacterial antigens and intact bacteria. IgG-heme complexes had an enhanced ability to trigger complement-mediated bacterial killing. It was also shown that heme, bound to immunoglobulins, acted as a cofactor in redox reactions. The potentiation of the antibacterial activity of IgG after contact with heme may represent a novel and inducible innate-type defense mechanism against invading pathogens.

Received for publication, March 30, 2007 , and in revised form, July 10, 2007.

^* This work was supported by Howard Hughes Medical Institute Grant 55000340 and by INSERM and CNRS, France. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Experimental Procedures, Refs. 1–5, and Figs. S1–S4.

This paper is dedicated to the memory of Dr. Jean-Pierre Bouvet.

¹ Both authors contributed equally to this work.

³ Howard Hughes Medical Institute International Research Scholar. To whom correspondence may be addressed. Tel.: 359-2-979-6348; Fax: 359-2-870-0109; E-mail: vassilev{at}microbio.bas.bg.

² To whom correspondence may be addressed: Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, Academy G. Bonchev St., Block 26, 1113 Sofia, Bulgaria. Tel.: 359-2-979-6348; Fax: 359-2-870-0109; E-mail: jdd{at}microbio.bas.bg or jd.dimitrov{at}gmail.com.

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