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Crucial Role of Aspartic Acid at Position 265 in the CH2 Domain for Murine IgG2a and IgG2b Fc-Associated Effector Functions¹

Lucie Baudino^*, Yasuro Shinohara, Falk Nimmerjahn, Jun-Ichi Furukawa, Munehiro Nakata, Eduardo Martínez-Soria^*, Franz Petry^¶, Jeffery V. Ravetch^||, Shin-Ichiro Nishimura and Shozo Izui^2,*

^* Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland; Laboratory of Advanced Chemical Biology, Graduate School of Advanced Life Science, Hokkaido University, Sapporo, Japan; Laboratory for Experimental Immunology and Immunotherapy, Nikolaus-Fiebiger-Center for Molecular Medicine, University of Erlangen-Nuremberg, Erlangen, Germany; Department of Applied Biochemistry, Tokai University, Hiratsuka, Kanagawa, Japan; ^¶ Institute of Medical Microbiology and Hygiene, Johannes Gutenberg-University, Mainz, Germany; and ^|| The Rockefeller University, New York, NY 10065

Replacement of aspartic acid by alanine at position 265 (D265A) in mouse IgG1 results in a complete loss of interaction between this isotype and low-affinity IgG Fc receptors (FcRIIB and FcRIII). However, it has not yet been defined whether the D265A substitution could exhibit similar effects on the interaction with two other FcR (FcRI and FcRIV) and on the activation of complement. To address this question, 34-3C anti-RBC IgG2a and IgG2b switch variants bearing the D265A mutation were generated, and their effector functions and in vivo pathogenicity were compared with those of the respective wild-type Abs. The introduction of the D265A mutation almost completely abolished the binding of 34-3C IgG2a and IgG2b to all four classes of FcR and the activation of complement. Consequently, these mutants were hardly pathogenic. Although oligosaccharide side chains of these mutants were found to contain higher levels of sialic acids than those of wild-type Abs, the analysis of enzymatically desialylated D265A variants ruled out the possibility that very poor Fc-associated effector functions of the D265A mutants were due to an increased level of the mutant Fc sialylation. Thus, our results demonstrate that aspartic acid at position 265 is a residue critically implicated in triggering the Fc-associated effector functions of IgG, probably by defining a crucial three-dimensional structure of the Fc region.

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.

¹ This work was supported by a grant from the Swiss National Foundation for Scientific Research, by Special Coordination Funds for Promoting Science and Technology of the Ministry of Education, Culture, Sports, Science and Technology of the Japanese Government and by a grant from the Roche Research Foundation. F.N. was supported by grants from the German Research Foundation (DFG) and from the Bavarian Genome Research Network (BayGene).

² Address correspondence and reprint requests to Dr. Shozo Izui, Department of Pathology and Immunology, Centre Médicale Universitaire, 1211 Geneva 4, Switzerland. E-mail address: Shozo.Izui{at}medecine.unige.ch

³ Abbreviations used in this paper: SPR, surface plasmon resonance; Ht, hematocrit; MS, mass spectrometry; IVIG, i.v. Ig; WT, wild type.