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Crucial role of aspartic acid at position 265 in the CH2 domain for murine IgG2a and IgG2b Fc-associated effector functions

Shinohara, Yasuro
Nimmerjahn, Falk
Furukawa, Jun-ichi
Nakata, Munehiro
Martínez-Soria, Eduardo
Petry, Franz
Ravetch, Jeffery V.
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Published in Journal of Immunology. 2008, vol. 181, no. 9, p. 6664-9
Abstract 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 (Fc gammaRIIB and Fc gammaRIII). However, it has not yet been defined whether the D265A substitution could exhibit similar effects on the interaction with two other Fc gammaR (Fc gammaRI and Fc gammaRIV) 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 Fc gammaR 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.
Keywords Alanine/geneticsAmino Acid Substitution/genetics/physiologyAnemia, Hemolytic, Autoimmune/genetics/immunologyAnimalsAntibodies, Monoclonal/toxicityAspartic Acid/genetics/physiologyAutoantibodies/toxicityComplement Activation/genetics/immunologyErythrocytes/immunologyImmunoglobulin G/chemistry/metabolismMiceMice, Inbred BALB CMice, Inbred C57BLMice, KnockoutProtein Isoforms/chemistry/deficiency/genetics/physiologyProtein Structure, Tertiary/genetics/physiologyReceptors, Fc/chemistry/deficiency/genetics/physiologySialic Acids/geneticsStructure-Activity Relationship
PMID: 18941257
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Other version: http://www.jimmunol.org/cgi/content/full/181/9/6664
Research group Lupus érythémateux systémique, de l'anémie hémolytique et de la glomérulonéphrite (168)
(ISO format)
BAUDINO, Lucie Clementine et al. Crucial role of aspartic acid at position 265 in the CH2 domain for murine IgG2a and IgG2b Fc-associated effector functions. In: Journal of Immunology, 2008, vol. 181, n° 9, p. 6664-9. doi: 10.4049/jimmunol.181.9.6664 https://archive-ouverte.unige.ch/unige:1395

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Deposited on : 2009-04-27

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