Antibodies (Abs) exert their function by binding to distinct Fc receptors and complement. The affinity of these interactions is traditionally ascribed to the Ab isotype. At least for the IgGs this view is evolving. N-linked glycans are increasingly proposed to influence binding to the classical Fc-gamma receptors (Fc?R) and allow for binding to non-classical type II receptors. This proposal will study the functional significance of Fc-glycosylation in potentiating or regulating the chronic inflammatory response in Multiple Sclerosis (MS) and its animal models. MS is a chronic disabling disease during which inflammatory lesions in the central nervous system cause local tissue damage, including demyelination and neuronal (axonal) loss. The genetic susceptibility points to a causal role for the immune response, but the triggers that provoke T and B cells to attack myelin, the factors that cause disease relapses, and the anatomical localisation and composition of the inflammatory lesions in relation to the heterogeneous clinical expression of MS remain active fields of investigation. Antibodies contribute to MS. Their presence in the cerebrospinal fluid is a diagnostic hallmark. Active lesions contain antibodies and reveal complement activation. Autoantibodies recognising potassium channel KIR4.1, Neurofascin, as well as glycolipids have been identified. Within MS lesions antibodies specific for Myelin oligodendrocyte glycoprotein (MOG) can be detected. The pathogenicity of MOG Abs is raising attention as their titers are increased in juvenile MS, but also optic neuritis, and in a subset of patients with Neuromyelitis Optica (NMO). The crystallisable fragment (Fc) of Abs binds to distinct Fc receptors (FcRs) and complement. For human IgGs this tightly regulated process relies on the structural heterogeneity of the Ig-Fc domain that arises from differences among the four subclasses (IgG1, IgG2, IgG3 and IgG4), and the complex bi-antennary N-linked glycan attached to the conserved Asn297. The glycosylation of the Fc-domain is proposed to create two structural conformations, an “open” conformation that favors binding to type I FcR that include the activating receptors Fc?RIA (CD64), Fc?RIIA (CD32a), Fc?RIIC, Fc?RIIIA (CD16a) and Fc?RIIIB, as well as the inhibitory receptor Fc?RIIB (CD32b). Accordingly, the absence of sialic acids and low levels of galactosylation confer important pro-inflammatory properties to IgG by facilitating their binding to activating Fc?Rs. In addition, the absence of core-fucose improves the affinity to the Fc?IIIA, thereby enhancing antibody-dependent cellular cytotoxicity. In contrast, a “closed” conformation favours binding to type II FcRs that comprise the C-type lectin receptor CD209 (DC-SIGN) and CD23. These sialylated Abs are endowed with a potential anti-inflammatory effect. The overarching aim of this research project is to assess whether this diversity of Fc-effector functions impacts on the severity of chronic inflammatory diseases of the central nervous system. Our strategy is to study this impact functionally using a translational approach. In MS patients we will analyse the N-glycome and the Fc-glycome of the antibody response. In animal models of MS we will study the pathogenicity of Fc-glycovariants.