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High pathogenic potential of low-affinity autoantibodies in experimental autoimmune hemolytic anemia

Fossati-Jimack, Liliane
Reininger, Luc
Clynes, R.
Ravetch, J. V.
Honjo, T.
Published in Journal of Experimental Medicine. 1999, vol. 190, no. 11, p. 1689-1696
Abstract 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.
Keywords Anemia, Hemolytic, Autoimmune/blood/ immunologyAnimalsAntibodies, MonoclonalAutoantibodies/ bloodCell LineErythrocytes/ immunologyFlow CytometryGenetic VariationHemolysisImmunoglobulin G/blood/geneticsImmunoglobulin M/blood/geneticsImmunoglobulin Switch RegionLiver/immunology/pathologyMiceMice, Inbred BALB CReceptors, Fc/immunologyReverse Transcriptase Polymerase Chain ReactionTransfection
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PMID: 10587359
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