Complement activation selectively potentiates the pathogenicity of the IgG2b and IgG3 isotypes of a high affinity anti-erythrocyte autoantibody.
By generating four IgG isotype-switch variants of the high affinity 34-3C anti-erythrocyte autoantibody, and comparing them to the IgG variants of the low affinity 4C8 anti-erythrocyte autoantibody that we have previously studied, we evaluated in this study how high affinity binding to erythrocytes influences the pathogenicity of each IgG isotype in relation to the respective contributions of Fcgamma receptor (FcgammaR) and complement. The 34-3C autoantibody opsonizing extensively circulating erythrocytes efficiently activated complement in vivo (IgG2a = IgG2b > IgG3), except for the IgG1 isotype, while the 4C8 IgG autoantibody failed to activate complement. The pathogenicity of the 34-3C autoantibody of IgG2b and IgG3 isotypes was dramatically higher (>200-fold) than that of the corresponding isotypes of the 4C8 antibody. This enhanced activity was highly (IgG2b) or totally (IgG3) dependent on complement. In contrast, erythrocyte-binding affinities only played a minor role in in vivo hemolytic activities of the IgG1 and IgG2a isotypes of 34-3C and 4C8 antibodies, where complement was not or only partially involved, respectively. The remarkably different capacities of four different IgG isotypes of low and high affinity anti-erythrocyte autoantibodies to activate FcgammaR-bearing effector cells and complement in vivo demonstrate the role of autoantibody affinity maturation and of IgG isotype switching in autoantibody-mediated pathology.
Azeredo da Silveira
Samareh
S
Department of Pathology, University of Geneva, 1211 Geneva 4, Switzerland.
Kikuchi
Shuichi
S
Fossati-Jimack
Liliane
L
Moll
Thomas
T
Saito
Takashi
T
Verbeek
J Sjef
JS
Botto
Marina
M
Walport
Mark J
MJ
Carroll
Michael
M
Izui
Shozo
S
D000744:Anemia, Hemolytic, Autoimmune / Q000209:etiology / Q000276:immunology; D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D003167:Complement Activation / Q000276:immunology*; D004912:Erythrocytes / Q000276:immunology*; D017578:Immunoglobulin Class Switching / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D017452:Receptors, IgG / Q000276:immunology
D001323:Autoantibodies; D007074:Immunoglobulin G; D017452:Receptors, IgG