The contribution of fucosylation and sialylation to the afferent and efferent pathways of humoral immunity

• Applicant: Dr. Benjamin-Maximillian Fiebiger, Ph.D.
• Subject Area: Immunology
• Term: from 2014 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 265089626

The presence of certain sugar moieties at the Fc core glycan of immunoglobulin G (IgG) molecules plays a critical role in both the efficiency of antibody-mediated anti-tumor responses, as well as in the treatment of autoimmune disorders using intravenous immunoglobulin G (IVIG) preparations. Thus, the modification of antibodies governs whether pro- or even anti-inflammatory responses are triggered and initiated. The attachment of fucose to the first N-Acetylglucosamine (GlcNAc) residue of the Fc core glycan occurs in about 95% of all antibodies and solely affects the Fcs binding affinity to the antibody receptor FcyRIV in mice or FcyRIIIa in humans. The lack of this modification clearly increases binding to these receptors. Furthermore, the presence of sialic acid at the very end of the biantennary glycan has been demonstrated to mediate anti-inflammatory responses. Thus, IVIG preparations that are enriched in sialylated IgG significantly ameliorate the onset and severity of autoimmune diseases such as rheumatoid arthritis (RA), immunothrombocytopenia (ITP), and chronic inflammatory demyelinating polyneuropathy (CIDP). This anti-inflammatory effect occurs indirectly by the activation of marginal zone macrophages, which respond by secreting interleukin-33 (IL-33). IL-33 activates basophils and triggers the expression and secretion of the TH2 cytokine IL-4, which acts on effector macrophages thereby inducing the up-regulation of the inhibitory Fc gamma receptor II B (FcyRIIB). This results in a dramatic change of the activation threshold of these macrophages towards inhibition. We will investigate the role of the enzymes Fut8 and St6gal1 that are essential to facilitate the production of specifically modified antibodies by participating not only in the efferent but also in the afferent arm of humoral immune responses. In this way, we will help to further improve antibody-based therapeutic strategies to treat various diseases and immune disorders.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Jeffrey V. Ravetch, Ph.D.