Xenogeneic Neu5Gc and self-glycan Neu5Ac epitopes are potential immune targets in MS.

OBJECTIVE: To explore the repertoire of glycan-specific immunoglobulin G (IgG) antibodies in treatment-naive patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: A systems-level approach combined with glycan array technologies was used to determine specificities and binding reactivities of glycan-specific IgGs in treatment-naive patients with RRMS compared with patients with noninflammatory and other inflammatory neurologic diseases. RESULTS: We identified a unique signature of glycan-binding IgG in MS with high reactivities to the dietary xenoglycan N-glycolylneuraminic acid (Neu5Gc) and the self-glycan N-acetylneuraminic acid (Neu5Ac). Increased reactivities of serum IgG toward Neu5Gc and Neu5Ac were additionally observed in an independent, treatment-naive cohort of patients with RRMS. CONCLUSION: Patients with MS show increased IgG reactivities to structurally related xenogeneic and human neuraminic acids. The discovery of these glycan-specific epitopes as immune targets and potential biomarkers in MS merits further investigation.

Fc-Galactosylation of Human Immunoglobulin Gamma Isotypes Improves C1q Binding and Enhances Complement-Dependent Cytotoxicity.

Binding of the complement component C1q to the CH2 domain of antigen-bound immunoglobulin gamma (IgG) activates the classical complement pathway and depends on its close proximity to Fc fragments of neighboring antibodies. IgG subclasses contain a highly conserved asparagine 297 (N)-linked biantennary glycan within their CH2 domains, the core structure of which can be extended with terminal galactose and sialic acid residues. To investigate whether Fc-glycosylation regulates effector functions of human IgG subclasses, we cloned the antigen-binding region of the CD20-specific monoclonal antibody rituximab into IgG isotype expression vectors. We found that Fc-galactosylation enhances the efficacy of CD20-targeting complement-fixing antibodies for C1q binding and complement-mediated tumor cell lysis. Increased efficacies were restricted to IgG1 and IgG3 subclasses indicating that Fc-galactosylation alone is not sufficient for IgG2 and IgG4 to acquire complement-fixing properties. Addition of terminal galactose to the N-glycan specifically improved binding of C1q without changing antigen- and FcγRIIIa-binding affinities of IgG isotypes. These data indicate that Fc galactosylation can be harnessed to enhance the complement-activating properties of IgG1 and IgG3 antibodies.

Regulation of antibody effector functions through IgG Fc N-glycosylation.

Immunoglobulin gamma (IgG) antibodies are key effector proteins of the immune system. They recognize antigens with high specificity and are indispensable for immunological memory following pathogen exposure or vaccination. The constant, crystallizable fragment (Fc) of IgG molecules mediates antibody effector functions such as complement-dependent cytotoxicity, antibody-mediated cellular cytotoxicity, and antibody-dependent cell-mediated phagocytosis. These functions are regulated by a single N-linked, biantennary glycan of the heavy chain, which resides just below the hinge region, and the presence of specific sugar moieties on the glycan has profound implications on IgG effector functions. Emerging knowledge of how Fc glycans contribute to IgG structure and functions has opened new avenues for the therapeutic exploitation of defined antibody glycoforms in the treatment of cancer and autoimmune diseases. Here, we review recent advances in understanding proinflammatory IgG effector functions and their regulation by Fc glycans.