title: IgM and IgA anti-erythrocyte autoantibodies induce anemia in a mouse model through multivalency-dependent hemagglutination but not through complement activation.
abstract: 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.
authors.affiliation: Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
authors.forename: Lucie
authors.initials: L
authors.lastname: Baudino
authors.forename: Liliane
authors.initials: L
authors.lastname: Fossati-Jimack
authors.forename: Christelle
authors.initials: C
authors.lastname: Chevalley
authors.forename: Eduardo
authors.initials: E
authors.lastname: Martinez-Soria
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Shulman
authors.forename: Shozo
authors.initials: S
authors.lastname: Izui
mesh_terms: 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
chemical_list: D001323:Autoantibodies; D003176:Complement C3; D007070:Immunoglobulin A; D007075:Immunoglobulin M; D011108:Polymers