Variable domain glycosylation as a marker and modulator of immune responses: Insights into autoimmunity and B-cell malignancies

Glycosylation of antibodies is essential for shaping immune responses, as it contributes significantly to antibody function and diversity. While immunoglobulin G (IgG) Fc glycosylation is well-characterized, variable domain glycosylation (VDG) introduces an additional and less understood layer of complexity. Notably, VDG is associated with rheumatoid arthritis, where disease-specific IgG autoantibodies abundantly express this modification. Moreover, its presence on these antibodies correlates with disease progression in at-risk individuals and therapeutic outcomes. Emerging evidence links increased VDG levels to other autoimmune diseases and B-cell malignancies, highlighting its potential as both a marker and modulator in disease onset and progression. Importantly, VDG on IgG is now recognized to influence antigen binding, enhance antibody stability, and modulate interactions with the human neonatal Fc receptor. In addition, glycans in the antigen-binding domains of autoreactive B-cell receptors (BCRs) can significantly impact B cell activation. In follicular lymphoma and other B-cell malignancies, the presence of N-glycosylation sites in the immunoglobulin variable domains leads to the introduction of oligomannose glycans, which are postulated to bind to mannose-specific lectins. This interaction might promote antigen-independent activation of BCRs, thereby supporting malignant B cell survival and proliferation. Here, we explore the regulatory pathways of VDG and its functional roles across both physiological and pathological conditions, underscoring its prevalence and significance in various autoimmune diseases and B-cell malignancies. Ultimately, advancing our understanding of the regulatory factors influencing VDG and its functional implications could be highly rewarding for identifying potential therapeutic targets and strategies to prevent and treat autoimmune diseases and B-cell malignancies.