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Original Article

^a Department of Pathology, University of Geneva, 1211 Geneva 4, Switzerland
^b Institut National de la Santé et de la Recherche Médicale U 399, F-13385 Marseille Cedex 5, France
^c The Rockefeller University, New York, New York 10021
^d Department of Medical Chemistry, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan
Department of Pathology, Centre Médical Universitaire, University of Geneva, 1211 Geneva 4, Switzerland.41-22-70-25-74641-22-70-25-741

shozo.izui{at}medecine.unige.ch

To assess the potency of low-affinity anti–red blood cell (RBC) autoantibodies in the induction of anemia, we generated an immunoglobulin (Ig)G2a class-switch variant of a 4C8 IgM anti–mouse RBC autoantibody, and compared its pathogenic potential with that of its IgM isotype and a high-affinity 34-3C IgG2a autoantibody. The RBC-binding activity of the 4C8 IgG2a variant was barely detectable, at least 1,000 times lower than that of its IgM isotype, having a high-binding avidity, and that of the 34-3C IgG2a monoclonal antibody (mAb). This low-affinity feature of the 4C8 mAb was consistent with the lack of detection of opsonized RBCs in the circulating blood from the 4C8 IgG2a–injected mice. However, the 4C8 IgG2a variant was highly pathogenic, as potent as its IgM isotype and the 34-3C IgG2a mAb, due to its capacity to interact with Fc receptors involved in erythrophagocytosis. In addition, our results indicated that the pentameric form of the low-affinity IgM isotype, by promoting the binding and agglutination of RBCs, is critical for its pathogenic activity. Demonstration of the remarkably high pathogenic potency of low-affinity autoantibodies, if combined with appropriate heavy chain effector functions, highlights the critical role of the Ig heavy chain constant regions, but the relatively minor role of autoantigen-binding affinities, in autoimmune hemolytic anemia.

Key Words: autoantibody • autoimmune hemolytic anemia • Fc receptor • Kupffer cell • knockout mouse

Abbreviations used in this paper: FcR, Fc receptor for IgG; FcR, FcR chain; HE, hematoxylin and eosin; Ht, hematocrit(s); NHS-biotin, N-hydroxysuccinimide biotin.

© 1999 The Rockefeller University Press

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