High pathogenic potential of low-affinity autoantibodies in experimental autoimmune hemolytic anemia.
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.
Fossati-Jimack
L
L
Department of Pathology, University of Geneva, 1211 Geneva 4, Switzerland.
Reininger
L
L
Chicheportiche
Y
Y
Clynes
R
R
Ravetch
J V
JV
Honjo
T
T
Izui
S
S
D000744:Anemia, Hemolytic, Autoimmune / Q000097:blood / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal; D001323:Autoantibodies / Q000097:blood*; D002460:Cell Line; D004912:Erythrocytes / Q000276:immunology*; D005434:Flow Cytometry; D014644:Genetic Variation; D006461:Hemolysis; D007074:Immunoglobulin G / Q000097:blood / Q000235:genetics; D007075:Immunoglobulin M / Q000097:blood / Q000235:genetics; D007134:Immunoglobulin Switch Region; D008099:Liver / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D011961:Receptors, Fc / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D011961:Receptors, Fc