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Blood, 16 April 2009, Vol. 113, No. 16, pp. 3716-3725.
Prepublished online as a Blood First Edition Paper on November 18, 2008; DOI 10.1182/blood-2008-09-179754.
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IMMUNOBIOLOGY
Specificity and affinity of human Fc receptors and their polymorphic variants for human IgG subclasses
Pierre Bruhns1,2,
Bruno Iannascoli1,2,
Patrick England3,4,
David A. Mancardi1,2,
Nadine Fernandez5,
Sylvie Jorieux6, and
Marc Daëron1,2
1 Institut Pasteur, Département d'Immunologie, Unité d'Allergologie Moléculaire et Cellulaire, Paris;
2 Inserm, U760, Paris;
3 Institut Pasteur, Département de Biologie Structurale et Chimie, Plateforme de Biophysique des Macromolécules et de leurs Interactions, Paris;
4 Centre National de la Recherche Scientifique (CNRS), URA 2185, Paris;
5 Laboratoire Français du fractionnement et des Biotechnologies, Les Ulis; and
6 Laboratoire Français du fractionnement et des Biotechnologies, Lille, France
Distinct genes encode 6 human receptors for IgG (hFc Rs), 3 of which have 2 or 3 polymorphic variants. The specificity and affinity of individual hFc Rs for the 4 human IgG subclasses is unknown. This information is critical for antibody-based immunotherapy which has been increasingly used in the clinics. We investigated the binding of polyclonal and monoclonal IgG1, IgG2, IgG3, and IgG4 to Fc RI; Fc RIIA, IIB, and IIC; Fc RIIIA and IIIB; and all known polymorphic variants. Wild-type and low-fucosylated IgG1 anti-CD20 and anti-RhD mAbs were also examined. We found that (1) IgG1 and IgG3 bind to all hFc Rs; (2) IgG2 bind not only to Fc RIIAH131, but also, with a lower affinity, to Fc RIIAR131 and Fc RIIIAV158; (3) IgG4 bind to Fc RI, Fc RIIA, IIB and IIC and Fc RIIIAV158; and (4) the inhibitory receptor Fc RIIB has a lower affinity for IgG1, IgG2, and IgG3 than all other hFc Rs. We also identified parameters that determine the specificity and affinity of hFc Rs for IgG subclasses. These results document how hFc R specificity and affinity may account for the biological activities of antibodies. They therefore highlight the role of specific hFc Rs in the therapeutic and pathogenic effects of antibodies in disease.

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