Markedly Different Pathogenicity of Four Immunoglobulin G Isotype-Switch Variants of an Antierythrocyte Autoantibody Is Based on Their Capacity to Interact in Vivo with the Low-Affinity Fc{gamma} Receptor III

doi:10.1084/jem.191.8.1293

Published online 17 April 2000.

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© The Rockefeller University Press, 0022-1007/2000/4/1293/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 8, April 17, 2000 1293-1302

Original Article

Markedly Different Pathogenicity of Four Immunoglobulin G Isotype-Switch Variants of an Antierythrocyte Autoantibody Is Based on Their Capacity to Interact in Vivo with the Low-Affinity Fc ${gamma}$ Receptor III

Liliane Fossati-Jimack^a, Andreea Ioan-Facsinay^b, Luc Reininger^c, Yves Chicheportiche^a, Norihiko Watanabe^d, Takashi Saito^d, Frans M. A. Hofhuis^e, J. Engelbert Gessner^f, Carsten Schiller^f, Reinhold E. Schmidt^f, Tasuku Honjo^g, J. Sjef Verbeek^b, and Shozo Izui^a

^a Department of Pathology, University of Geneva, 1211 Geneva 4, Switzerland
^b Department of Human and Clinical Genetics, Leiden University Medical Center, 2300 RA Leiden, The Netherlands
^c Institut National de la Santé et de la Recherche Médicale U 399, F-13385 Marseille, France
^d Department of Molecular Genetics, Chiba University Graduate School of Medicine, Chiba 260, Japan
^e Department of Immunology, University Hospital Utrecht, 3508 GA Utrecht, The Netherlands
^f Department of Clinical Immunology, Hannover Medical School, 30625 Hannover, Germany
^g Department of Medical Chemistry, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan
Department of Pathology, Centre Médical Universitaire, 1 rue Michel-Servet, Geneva 4, 1211, Switzerland.41-22-70-25-74641-22-70-25-741

shozo.izui{at}medecine.unige.ch

Using three different Fc ${gamma}$ receptor (Fc ${gamma}$ R)-deficient mouse strains,we examined the induction of autoimmune hemolytic anemia byeach of the four immunoglobulin (Ig)G isotype-switch variantsof a 4C8 IgM antierythrocyte autoantibody and its relation tothe contributions of the two Fc ${gamma}$ R, Fc ${gamma}$ RI, and Fc ${gamma}$ RIII, operativein the phagocytosis of opsonized particles. We found that thefour IgG isotypes of this antibody displayed striking differencesin pathogenicity, which were related to their respective capacityto interact in vivo with the two phagocytic Fc ${gamma}$ Rs, defined asfollows: IgG2a > IgG2b > IgG3/IgG1 for Fc ${gamma}$ RI, and IgG2a> IgG1 > IgG2b > IgG3 for Fc ${gamma}$ RIII. Accordingly, theIgG2a autoantibody exhibited the highest pathogenicity, $~$ 20–100-foldmore potent than its IgG1 and IgG2b variants, respectively,while the IgG3 variant, which displays little interaction withthese Fc ${gamma}$ Rs, was not pathogenic at all. An unexpected criticalrole of the low-affinity Fc ${gamma}$ RIII was revealed by the use of twodifferent IgG2a anti–red blood cell autoantibodies, whichdisplayed a striking preferential utilization of Fc ${gamma}$ RIII, comparedwith the high-affinity Fc ${gamma}$ RI. This demonstration of the respectiveroles in vivo of four different IgG isotypes, and of two phagocyticFc ${gamma}$ Rs, in autoimmune hemolytic anemia highlights the major importanceof the regulation of IgG isotype responses in autoantibody-mediatedpathology and humoral immunity.

Key Words: autoantibody • autoimmune hemolytic anemia • Fc receptor • IgG isotype • knockout mouse

Abbreviations used in this paper: Fc ${gamma}$ R, Fc receptor; FcR ${gamma}$ , FcRcommon ${gamma}$ chain; Ht, hematocrit; IC, immune complex; WT, wild-type.

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