The glycobiology of B cell receptors in autoimmunity, health and lymphoma

Abstract

ACPA are the prototypical variable domain glycosylated IgG response and are directed against proteins carrying citrullinated epitopes. ACPA exhibit relatively low affinity for citrullinated antigens, carry a large number of SHMs and harbor characteristic VDGs, which are introduced before disease onset and are predictive for future RA development. These features together suggest that VDGs may play a role in the breach of immunological tolerance.

The studies presented in this thesis chiseled away at elucidating the biological role of VDGs on B cell biology by investigating BCR (variable domain) glycans from several perspectives. Of note, this work can be summarized in 3 key conclusions. Firstly, we provide evidence to the contrary of a longstanding hypothesis in the field and show that B cell SIGLECs such as CD22 and SIGLEC-10 do not bind to BCR VDGs, or Fc glycans for that matter, in situ. Secondly, we characterized the structure of conserved IgM BCR glycans and find that their effects on B cell biology distinct to the roles of ACPA VDGs. Thirdly, we show that VDGs expressed by patient-derived B cell lymphomas indeed are enriched in oligomannose-type glycans.