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Scientific article
English

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

Contributors

Baudino, Lucie Clementine; Shinohara, Yasuro; Nimmerjahn, Falk; Furukawa, Jun-ichi; Nakata, Munehiro; Martínez-Soria, Eduardo; Petry, Franz; Ravetch, Jeffery V.; Nishimura, Shin-ichiro; Izui, Shozo

Published in

The Journal of immunology, vol. 181, no. 9, p. 6664-6669

Publication date

2008

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/genetics
  • Amino Acid Substitution/genetics/physiology
  • Anemia, Hemolytic, Autoimmune/genetics/immunology
  • Animals
  • Antibodies, Monoclonal/toxicity
  • Aspartic Acid/genetics/physiology
  • Autoantibodies/toxicity
  • Complement Activation/genetics/immunology
  • Erythrocytes/immunology
  • Immunoglobulin G/chemistry/metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Protein Isoforms/chemistry/deficiency/genetics/physiology
  • Protein Structure, Tertiary/genetics/physiology
  • Receptors, Fc/chemistry/deficiency/genetics/physiology
  • Sialic Acids/genetics
  • Structure-Activity Relationship

UNIGE affiliation entities

UNIGE research groups

Citation (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: The Journal of immunology, 2008, vol. 181, n° 9, p. 6664–6669. doi: 10.4049/jimmunol.181.9.6664

Main files (1)

Article (Accepted version)

Identifiers

Additional URL for this publication

http://www.jimmunol.org/cgi/content/full/181/9/6664

Journal ISSN

0022-1767
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Technical informations

Creation

07/04/2009 09:41:00

First validation

07/04/2009 09:41:00

Update

14/03/2023 15:04:22

Status update

14/03/2023 15:04:22

Last indexation

29/10/2024 11:27:52
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