FcR gamma-chain is essential for both surface expression and function of human Fc gamma RI (CD64) in vivo

Vugt, Martine J. van; Heijnen, Ingmar; Capel, P. J. A.; Park, S. Y.; Ra, C.; Saito, Takashi; Verbeek, J. Sjef; Winkel, Jan G. J. van de

doi:10.1182/blood.v87.9.3593.bloodjournal8793593

Cited by 128 publications

(59 citation statements)

References 31 publications

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“…Monovalent engagement leads to homeostatic recycling in contrast to multivalent engagement, which can trigger cell activation via the FcR γ-chain. 9,[15][16][17] Since we previously separately addressed thymus-independent (TI) and thymus-dependent (TD) antibody production, 2 here we will also discuss effector functions using this categorization. We need to keep in mind, however, that these events actually show an overlap and continuity when represented in our molecular interaction space (Figures 3a and b).…”

Section: Fcr-mediated Effector Functionsmentioning

confidence: 99%

A generalized quantitative antibody homeostasis model: maintenance of global antibody equilibrium by effector functions

Prechl¹

2017

Clin & Trans Imm

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The homeostasis of antibodies can be characterized as a balanced production, target-binding and receptor-mediated elimination regulated by an interaction network, which controls B-cell development and selection. Recently, we proposed a quantitative model to describe how the concentration and affinity of interacting partners generates a network. Here we argue that this physical, quantitative approach can be extended for the interpretation of effector functions of antibodies. We define global antibody equilibrium as the zone of molar equivalence of free antibody, free antigen and immune complex concentrations and of dissociation constant of apparent affinity: [Ab]=[Ag]=[AbAg]=KD. This zone corresponds to the biologically relevant KD range of reversible interactions. We show that thermodynamic and kinetic properties of antibody–antigen interactions correlate with immunological functions. The formation of stable, long-lived immune complexes correspond to a decrease of entropy and is a prerequisite for the generation of higher-order complexes. As the energy of formation of complexes increases, we observe a gradual shift from silent clearance to inflammatory reactions. These rules can also be applied to complement activation-related immune effector processes, linking the physicochemical principles of innate and adaptive humoral responses. Affinity of the receptors mediating effector functions shows a wide range of affinities, allowing the continuous sampling of antibody-bound antigen over the complete range of concentrations. The generation of multivalent, multicomponent complexes triggers effector functions by crosslinking these receptors on effector cells with increasing enzymatic degradation potential. Thus, antibody homeostasis is a thermodynamic system with complex network properties, nested into the host organism by proper immunoregulatory and effector pathways. Maintenance of global antibody equilibrium is achieved by innate qualitative signals modulating a quantitative adaptive immune system, which regulates molecular integrity of the host by tuning the degradation and recycling of molecules from silent removal to inflammatory elimination.

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Section: Fcr-mediated Effector Functionsmentioning

confidence: 99%

A generalized quantitative antibody homeostasis model: maintenance of global antibody equilibrium by effector functions

Prechl¹

2017

Clin & Trans Imm

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“…The typically functional FccRI receptor complex is composed of the ligand binding a chain associated with the dimeric signal-transducing FcRc chain via transmembrane domain interactions (see below) (70)(71)(72). The FcRc chain is a covalent homodimeric signal transducing adaptor molecule which contains an ITAM in each cytoplasmic domain.…”

Section: Structural and Functional Comparison Of Human And Macaque Fccrimentioning

confidence: 99%

“…The homodimeric FcRc chain is a promiscuous signaling subunit which interacts with FcRs in two distinct manners as exemplified by either the IgA receptor FcaRI, which contains a charged Arg 209 within its transmembrane region (109,110), or FceRIa (72,(111)(112)(113), which has a distinct transmembrane region containing a polar aspartic acid residue. The first reports of the physical association of FccRI with FcRc chain noted the high similarity of the sequence Leu-Ala-Val-Gly-Ile-Met-Phe-Leu-Val-Asn 306 -Thr-Val-Leu within the predicted transmembrane with a conserved transmembrane region of FccRIIIa (Leu-Val-Met-Val-Leu-Leu-Phe-Ala-Val-Asp-Thr-Gly-Leu) and FceRIa (Leu-Leu-Val-Val-Ile-Leu-Phe-Ala-Val-Asp-Thr-Gly-Leu) that interacts with the FcRc chain (114,115).…”

Section: Fcrc Chain Associationmentioning

confidence: 99%

The high‐affinity receptor for IgG, FcγRI, of humans and non‐human primates

Chenoweth

Trist

Tan

et al. 2015

Immunological Reviews

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Non-human primate (NHP) models, especially involving macaques, are considered important models of human immunity and have been essential in preclinical testing for vaccines and therapeutics. Despite this, much less characterization of macaque Fc receptors has occurred compared to humans or mice. Much of the characterization of macaque Fc receptors so far has focused on the low-affinity Fc receptors, particularly FcγRIIIa. From these studies, it is clear that there are distinct differences between the human and macaque low-affinity receptors and their interaction with human IgG. Relatively little work has been performed on the high-affinity IgG receptor, FcγRI, especially in NHPs. This review will focus on what is currently known of how FcγRI interacts with IgG, from mutation studies and recent crystallographic studies of human FcγRI, and how amino acid sequence differences in the macaque FcγRI may affect this interaction. Additionally, this review will look at the functional consequences of differences in the amino acid sequences between humans and macaques.

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“…Constructs were stably transfected into FcR-negative murine IIA1.6 cells [8] in the presence of FcR + -chain. This was done because + -chain proved important for both surface expression and function of hFc + RIa1 [9]. RNA was isolated from the different transfectants, reverse transcribed to cDNA, and amplified with CD64-specific primers.…”

Section: Generation Of Constructs and Detection Of Mrnamentioning

confidence: 99%

The alternatively spliced CD64 transcript FcγRIb2 does not specify a surface‐expressed isoform

et al. 1999

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Three highly homologous genes (A, B and C) and six transcripts have been identified for the class I human IgG receptor (CD64). The hFcgammaRIa1 isoform encodes the prototypic high-affinity receptor for IgG. The alternatively spliced hFcgammaRIb2 transcript was postulated to exist as a second surface-expressed CD64 isoform on myeloid cells. In this report we assessed this proposed role for hFcgammaRIb2 in detail. As CD64 monoclonal antibodies might not recognize hFcgammaRIb2, we tagged the receptor with an hemagglutinin tag and transfected hFcgammaRIb2tag in the presence of FcR gamma-chain into IIA1.6 cells. Both transcript and protein of hFcgammaRIb2tag were clearly present in transfectants. However, in contrast to the (control) hFcgammaRIa1tag, no surface expression of hFcgammaRIb2tag was detectable with a tag-specific monoclonal antibody. Confocal scan laser microscopy revealed hFcgammaRIb2tag to be retained in the endoplasmic reticulum, resulting in absent plasma membrane expression. These results show hFcgammaRIb2 neither to be surface expressed, nor to represent a separate CD64 isoform. This finding, furthermore, implicates that other FcR transcripts defined at the mRNA level may not represent true FcR isoforms either.

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FcR gamma-chain is essential for both surface expression and function of human Fc gamma RI (CD64) in vivo

Cited by 128 publications

References 31 publications

A generalized quantitative antibody homeostasis model: maintenance of global antibody equilibrium by effector functions

A generalized quantitative antibody homeostasis model: maintenance of global antibody equilibrium by effector functions

The high‐affinity receptor for IgG, FcγRI, of humans and non‐human primates

The alternatively spliced CD64 transcript FcγRIb2 does not specify a surface‐expressed isoform

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