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

J Exp Med. 1999 Dec 6;190(11):1689-96. doi: 10.1084/jem.190.11.1689.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anemia, Hemolytic, Autoimmune / blood
  • Anemia, Hemolytic, Autoimmune / immunology*
  • Animals
  • Antibodies, Monoclonal
  • Autoantibodies / blood*
  • Cell Line
  • Erythrocytes / immunology*
  • Flow Cytometry
  • Genetic Variation
  • Hemolysis
  • Immunoglobulin G / blood
  • Immunoglobulin G / genetics
  • Immunoglobulin M / blood
  • Immunoglobulin M / genetics
  • Immunoglobulin Switch Region
  • Liver / immunology
  • Liver / pathology
  • Mice
  • Mice, Inbred BALB C
  • Receptors, Fc / immunology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transfection

Substances

  • Antibodies, Monoclonal
  • Autoantibodies
  • Immunoglobulin G
  • Immunoglobulin M
  • Receptors, Fc