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* Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland;
Laboratory for Experimental Immunology and Immunotherapy, Nikolaus-Fiebiger-Center for Molecular Medicine, University of Erlangen-Nuremberg, Erlangen, Germany;
Laboratory of Advanced Chemical Biology, Graduate School of Advanced Life Science, Hokkaido University, Sapporo, Japan;
Institute of Medical Microbiology and Hygiene, Johannes Gutenberg-University, Mainz, Germany;
¶ Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands; and
|| The Rockefeller University, New York, NY 10065
Four murine IgG subclasses display markedly different Fc-associated effector functions because of their differential binding to three activating IgG Fc receptors (Fc
RI, FcRIII, and FcRIV) and C1q. Previous analysis of IgG subclass switch variants of 34-3C anti-RBC monoclonal autoantibodies revealed that the IgG1 subclass, which binds only to FcRIII and fails to activate complement, displayed the poorest pathogenic potential. This could be related to the presence of a three amino acid deletion at positions 233–235 in the CH2 domain uniquely found in this subclass. To address this question, IgG1 insertion and IgG2b deletion mutants at positions 233–235 of 34-3C anti-RBC Abs were generated, and their ability to initiate effector functions and their pathogenicity were compared with those of the respective wild-type Abs. The insertion of amino acid residues at positions 233–235 enabled the IgG1 subclass to bind FcRIV but did not improve the binding to C1q. Accordingly, its pathogenicity was enhanced but still inferior to that of IgG2b. In contrast, the IgG2b deletion mutant lost its ability to bind to FcRIV and activate complement. Consequently, its pathogenicity was markedly diminished to a level comparable to that of IgG1. Our results demonstrated that the initiation of FcR- and complement-mediated effector functions of IgG2b was profoundly affected by the three amino acid deletion at positions 233–235, but that this natural three amino acid deletion could only partially explain the poor binding of IgG1 to FcRIV and C1q. This indicates the lack in the IgG1 subclass of as yet unknown motifs promoting efficient interaction with FcRIV and C1q.
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, 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: WT, wild type; SPR, surface plasmon resonance; Ht, hematocrit; MS, mass spectrometry; MBL, mannose-binding lectin.
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