IgG bears
asparagine-linked
oligosaccharide side chains in the Fc region. Variations in their extent of galactosylation and sialylation could modulate
IgG Fc-dependent effector functions, and hence Ab activity. However, it has not yet been clarified whether the pathogenic potential of
IgG autoantibodies is consistently enhanced by the absence of
galactose residues per se or the lack of terminal sialylation, which is dependent on galactosylation. Moreover, it remains to be defined whether the increased pathogenicity of agalactosylated
IgG is related to activation of the
complement pathway by
mannose-binding lectin, as suggested by in vitro studies. Using a murine model of
autoimmune hemolytic anemia, we defined the contribution of galactosylation or sialylation to the pathogenic activity of
IgG1 and
IgG2a anti-erythrocyte class-switch variants of 34-3C monoclonal
autoantibody. We generated their degalactosylated or highly sialylated glycovariants and compared their pathogenic effects with those of highly galactosylated or desialylated counterparts. Our results demonstrated that lack of galactosylation, but not sialylation, enhanced the pathogenic activity of 34-3C
IgG1, but not
IgG2a autoantibodies. Moreover, analysis of in vivo complement activation and of the pathogenic activity in mice deficient in C3 or
IgG FcRs excluded the implication of
mannose-binding lectin-mediated complement activation in the enhanced pathogenic effect of agalactosylated
IgG1 anti-erythrocyte
autoantibodies.