Amyotrophic lateral sclerosis is a fatal neurodegenerative disease caused by degeneration of upper and lower motor neurons. In a small scale study, we recently found a distinct glycan, bisecting bi-antennary without core fucose; A2BG2, in IgG derived from ALS patient sera. The glycan increased IgG affinity to CD16 on effector cells and consequently stimulated effector cell activity and lysis of motor neuron cell lines, in vitro. In situ study revealed over-expression of CD16 and co-localization of intact ALS-IgGs with CD16 and with activated microglia cells of 75 and 130 days old ALS transgenic mice; G93A-SOD1. Accordingly, we aim to study the mechanism underlying Fc-glycan roles in G93A-SOD1mice. Preliminary analyses of the Fc-glycans enriched from mSOD1 and littermate blood at four different clinical severities; presymptomatic, onset of symptomatic, progressive disease with severe weakness and prior to paralysis and at the end-stage of the disease demonstrated altered disease severity-dependent Fc-glycan structures. The data were confirmed by real time quantitative PCR of glycosyltrasferase expressed in plasma B-cells. We then evaluated splenocyte profiles and the expression of specific IgG receptors like, FcgRIIIA, FcgRIIB and SIGN-R1, which their interaction with the Fc domain is governed by the Fc-glycan structure, and found a correlation between the receptor expression and clinical severities. These data were confirmed by immunostaining of brain and spinal cord sections. We next plan to modulate the IgG interactions with its receptors by fabricated Fc with standardized N-glycans. The establishment of structure-activity profiles should lead to Fc fragments with unique N-glycan structures capable of reducing ALS disease severity and prolonging patient’s lives.
