Edited by: Jan Terje Andersen, Oslo University Hosiptal, Norway
Reviewed by: Beatrice Jahn-Schmid, Medical University of Vienna, Austria; Sylvie Fournel, Strasbourg University, France
†Caitlin Gillis and Aurélie Gouel-Chéron have contributed equally to this work.
‡Friederike Jönsson and Pierre Bruhns are Co-senior authors.
This article was submitted to Immunotherapies and Vaccines, a section of the journal Frontiers in Immunology.
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The biological activities of human IgG antibodies predominantly rely on a family of receptors for the Fc portion of IgG, FcγRs: FcγRI, FcγRIIA, FcγRIIB, FcγRIIC, FcγRIIIA, FcγRIIIB, FcRL5, FcRn, and TRIM21. All FcγRs bind IgG at the cell surface, except FcRn and TRIM21 that bind IgG once internalized. The affinity of FcγRs for IgG is determined by polymorphisms of human FcγRs and ranges from 2 × 104 to 8 × 107 M−1. The biological functions of FcγRs extend from cellular activation or inhibition, IgG-internalization/endocytosis/phagocytosis to IgG transport and recycling. This review focuses on human FcγRs and intends to present an overview of the current understanding of how these receptors may contribute to various pathologies. It will define FcγRs and their polymorphic variants, their affinity for human IgG subclasses, and review the associations found between FcγR polymorphisms and human pathologies. It will also describe the human FcγR-transgenic mice that have been used to study the role of these receptors in autoimmune, inflammatory, and allergic disease models.
Human myeloid cells, NK cells, and B cells are equipped with a variety of receptors that enable their interaction with monomeric or aggregated immunoglobulins, antigen–antibody immune complexes, and opsonized (antibody-coated) particles, cells, or surfaces. Most of these receptors bind the Fc portion of immunoglobulins (receptors for the Fc portion of immunoglobulins, FcR) and endow these cells with the capacity to interact with IgM, IgA, IgG, and/or IgE. This review will focus on IgG-binding human FcRs, FcγRs.
Humans express nine FcγRs: the six classical FcγRs, FcγRI, FcγRIIA, FcγRIIB, FcγRIIC, FcγRIIIA, and FcγRIIIB; as well as FcRn, FcRL5 (
Human FcγR expression on different cell types has been fairly comprehensively described, mostly by the use of FcγR-specific monoclonal antibodies (mAb) but also from data using mRNA profiling (Figure
These expression patterns highlight that hFcγRIIA is the only activating IgG receptor constitutively expressed by mast cells, basophils, neutrophils, and eosinophils, and that FCRL5 is the only activating IgG receptor constitutively expressed by B cells. Importantly, signal transduction events induced by human activating IgG receptors may be negatively regulated by hFcγRIIB only in B cells, dendritic cells, and basophils, and rare fractions of monocytes and neutrophils. Indeed, mast cells, NK cells, and most neutrophils and monocytes do not express this inhibitory receptor. hFcRn has been reported in dendritic cells, monocytes/macrophages (
These patterns correspond to the expression of FcγRs in healthy individuals. These may be modified during pathological conditions or following therapeutic treatments. Certain cytokines for example have been reported to up-regulate or down-regulate some hFcγRs; e.g., B cells express higher levels of hFcγRIIB following IFN-γ but lower levels following IL-4 stimulation, whereas opposite effects have been reported for monocytes [reviewed in Ref. (
Activating FcγRs signal through an immunoreceptor tyrosine-based activation motif (ITAM) that is either present in their intracytoplasmic domain or in associated signaling subunits, such as the FcRγ chain (Figure
Internalization of antibodies, and of the antigens they are bound to, represents the only shared function of IgG receptors expressed at the cell surface (that is, all except FcRn and TRIM21), whether ITAM-bearing, ITIM-bearing, or neither. FcγRs thereby enable antigen capture and internalization by all FcγR-expressing nucleated cells, as well as phagocytosis of opsonized bacteria, viruses, or cells by phagocytes. FcRn is the only receptor enabling transcytosis of IgG or IgG-IC by polarized cells (
The multiplicity of human FcγRs (Figure
Receptor | Variant | Effect | Reference |
---|---|---|---|
FcγRIIA | H/R131 | H131: |
( |
FcγRIIA-exon 6* | ( |
||
FcγRIIB | −386G/c | ( |
|
−120T/a | |||
I/T232 | T232: |
( |
|
FcγRIIC | Q/stop13 | Q13: expression on NK cells, monocytes, neutrophils | ( |
CNV | Correlation with protein expression levels | ( |
|
FcγRIIIA | V/F158 | V158: |
( |
CNV | Correlation with protein expression levels; impaired NK cell cytotoxic function | ( |
|
FcγRIIIB | NA1/NA2/SH | NA1: |
( |
SH: |
|||
CNV | Correlation with protein expression levels | ( |
A polymorphism resulting in the presence of a histidine or an arginine residue at position 131 may also be referred to as low-responder (H131) or high-responder (R131) (
A novel splice variant of
Single-nucleotide polymorphisms (SNPs) at positions 386 [IIB-386 (G/c)] and 120 [IIB-120 (T/a)], collectively constitute the 2B.4 promoter haplotype, which displays increased binding capacity for transcription factors GATA4 and Yin-Yang1, resulting in increased promoter activity and higher expression of FcγRIIB on monocytes, B lymphocytes, neutrophils, and myeloid DCs (
A polymorphism encoding an isoleucine to threonine substitution at position 232 in the transmembrane domain of FcγRIIB (T232) may disable receptor function via exclusion from lipid rafts (
In 20% of individuals
A subset of individuals carrying
A SNP determines the presence of a valine or phenylalanine at position 158 (
FcγRIIIB bears the neutrophil antigen (NA) in its membrane-distal Ig-like domain, generating three variants termed NA1 (R36 N65 A78 D82 V106), NA2 (S36 S65 A78 N82 I106) (
Recognized as an important indicator for inter-individual differences, can alter the expression of activating IgG receptors. The balance between activating and inhibitory FcγRs can therefore be perturbed, altering cellular responses toward IgG-immune complexes. CNV of
Several
FcγR polymorphisms may also influence patients’ response to treatment with intravenous immunoglobulin and therapeutic mAb. Almost all mAb used in therapy are based on human IgG1 antibodies, either chimeric mouse/human or fully human, allowing their interaction with all human FcγRs (
Altogether, particular FcγR polymorphisms have been described to be associated with the induction or severity of antibody-related disease, or patient responsiveness to antibody-based therapies. Nonetheless one should keep in mind that most FcγR-encoding genes are located within the 1q23 locus (
Transgenic mouse studies have greatly enhanced our understanding of the
Gene | SNP | Disease | Reference |
---|---|---|---|
H131 | GBS, Kawasaki disease, idiopathic pulmonary fibrosis, and, for homozygous genotypes, MG, and children chronic ITP | ( |
|
R131 | Bronchial asthma and allergic rhinitis, Still disease, Behçet’s disease, refractory ITP, WG, MS, SLE, lupus nephritis, antiphospholipid syndrome, giant cell arteritis, rheumatic fever, ITP, and IgA nephropathy | ( |
|
FcγRIIa-exon 6* | Anaphylaxis in patients with hypogammaglobulinemia, common variable immunodeficiency | ( |
|
T232 | SLE, anti-GBM disease | ( |
|
−386C/−120A | SLE, chronic inflammatory demyelinating polyneuropathy | ( |
|
CNV | ITP, Kawasaki disease | ( |
|
F158 | SLE, Crohn’s disease, Behçet’s disease, severe GBS, bullous pemphigoid, WG relapses, RA, and for homozygotes, chronic ITP, and nephritis | ( |
|
V158 | For homozygotes: RA susceptibility and severity, idiopathic inflammatory myopathies, and IgA nephropathy | ( |
|
CNV | Anti-GBM disease, RA | ( |
|
NA1 | For homozygotes: anti-neutrophil cytoplasmic antigen systemic vasculitis, chronic ITP in children, and severe course of MG | ( |
|
NA2 | SLE, severe GBS, Behçet’s disease, IgA nephropathy, and MS | ( |
|
SH | Alloimmune neonatal neutropenia, transfusion reactions | ( |
|
CNV | Glomerulonephritis, SLE, systemic autoimmunity, RA, idiopathic pulmonary fibrosis, systemic sclerosis, and Kawasaki disease | ( |
The common approach to reproduce hFcγR expression patterns in mice is to use the genuine human promoter to drive transgene expression (Table
FcR-mediated uptake of immune complexes and subsequent antigen presentation is a critical aspect of the immune response to foreign pathogens. Targeting of antigen to hFcγRI in hFcγRItg mice induced a strong antibody response, suggesting that hFcγRI on myeloid cells is capable of mediating antigen uptake and presentation
Mice deficient for the FcRγ-subunit that is necessary for the expression of all mouse activating FcγRs are resistant to antibody-mediated platelet destruction, demonstrating the importance of activating FcγRs in this model of autoimmune thrombocytopenia (
Individuals who have developed antibodies against a given allergen can, upon re-exposure, develop a severe systemic allergic reaction (anaphylaxis). Allergen re-exposure induces the rapid formation of immune complexes that leads to cellular activation and release of vasoactive mediators, which drives the phenotype of systemic shock, including symptoms of hypotension and respiratory distress. Although anaphylaxis is classically attributed to an IgE-mediated mast cell-dependent paradigm of allergic reactivity, the same systemic symptoms can be reproduced experimentally in mice by the transfer of specific IgG antibodies and allergen, of preformed immune complexes (passive systemic anaphylaxis, PSA), or by repeated immunization with an antigen prior to challenge (active systemic anaphylaxis, ASA). hFcγRI and hFcγRIIA expressed in transgenic mice were each individually sufficient to mediate PSA, the symptoms of which may be alleviated by pre-treatment with blocking antibodies (
The formation of immune complexes is a hallmark of many human diseases, and their accumulation is an important trigger of inflammation-induced tissue damage. Pathogenic antibodies may bind directly to host cells, or immune complexes may deposit within tissues and trigger activation of local or circulating hFcγR-expressing cells. Using hFcγRIIAtg mice, it was demonstrated that hFcγRIIA expressed on skin mast cells could trigger their activation following intradermal injection of immune complexes resulting in an inflammatory reaction in the skin (
Rheumatoid arthritis is an autoimmune disease in which the formation of immune complexes within the joints drives an inflammatory pathology. Autoantibodies directed against joint proteins such as collagen type II or glucose-6-phosphate isomerase (GPI) are found in RA patients, and the arthritis pathology may be modeled in mice by either active immunization with joint-associated components or by passive antibody transfer. hFcRntg mice provided direct evidence for the role of this receptor in serum persistence and transport of antibodies into tissues (
Studies using hFcγRtg mice have enabled the description of specific
Although, it is tempting to draw conclusions from genetic association studies performed in humans, it would be overreaching to delineate causal relationships between particular FcγR variants and antibody-mediated human disease. Importantly, all the human FcγR-transgenic mouse strains that have been reported express a single polymorphic variant of each FcγR (Table Expression of hFcγRIIA (R131) renders mice susceptible to arthritis and autoimmune pathologies including thrombocytopenia (Table The NA1 allotypic variant of FcγRIIIB confers increased phagocytosis of IgG-immune complexes, and is associated with thrombocytopenia in humans; whereas FcγRIIIB-NA2 and CNV are associated with inflammatory and autoimmune conditions characterized by immune complex deposition. These data are congruent with findings in NA2-hFcγRIIIBtg mice (Table
Promoter | Expression | Variant | Strain | Reference | |
---|---|---|---|---|---|
Monocytes, macrophages, DCs, neutrophils | FVB/N | Bi-specific mAb-dependent hFcγRI-triggered killing ( |
( |
||
FVB/N | Anti-hFcγRI mAb immunization elicits higher Ab responses | ( |
|||
FVB/N | hFcγRI-mediated binding and phagocytosis of opsonized RBCs | ( |
|||
? | Antigen targeting to hFcγRI increased vaccination potency | ( |
|||
FVB/N | Weak antigen targeting to hFcγRI enhances immunogenicity | ( |
|||
FVB/N | Immunotoxin targeting of hFcγRI reduces inflammation | ( |
|||
5KO (B6 F6) | hFcγRI-dependent arthritis, thrombocytopenia, airway inflammation, and anaphylaxis (PSA and ASA) | ( |
|||
Monocytes, macrophages, neutrophils, eosinophils, basophils, mast cells, DCs, megakaryocyte, platelets | R131 | FcRγ−/−(B6xSJL) | Immune thrombocytopenia can be induced via hFcγRIIA | ( |
|
FcRγ−/−(B6) | hFcγRIIA-dependent thrombosis and shock | ( |
|||
hPF4tg (B6) | hFcγRIIA-dependent Heparin-induced thrombocytopenia | ( |
|||
C57BL/6 | Increased active and passive collagen-induced arthritis | ( |
|||
FcRγ−/−(B6xSJL) | hFcγRIIA mediates experimental immune hemolytic anemia | ( |
|||
hPF4tg lo/hi (B6) | PF4-hFcγRIIA-dependent Heparin-induced thrombocytopenia | ( |
|||
C57BL/6 × SJL F1 | hFcγRIIA-dependent platelet activation by Bevacizumab IC | ( |
|||
C57BL/6 × SJL F1 | Small chemical entities inhibit collagen-induced arthritis | ( |
|||
C57BL/6 × SJL F1 | hFcγRIIA-dependent platelet activation by CD40L IC | ( |
|||
C57BL/6 × SJL F1 | Increased sensitivity to autoimmune arthritis | ( |
|||
C57BL/6 | Inhibition of hFcγRIIA-signaling pathway to inhibit thrombosis and thrombocytopenia | ( |
|||
FcRγ−/−,5KO | hFcγRIIA induces anaphylaxis and airway inflammation | ( |
|||
C57BL/6J | hFcγRIIA cooperates with integrin signaling in platelets | ( |
|||
Neutrophils, some monocytes | R131 | FcγR−/− | hFcγRIIA-dependent nephritis, Arthus reaction, neutrophil recruitment and tissue injury | ( |
|
FcγR−/− | Neutrophil hFcγRIIA is sufficient for arthritis induction | ( |
|||
FcγR−/− | hFcγRIIA-dependent NETosis in Arthus reaction | ( |
|||
B cells, splenic CD11c DCs, monocytes, neutrophils, eosinophils | I232 | C57Bl/6 | Crosslinking hFcγRIIB and CD19 suppresses humoral immunity in systemic lupus erythematosus | ( |
|
FcRγ−/−or FcγRIIB−/− | hFcγRIIB-enhanced immunostimulatory and anti-tumor activity of chimeric mouse–human agonistic anti-CD40 Abs | ( |
|||
CD40−/− | Anti-tumor activity of agonistic anti-TNFR Abs requires differential hFcγRIIB coengagement | ( |
|||
NK cells, macrophages | F158 | B6xCBAFl | Promoter/expression analysis | ( |
|
? | NK cells and ? | ? | SCID | Glycoengineering of a humanized anti-EGFR Ab leads to enhanced ADCC through hFcγRIIIA | ( |
Neutrophils | ? | B6xCBAFl | Promoter/expression analysis | ( |
|
Neutrophils, some monocytes | NA2 | FcRγ−/− | hFcγRIIIB is sufficient for NTS nephritis, cutaneous RPA reaction and promotes neutrophil recruitment | ( |
|
FcRγ−/− | hFcγRIIIB mediates neutrophil tethering to intravascular immune complexes and their uptake | ( |
|||
Neutrophils, some monocytes | IIA: R131 | FcRγ−/− | hFcγRIIA and hFcγRIIIB cooperate to induce nephritis and cutaneous Arthus reaction | ( |
|
IIIB:NA2 | |||||
Please refer to single transgenic mice | I | mFcγRI−/− | Antibody-mediated FcγR-dependent cell depletion (B cells, T cells, platelets), and B16-F10 lung metastasis clearanceFcγR-mediated IC-induced systemic anaphylaxis | ( |
|
IIA-R131 | mFcγRIIB−/− | ||||
IIB-I232 | mFcγRIII−/− | ||||
IIIA-F158 | mFcγRIV−/− | ||||
IIIB-? | |||||
Intestine and ? | mFcRn−/− | hFcRn expression restores serum half life of hIgG in mFcRn−/−mice | ( |
||
mFcRn−/−; mFcRn−/−FcγRIIB−/− | hIgG with engineered high FcRn binding affinity has enhanced half life |
( |
|||
mFcRn−/−mβ2m−/−hFcRntg hβ2mtg | Blocking hFcRn using a peptide antagonist increases hIgG catabolism | ( |
|||
6KO (B6 F6) | hFcRn restores arthritis susceptibility in 6KO mice | ( |
While genetic association studies identify important risk factors and inform on the involvement of FcγR in human disease; hFcγRtg mice allow us to more precisely dissect pathological mechanisms, and describe the role of human FcγR and the cells expressing them in various clinically relevant pathologies. Together, these data in humans and transgenic models highlight the contribution of hFcγR to antibody-mediated diseases, and open avenues for understanding pathogenic mechanisms. Such data will continue to impact on therapeutic choices and potentially identify new interventional targets.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Works of our laboratory discussed in this review were supported by the Institut Pasteur, the Institut National de la Santé et de la Recherche Médicale (INSERM), the Agence Nationale pour la Recherche (grant GENOPAT-09-GENO-014-01), the Société Française d’Allergologie (SFA), and the company Balsan. Caitlin Gillis is a scholar of the Pasteur Paris University International Doctoral Program (PPUIDP) and received a stipend from the Institut Carnot Pasteur Maladies Infectieuses. Friederike Jönsson is a
1Note: for the sake of clarity, this section will use the terminology “hFcγR” for human IgG receptors, and “mFcγR” for mouse IgG receptors.