Glycans as Master Switches of B Cell Activity in Autoimmunity

ongoing

Autoimmune diseases including rheumatoid arthritis (RA) are often life-threatening disorders with increasing disability having a negative impact on patients’ quality of life. Mechanisms leading to the breach of tolerance in development of autoimmunity are still largely unknown. Protein glycosylation is an essential regulatory mechanism in the immune system. We recently demonstrated that N-glycosylation of the variable region (Fab) of autoantibodies is a hallmark of RA development and progression. We also demonstrated that autoantibodies acquire these Fab glycosylation signatures already many years before disease onset. We herein hypothesize that Fab glycosylation at the level of the B cell receptor is a key molecular switch promoting the selection, activation and proliferation of autoreactive B cells leading to the concomitant breach of immunotolerance. Within GlycanSwitch, we will map the Fab glycome of various types of RA autoantibodies and autoreactive B cells. We will study the factors and underlying cellular mechanisms that regulate Fab glycosylation of B cell receptors and autoantibodies. We will investigate the immunological effects of Fab glycosylation and the impact in B cells signalling and activation in the context of molecular and cellular interacting partners in the immune microenvironment. Finally, we will test in relevant mouse models how Fab glycosylation of autoantibodies and autoreactive B cells contributes to the breach of tolerance. We expect that the obtained insights into the role of glycans as key checkpoint for the selection of autoreactive B cells and the rise of autoimmunity will provide leads for targeted therapeutic interventions as well as rationales for the early detection of RA and autoimmune diseases in general. We foresee that the knowledge generated will allow us to embark on a targeted prevention clinical study in patients at risk for RA to turn off the GlycanSwitch leading to chronic RA.