Abstract
The composition of the conserved N297 glycan in immunoglobulin G (IgG) has been shown to affect antibody effector functions via C1q of the complement system and Fc gamma receptors (FcγR) on immune cells. Changes in the general levels of IgG-glycoforms, such as lowered total IgG galactosylation observed in many autoimmune diseases have been associated with elevated disease severity. Agalactosyslated IgG has therefore been regarded and classified by many as pro-inflammatory. However, and somewhat counterintuitively, agalactosylation has been shown by several groups to decrease affinity for FcγRIII and decrease C1q binding and downstream activation, which seems at odds with this proposed pro-inflammatory nature. In this review, we discuss these circumstances where altered IgG galactosylation/glycosylation is found. We propose a novel model based on these observations and current biochemical evidence, where the levels of IgG galactosylation found in the total bulk IgG affect the threshold required to achieve immune activation by autoantibodies through either C1q or FcγR. Although this model needs experimental verification, it is supported by several clinical observations and reconciles apparent discrepancies in the literature, and suggests a general mechanism in IgG-mediated autoimmune diseases.
Highlights
Antibodies are crucial sentinels of the immune system, generated by B cells that sense incoming foreign antigens by their membrane-bound immunoglobulins or B cell receptor (BCR)
Using detailed glycoengineered immunoglobulin G (IgG) [60], we find no binding of any glycoform to the human receptors (Temming et al manuscript in preparation)
We have recently found that IgG agalactosylation—irrespective of all other glycan end groups—does not induce activation of complement via the lectin pathway, confirming various other studies on this subject [60, 95, 96]
Summary
Antibodies are crucial sentinels of the immune system, generated by B cells that sense incoming foreign antigens by their membrane-bound immunoglobulins or B cell receptor (BCR). With each B cell carrying a unique BCR, collectively they are able to respond to virtually any invading substance, let alone a complex pathogen [1]. Once recognizing their cognate antigen, each B cell becomes activated and can class switch from the initial IgM and IgD type of BCR, to immunoglobulin G (IgG), IgA, or IgE [2]. Since the first structures of IgG were solved, it became apparent that these structures are glycoproteins, with a conserved N-linked Fc-glycan attached to the asparagine found at position 297, situated in the constant region of the heavy chain domains [3] (Figure 1).
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