IgM and IgA anti-erythrocyte autoantibodies induce anemia in a mouse model through multivalency-dependent hemagglutination but not through complement activation.
By generating IgM and IgA switch variants of the 34-3C IgG2a anti-red blood cell (RBC) autoantibody, we evaluated the pathogenic activity of these 2 isotypes in view of the Fc-associated effector functions (ie, complement activation and polyvalency-dependent agglutination). We found that polymeric forms of 34-3C IgM and IgA anti-RBC autoantibody were as pathogenic as IgG2a, which was the most pathogenic among 4 different IgG subclasses, whereas their monomeric variants completely lacked pathogenic effects. Histological examination showed that 34-3C IgM and IgA autoantibodies caused anemia as a result of multivalency-dependent hemaggultination and subsequent sequestration of RBC in the spleen, in contrast to Fc receptor- and complement receptor-mediated erythrophagocytosis by Kupffer cells with IgG isotypes. In addition, the development of anemia induced by IgM and IgA isotypes of 34-3C antibody and by 2 additional IgM anti-RBC monoclonal autoantibodies was not inhibited at all in C3-deficient mice, indicating the lack of involvement of complement activation in the pathogenesis of IgM- and IgA-induced anemia. Our data demonstrate a remarkably high pathogenic potential of polymeric forms of IgM and IgA anti-RBC autoantibodies due to their ability to induce hemagglutination but completely independent of complement activation.
Baudino
Lucie
L
Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
Fossati-Jimack
Liliane
L
Chevalley
Christelle
C
Martinez-Soria
Eduardo
E
Shulman
Marc J
MJ
Izui
Shozo
S
D000740:Anemia / Q000209:etiology* / Q000276:immunology; D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D003167:Complement Activation; D003176:Complement C3 / Q000172:deficiency; D004195:Disease Models, Animal; D004912:Erythrocytes / Q000276:immunology*; D006384:Hemagglutination / Q000276:immunology*; D007070:Immunoglobulin A; D007075:Immunoglobulin M; D051379:Mice; D018345:Mice, Knockout; D011108:Polymers
D001323:Autoantibodies; D003176:Complement C3; D007070:Immunoglobulin A; D007075:Immunoglobulin M; D011108:Polymers