Collection: Fc Receptors old

Antibodies are bi-functional molecules. The first half of the antibody contains the variable regions (Fab) recognizing the antigen. The second half of the antibody contains the crystallizable fragment (Fc) interacting with an array of Fc receptors (FcRs). The Fc-FcR interaction(s) brings the Fab-bound antigen to the proximity of immune effector cells. FcRs are primarily named after the class of antibody they bind: Fc gamma receptors (FcγRs) bind to IgG, Fc alpha receptors (Fcα Rs) bind to IgA, Fc epsilon receptors (Fc𝛆 Rs) bind to IgE, and Fc mu receptor (FcmR) binds to IgM and IgA. In addition to the canonical (structurally related to Ig superfamily) receptors, IgG also binds to two non-canonical receptors, the neonatal Fc receptor (FcRn) and DC-SIGN.

The canonical FcRs belong to the immunoglobulin superfamily. In human this family includes five members, FcγRI, FcγRIIa, FcγRIIb, FcγRIIIa, and FcγRIIIb. In mouse, this family includes 4 members, FcγRI, FcγRIIb, FcγRIII, and FcγRIV. Among the non-canonical Fcγ receptors, FcRn is structurally related to Class I major histocompatibility complexes (MHC-1), and the DC-SIGN (SIGNR1 in mouse) is related to C-type lectins.

All canonical human Fcγ receptors, except FcγRIIb and FcγRIIIb, transduce activation signals via the ITAM motif that is either intrinsic (FcγRIIa) or associated with the Fcγ chain (FcγRI, and FcγRIIIa). In contrast, FcγRIIb transduces an inhibitory signal through the intrinsic ITIM motif and FcγRIIIb lacks the transmembrane region and intracellular domain. Instead it is GPI-anchored on the cell surface and is considered as a decoy receptor. The intracellular domain is absent in both FcRn and DC-SIGN. In mouse, all activating receptors (FcγRI, FcγRIII, and FcγRIV) transduce the activating signals through the ITAM motif in the associated Fcγ chains and the mouse FcγRIIb transduces inhibitory signal through an intrinsic ITIM motif. Neither FcRn nor SIGNR1 transduces intracellular signals as both lack the intracellular domain.

Human IgG₁, the most abundant class of antibody, binds to FcγRI and FcRn with high affinity and to FcγRIIa, FcγRIIb, FcγRIIIa, FcγRIIIb, and DC-SIGN with low affinities. As such only the IgG-antigen immune complexes can productively bind to these receptors through the multi-valent interaction (avidity binding). Similarly, mouse IgG_2a, the most abundant class of antibody in mouse, binds to FcγRI and FcRn with high affinity, and only binds to FcγRIIb, FcγRIII, FcγRIV, and SIGNR1 when complexed with antigen.

Both human IgG₁ and mouse IgG_2a are glycosylated at the Asn297 residue. Subtle variations on this glycan moiety can significantly affect the binding of the IgG to Fcγ receptors. For example, the fucosyl moiety partially impedes the binding of the IgG to FcγRIIIa (human) and FcγRIV (mouse). As such antibodies missing this fucose (afucosyl antibodies) can bind to these receptors with elevated affinities and have been explored for better efficacy of therapeutic antibodies.