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Regarding Fc Receptors

Regarding Fc Receptors

Yen-Ming Hsu

IgG Fc receptors

By interacting with antigen at one end and cell surface Fc receptors on another, antibody effectively brings together the humoral and cell-mediated immunity.

Based on their functionality, Fc -interacting proteins can be categorized into two groups.  One group of receptors on the surface of various effector cells are capable of trigger biological responses when interacting with antigen-antibody complexes. Among these receptors, the Fcγ receptors and Fc𝛆 receptors for interacting with IgG and IgE, respectively, are best characterized. The second group of receptors are responsible for transporting antibodies across epithelial tissues. These include the neonatal Fc receptor (FcRn) which transports IgG, and polymeric Ig receptor (pIgR) which transports IgM and IgA.

Human IgG Fc Receptors

In human, Fcγ receptors family consists of three classes (I, II, and III) with a total of six members. Among these, FcγRI, FcγRIIA, FcγRIIC, and FcγRIIIA are activating receptors each transmits the activation signals through an intrinsic ITAM motif (FcγRIIA and FcγRIIC) or the associated FcRγ chain dimer (FcγRI and FcγRIIIA); FcγRIIB is an inhibitory receptor carrying an intrinsic ITIM motif that transmits the inhibitory signals; FcγRIIIB is membrane anchored through a GPI linkage and does not contain a cytoplasmic domain for signaling.

There are four IgG subclasses in human, the IgG1, IgG2, IgG3 and IgG4 account for 60%, 32%, 4 % and 4%, respectively of circulating IgG molecules.  During the subclass switching, IgG3 switches forward to IgG1, IgG2 and lastly IgG4 irreversibly due to the genomic lineup of these heavy chains. Interestingly, this lineup is correlated with their respective affinities toward Fcγ receptors with IgG3 exhibits the highest affinity, followed by IgG1 with similar affinity and IgG2 and IgG4 with the least affinities. It should be mentioned that in Caucasians IgG3 has a short half-life in circulation due to its low affinity toward FcRn. With mutations in the hinge region which allows an enhanced binding to FcRn, IgG3 from non-Caucasians has a longer half-life in circulation. In all, while IgG3 exhibits an overall higher affinity toward Fcγ receptors, the IgG1 is 15x more abundant than IgG3 and therefore IgG1 is likely to be the dominant effector molecule in blood.

Structurally, Fcγ receptors are classified into the canonical and non-canonical groups. The canonical ones whose extracellular domains (ECDs) belongs to the Ig superfamily (IgSF) include all receptors except the FcγRn. Among these canonical Fc receptors, the ECD of FcγRI contains three Ig-like domains while the ECDs of all other canonical Fc receptors contains only two Ig-like domains. The extracellular domain of FcRn is a heterodimer consists of a protein related to the Class I major histocompatibility complexes (MHC-1) molecule and a β2 microglobulin. These structural differences are correlated with their binding sites with the Ig Fc regions: near the hinge region for binding of FcγRI, upper CH2-CH3 interface for bindings of all canonical receptors and lower CH2-CH3 interface for binding of FcRn. In addition, the glycan moiety associated with the 297 Asn residue within the CH2 region is critical for binding of the canonical Fcγ receptors but not the FcRn.

Allotypes of Fcγ receptors are implicated for functional differences. For example, in FcγRIIA a single amino acid substitution in position 131, Histidine (H131) or Arginine (R131), influences its binding to IgG2 with H131 exhibiting a 5x higher affinity than R131. The fact that persons with bacteremic infection are more likely to be homozygous for FcγRIIa-R131 is consistent with the observations that FcγRIIA is the principal receptor of human polymorphonuclear leukocytes (PMN) and that IgG2a subclass is primarily responsible for humoral responses to encapsulated bacteria.  Similarly, in FcγRIIIA, a single amino acid substitution in position 158, Valine (V158) or Phenylalanine (F158) influences its binding to IgG1 with the allotype V158 exhibiting enhanced affinity than allotype F158. The V158 allotype has greater affinity for all IgG subclasses and for IgG3, the binding efficiency approaches that of FcγRI. The differential binding affinity toward IgG within the FcγRIIIA variants is consistent with the observation that persons carrying V158 respond better to rituximab in the treatment of non-Hodgkin lymphoma.

Mouse IgG Fc Receptors

In mouse, Fcγ receptor family contains four members, FcγRI, FcγRIIB, FcγRIII, and FcγRIV . Among these, FcγRI, FcγRIII, and FcγRIV, each is associated with the FcRγ chain dimer, are activating receptors; and similar to its human counterpart, mouse FcγRIIB carries an intrinsic ITIM motif and is an inhibitory receptor. Thus, no mouse Fc receptor carries the intrinsic ITAM motif like that was found in human Fc receptors, FcγRIIA and FcγRIIC.

The interactions between mouse Fcγ receptors and mouse IgG are quite different from those in human. First, there are four mouse IgG isotypes, IgG1, IgG2a, IgG2b, and IgG3. Mouse FcγRI, like the human ortholog, its extracellular domain contains three Ig-like domains. It binds to mouse IgG2a with high affinity, mouse IgG2b and IgG3 with low affinity, and does not bind to mouse IgG1. Mouse FcγRIIB has a two Ig-like extracellular domains, it binds with low affinity to mouse IgG1, IgG2a, IgG2b and mouse IgE with low affinity. Several polymorphic variants have been described for the FcγRIIB but no functional impact has been reported.  Mouse FcγRIII contains a two-Ig-Like extracellular domain, it binds to mouse IgG1, IgG2a, IgG2b and IgE with low affinity. Similar to Mouse FcγRIIB, several polymorphic variants have been described for the FcγRIII but no functional impact has been reported. Mouse FcγRIV is the most recently identified mouse Fcγ receptor. It contains a two-Ig-Like extracellular domains and binds to IgG2a and IgG2b with high affinity and IgE with low affinity. Mouse FcγRIV does not bind to mouse IgG1 and IgG3. Thus, mouse IgG2a and IgG2b can interact with all three activating Fcγ receptors, whereas IgG1 can only interact with one activating receptor, FcRIII; and similarly, IgG3 can only interact with another activating receptor, FcγRI.

Comparison of human and mouse IgG Fc receptors

The comparison of human and mouse Fcγ receptor is complicated at least from the following aspects: (1) there are four receptors in human, three in mouse, ortholog assignment is based on sequence similarity only; (2) different functions/expression patterns; (3) difference in interacting with IgG subclasses. The following table summarizes the similarities and difference (based on Chap 8, FcγRs Across Species, Moldt and Hessell, Antibody Fc, Elsevier Inc. 2014, p.145-157) 

Human Fcγ Receptor Mouse Ortholog Similarity Difference
h.FcγRI m.FcγRI
  • High affinity;
  • Activating via the associated FcRg chain.
  • h.FcγRI binds to IgG1, IgG3, and IgG4;
  • m.FcγRI binds to IgG2a (to IgG2b and IgG3 with low affinity, does not bind to IgG1);
  • h.FcγRI is expressed on multiple cell types;
  • m.FcγRI is only expressed on monocyte-derived dendritic cells.
h.FcγRIIA m.FcγRIII
  • Low affinity;
  • Shared expression cell types: monocytes, macrophages, neutrophils, dendritic cells, basophils, mast cells, eosinophils.
  • h.FcγRIIA activates via the intrinsic ITAM motif; m.FcγRIII activates via the associated FcRg chain;
  • h.FcγRIIA is expressed on platelets, m.FcγRIII is not;
  • m.FcγRIII is expressed on NK cells, h.FcγRIIA is not;
  • h.FcγRIIA has 2 allelic forms differ in binding affinity, not found in m.FcγRIII;
  • m.FcγRIII binds to IgE, h.FcγRIIA does not.

h.FcγRIIB

m.FcγRIIB

  • Low affinity;
  • Containing the inhibitory ITIM motif.
  • h.FcγRIIB has lower affinity for IgG1, IgG2 and IgG3 than the human activating receptors; m. FcγRIIB has a similar affinity to IgG1 and IgG2b compared to the mouse activating receptors;
  • h.FcγRIIB is limitedly expressed on B cells and basophils; m.FcγRIIB is expressed on monocytes, macrophages, neutrophils, in addition;
  • m.FcγRIIB binds to IgE, h.FcγRIIB does not.
h.FcγRIIC No ortholog

 

h.FcγRIIIA

m.FcγRIV

  • Expressed on monocytes and macrophages;
  • High affinity toward afucosylated IgG;
  • Activated through the associated FcRg chain.
  • h.FcγRIIIA is expressed on NK cells, m.FcγRIV is express on neutrophils;
  • h.FcγRIIIA has 2 allelic forms differ in binding affinity, not found in m.FcγRIV;
  • h.FcγRIIIA is a low affinity receptor, m.FcγRIV is is a high affinity receptor;
  • m.FcγRIV binds to IgE, h.FcγRIIIA does not.
h.FcγRIIIB No ortholog

 

 



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