Figure 1.
Figure 1. A schematic representation of the potential mechanisms of tolerance induction by the Fc portion of IgG. (A) The ligation of the inhibitory receptor FcγRIIb by IgG IC (potentially composed of FVIII–anti-FVIII IgG or rFVIIIFc–anti-FVIII IgG) on B cells has different consequences depending on B-cell maturity and has been shown to (1) prevent B cells with a higher-affinity self-reactive receptor from becoming IgG+ plasma cells and (2) induce apoptosis. When sialylated IgG engages CD23, (3) B cells upregulate FcγRIIb expression. (B) In the CH2 domain of the IgG Fc region, a single conserved glycosylation site is located (asparagine, N297). This site hosts 2 sugar moieties per IgG with extensive heterogeneity due to the variable addition of fucose, galactose, bisecting N-acetylglucosamine, or sialic acid. These differences result in altered IgG binding to FcγRs, among others, which ultimately influences the effector functions of the Fc domain. For instance, (C) ligation of sialylated IgGs to DC-SIGN is involved in upregulation of inhibitory FcγRIIb on the surface of the APC, which modulates downstream APC functions. (D-E) Although APCs express FcRn on the surface, FcRn does not bind IgG at neutral pH. Thus, monomeric IgG or rFVIIIFc is internalized by (i) fluid-phase endocytosis and binds to FcRn in (ii-iii) an acidic endosomal compartment, the pH at which FcRn binds IgG. FcRn then recycles (iv) IgG or rFVIIIFc back into the neutral pH milieu of the circulation. FcRn unbound IgG or other internalized soluble proteins (FVIII) will be subsequently degraded in (v) lysosomes and routed to (vi-vii) Ag-processing compartments where loading onto MHC class II molecules takes place. Therefore, FcRn diverts IgG or recombinant protein fused to Fc from Ag presentation. (E) IgG not bound to FcRn due to levels that exceed FcRn capacity will also be degraded and peptides derived from IgG can be presented in the context of MHC class II molecules. (viii) Within the CH2 domain of Fc, tolerogenic epitopes are present and promote tolerance via TREG cell activation (Tregitope). As tolerance can be imposed upon proteins attached to Fc, these regulatory effects are likely to be transmissible. TEFF, T effector.

A schematic representation of the potential mechanisms of tolerance induction by the Fc portion of IgG. (A) The ligation of the inhibitory receptor FcγRIIb by IgG IC (potentially composed of FVIII–anti-FVIII IgG or rFVIIIFc–anti-FVIII IgG) on B cells has different consequences depending on B-cell maturity and has been shown to (1) prevent B cells with a higher-affinity self-reactive receptor from becoming IgG+ plasma cells and (2) induce apoptosis. When sialylated IgG engages CD23, (3) B cells upregulate FcγRIIb expression. (B) In the CH2 domain of the IgG Fc region, a single conserved glycosylation site is located (asparagine, N297). This site hosts 2 sugar moieties per IgG with extensive heterogeneity due to the variable addition of fucose, galactose, bisecting N-acetylglucosamine, or sialic acid. These differences result in altered IgG binding to FcγRs, among others, which ultimately influences the effector functions of the Fc domain. For instance, (C) ligation of sialylated IgGs to DC-SIGN is involved in upregulation of inhibitory FcγRIIb on the surface of the APC, which modulates downstream APC functions. (D-E) Although APCs express FcRn on the surface, FcRn does not bind IgG at neutral pH. Thus, monomeric IgG or rFVIIIFc is internalized by (i) fluid-phase endocytosis and binds to FcRn in (ii-iii) an acidic endosomal compartment, the pH at which FcRn binds IgG. FcRn then recycles (iv) IgG or rFVIIIFc back into the neutral pH milieu of the circulation. FcRn unbound IgG or other internalized soluble proteins (FVIII) will be subsequently degraded in (v) lysosomes and routed to (vi-vii) Ag-processing compartments where loading onto MHC class II molecules takes place. Therefore, FcRn diverts IgG or recombinant protein fused to Fc from Ag presentation. (E) IgG not bound to FcRn due to levels that exceed FcRn capacity will also be degraded and peptides derived from IgG can be presented in the context of MHC class II molecules. (viii) Within the CH2 domain of Fc, tolerogenic epitopes are present and promote tolerance via TREG cell activation (Tregitope). As tolerance can be imposed upon proteins attached to Fc, these regulatory effects are likely to be transmissible. TEFF, T effector.

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