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Title

Impact of a three amino acid deletion in the CH2 domain of murine IgG1 on Fc-associated effector functions

Authors
Nimmerjahn, Falk
Shinohara, Yasuro
Furukawa, Jun-Ichi
Petry, Franz
Verbeek, J Sjef
Nishimura, Shin-Ichiro
Ravetch, Jeffery V.
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Published in Journal of Immunology. 2008, vol. 181, no. 6, p. 4107-12
Abstract Four murine IgG subclasses display markedly different Fc-associated effector functions because of their differential binding to three activating IgG Fc receptors (FcgammaRI, FcgammaRIII, and FcgammaRIV) 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 FcgammaRIII 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 FcgammaRIV 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 FcgammaRIV and activate complement. Consequently, its pathogenicity was markedly diminished to a level comparable to that of IgG1. Our results demonstrated that the initiation of FcgammaR- 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 FcgammaRIV and C1q. This indicates the lack in the IgG1 subclass of as yet unknown motifs promoting efficient interaction with FcgammaRIV and C1q.
Keywords Amino Acids/chemistry/genetics/metabolismAnemia, Hemolytic, Autoimmune/genetics/immunologyAnimalsAntibody Affinity/geneticsDown-Regulation/genetics/immunologyImmunoglobulin G/genetics/metabolismImmunoglobulin Heavy Chains/biosynthesis/genetics/metabolismImmunoglobulin Switch RegionMiceMice, Inbred BALB CMice, Inbred NZBMice, KnockoutMutagenesis, Site-DirectedProtein Structure, Tertiary/geneticsReceptors, IgG/antagonists & inhibitors/genetics/metabolismSequence Deletion
Stable URL http://archive-ouverte.unige.ch/unige:1251
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Other version: http://www.jimmunol.org/cgi/content/full/181/6/4107
Identifiers
PMID: 18768867
Structures
Research group Lupus érythémateux systémique, de l'anémie hémolytique et de la glomérulonéphrite (168)

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Deposited on : 2009-03-30

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