Complement Activation Selectively Potentiates the Pathogenicity of the IgG2b and IgG3 Isotypes of a High Affinity Anti-Erythrocyte Autoantibody

doi:10.1084/jem.20012024

Published 11 March 2002. doi:10.1084/jem.20012024

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© Rockefeller University Press, 0022-1007/2002/3/665/ $5.00
The Journal of Experimental Medicine, Volume 195, Number 6, March 18, 2002 665-672

Original Article

Complement Activation Selectively Potentiates the Pathogenicity of the IgG2b and IgG3 Isotypes of a High Affinity Anti-Erythrocyte Autoantibody

Samareh Azeredo da Silveira¹, Shuichi Kikuchi¹, Liliane Fossati-Jimack², Thomas Moll¹, Takashi Saito³, J. Sjef Verbeek⁴, Marina Botto², Mark J. Walport², Michael Carroll⁵ and Shozo Izui¹

¹ Department of Pathology, University of Geneva, 1211 Geneva 4, Switzerland
² Rheumatology Section, Hammersmith Campus, Imperial College School of Medicine, London W12 0NN, United Kingdom
³ Department of Molecular Genetics, Chiba University Graduate School of Medicine, Chiba 260, Japan
⁴ Department of Human and Clinical Genetics, Leiden University Medical Center, 2300 RA Leiden, Netherlands
⁵ Center for Blood Research and Department of Pathology, Harvard Medical School, Boston, MA 02115

Address correspondence to Dr. Shozo Izui, Department of Pathology, C.M.U., 1211 Geneva 4, Switzerland. Phone: 022-70-25-741; Fax: 022-70-25-746; E-mail: Shozo.Izui{at}medecine.unige.ch

By generating four IgG isotype-switch variants of the high affinity34–3C anti-erythrocyte autoantibody, and comparing themto the IgG variants of the low affinity 4C8 anti-erythrocyteautoantibody that we have previously studied, we evaluated inthis study how high affinity binding to erythrocytes influencesthe pathogenicity of each IgG isotype in relation to the respectivecontributions of Fc ${gamma}$ receptor (Fc ${gamma}$ R) and complement. The 34–3Cautoantibody opsonizing extensively circulating erythrocytesefficiently activated complement in vivo (IgG2a = IgG2b > IgG3),except for the IgG1 isotype, while the 4C8 IgG autoantibodyfailed to activate complement. The pathogenicity of the 34–3Cautoantibody of IgG2b and IgG3 isotypes was dramatically higher(>200-fold) than that of the corresponding isotypes of the 4C8antibody. This enhanced activity was highly (IgG2b) or totally(IgG3) dependent on complement. In contrast, erythrocyte-bindingaffinities only played a minor role in in vivo hemolytic activitiesof 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 isotypesof low and high affinity anti-erythrocyte autoantibodies toactivate Fc ${gamma}$ R-bearing effector cells and complement in vivo demonstratethe role of autoantibody affinity maturation and of IgG isotypeswitching in autoantibody-mediated pathology.

Key Words: autoimmune hemolytic anemia • complement receptor • Fc receptor • IgG isotype • phagocytosis

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