Development of stage-dependent glycans on the Fc domains of IgG antibodies of ALS animals

We recently revealed a unique glycan on the Fc domain of IgG antibodies in ALS patients that mediates antibody-dependent cell cytotoxicity (ADCC). This glycan has a bi-antennary structure that lacks the core fucose and sialic acid residues but contains a bisecting GlcNAc (A2BG2). Little is known, however, about the incidence of A2BG2 expression and IgG cytotoxicity under ALS conditions within well-defined clinical stages. Here, we characterize the IgG antibodies produced in ALS Tg mice by detecting intra- and extra-cellular antigens of motor neurons that express different glycan patterns during the disease. The increased number of innate immune cells found at the disease onset was insufficient to induce an optimal systemic T-cell response. Nevertheless, IgG antibodies were produced against intracellular antigens at the pre-symptomatic stage in the secondary lymphoid organs under the conditions of a poor systemic immune response. Moreover, while the glycosyltransferases of plasma B-cells that synthesize the Fc-glycans were regulated by IL-2 or IL-4, the observed glycosyltransferase pattern did not match that found in ALS Tg mice. We further found that A2BG2 glycan is specific for ALS, its quantity increased with disease progression and that the IgG antibodies identifying extracellular motor neuron antigens were developed at the final stage of the disease. Therefore, the most effective ADCC of motor neurons was observed at the end stage of the disease. We conclude that in ALS, IgG antibodies are produced despite the poor systemic immune response and that the frequency and quantity of A2BG2 glycan expression on the Fc domain depends on the clinical stage. Therefore, A2BG2 is a potential prognostic biomarker for ALS.