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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{gamma} 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{gamma}Rs), 3 of which have 2 or 3 polymorphic variants. The specificity and affinity of individual hFc{gamma}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{gamma}RI; Fc{gamma}RIIA, IIB, and IIC; Fc{gamma}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{gamma}Rs; (2) IgG2 bind not only to Fc{gamma}RIIAH131, but also, with a lower affinity, to Fc{gamma}RIIAR131 and Fc{gamma}RIIIAV158; (3) IgG4 bind to Fc{gamma}RI, Fc{gamma}RIIA, IIB and IIC and Fc{gamma}RIIIAV158; and (4) the inhibitory receptor Fc{gamma}RIIB has a lower affinity for IgG1, IgG2, and IgG3 than all other hFc{gamma}Rs. We also identified parameters that determine the specificity and affinity of hFc{gamma}Rs for IgG subclasses. These results document how hFc{gamma}R specificity and affinity may account for the biological activities of antibodies. They therefore highlight the role of specific hFc{gamma}Rs in the therapeutic and pathogenic effects of antibodies in disease.


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