Contribution of Human FcγRs to Disease with Evidence from Human Polymorphisms and Transgenic Animal Studies

Abstract

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.

Introduction on Human FcγRs: Definition and Basic Functions

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 (1, 2), and TRIM21 (3) (Figure 1). These FcγRs all bind IgG on the surface of the cells expressing them, except FcRn (4, 5) and TRIM21 (6, 7) that bind IgG once internalized. Notably, all IgG receptors bind at least two human IgG subclasses, albeit with varying binding affinity: the association constants (K_A) of IgG–FcγR interactions range from 8 × 10⁷ down to 2 × 10⁴ M⁻¹ (8) (Figure 1). Historically, FcγRs were categorized as either low-affinity receptors that can only bind IgG when present in an immune complex, aggregated, or opsonized; or high-affinity receptors that can also bind free or monomeric IgG. This terminology has become rather obsolete considering reports of high- and low-affinity interactions for a single receptor toward different Ig subclasses. Furthermore, although the prevailing belief was that occupancy of high-affinity receptors with pre-bound monomeric IgG prevents their participation in immediate IgG-dependent reactions; this has recently been refuted in vivo (9). Adding to this complexity, human FcγR polymorphisms that modulate affinity for some human IgG subclasses have been described (8) (refer to part 2; Figure 1).

Figure 1

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 2). Generally, the following observations can be made: hFcγRI (CD64) is restricted to monocytes/macrophages and dendritic cells and is inducibly expressed on neutrophils (10) and mast cells (11); hFcγRIIA (CD32A) is expressed on all myeloid cells but not on lymphocytes; hFcγRIIB (CD32B) is expressed at high levels only on B cells (12) and basophils (13). It is also expressed on tissue macrophages and dendritic cells (12), but only at low levels on 20% of circulating monocytes and 4% of circulating neutrophils (12, 14), and is not expressed on primary skin mast cells (15); hFcγRIIC (CD32C; refer to Section “Human FcγR Polymorphisms” for its “stop₁₃” polymorphism) is expressed on NK cells (16), monocytes, and neutrophils (17); hFcγRIIIA (CD16A) is expressed on NK cells and monocytes/macrophages; hFcγRIIIB (CD16B) is highly expressed on neutrophils and at low levels on some basophils (18). TRIM21 (aka Ro52) was described to be widely expressed among lymphoid and myeloid populations, but also on endothelial cells (19). FcRL5 has been reported to be restricted to B cells (2).

Figure 2

20). ^♮In Fcgr2c-ORF persons (17). ^#Detectable and functional expression in non-conventional Fcgr2c-Stop persons (17).

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 (21), neutrophils (22), and endothelial cells (23), but expression on platelets and mast cells has not been examined so far.

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. (24)]. On the latter cells, expression of hFcγRIIA is increased following IFN-γ and decreased following IL-4 stimulation (25). IL-3 stimulation, however, induces higher expression of both receptors (activating hFcγRIIA and inhibitory hFcγRIIB) on basophils (13). Mucosal mast cells express hFcγRI upon IFN-γ stimulation (11). Surprisingly, IL-3 stimulation of primary monocytes did not modify hFcγRI expression, but increased its ability to bind IgG-immune complexes and to induce intracellular activation signals (26).

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 1), the FcRβ chain (exclusively in mast cells and basophils), or the CD3ζ chain (exclusively in NK cells). These ITAM-containing structures allow FcγRs, once aggregated by multimeric ligands, to activate signaling cascades via SRC family kinases and spleen tyrosine kinase (SYK) leading to cell activation, cytokine/chemokine production, and cell migration (27–29). The inhibitory receptor FcγRIIB possesses instead an immunoreceptor tyrosine-based inhibition motif (ITIM) in its intracytoplasmic domain (30), which allows this receptor, once co-engaged with an activating FcγR, to recruit the inositol polyphosphate-5-phosphatase SHIP1 (31) that counteracts the signaling cascades initiated by activating FcγRs (24). FcRL5 possesses both an ITAM and two ITIMs; however, it has been reported to exert mainly negative regulatory functions (32). IgG receptors devoid of both ITAM and ITIM may induce cell activation by associating with other receptors at the cell membrane, for example the glycophosphatidylinositol-anchored FcγRIIIB (33, 34) associates with integrins (35); or by activating transcription pathways or proteasome-related mechanisms as does TRIM21 (7, 36).

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 (23). Enhanced uptake of antibody-bound antigen enables antigen-presenting cells to activate antigen-specific T cells considerably more efficiently than free antigen (37), signifying the pivotal role of FcγRs in the initial phase of humoral and cellular immune responses. Receptors that bind IgG only when it has already been internalized, FcRn (the topic of this review series) and the ubiquitously expressed intracellular receptor TRIM21, may possibly contribute to this phenomenon [reviewed in Ref. (20)].

Human FcγR Polymorphisms

Definitions

The multiplicity of human FcγRs (Figure 1) is increased by a series of genetic polymorphisms, for which we will describe herein only those leading to known functional modifications. These are summarized in Table 1.

FcγRIIA

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) (38). The FcγRIIA-H₁₃₁ allotype was originally reported to allow binding to IgG2 (53), subject to ethnic variation (54, 55), and was later described to also have increased binding for IgG3 (39). More recently, we have identified that only the binding to IgG1 and IgG2 are increased for H₁₃₁ compared to R₁₃₁ (8).

A novel splice variant of FCGR2A, FcγRIIA-exon 6*, containing an expressed cryptic exon 6* was identified in 2013 (41), and is associated with increased neutrophil sensitivity to IgG stimulation (56).

FcγRIIB

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 (24, 42).

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 (43, 57).

FcγRIIC

In 20% of individuals FCGR2C encodes for a glutamine at position 13 (Q₁₃ or ORF) and FcγRIIC is expressed; but in 80% of individuals a SNP generates a stop codon (stop₁₃), in which case FCGR2C represents a pseudogene (16).

A subset of individuals carrying FCGR2C-ORF do not express FcγRIIC due to splice-site mutations and loss of exon 7. Inversely, this polymorphism leads to the expression of inhibitory hFcγRIIB expression on NK cells that has been shown to negatively regulate IgG-induced NK cell activation (17).

FcγRIIIA

A SNP determines the presence of a valine or phenylalanine at position 158 (45). The FcγRIIIA-V₁₅₈ variant demonstrates increased affinity for IgG1, IgG2, and IgG3, and increased IgG-induced cell activation and elimination of immune complexes (8, 46, 58).

FcγRIIIB

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) (48, 59), and SH (S₃₆ S₆₅ D₇₈ N₈₂ I₁₀₆) (50) that do not demonstrate detectable differences in affinity for hIgG subclasses (8). The NA1 allotype was, however, reported to increase phagocytosis of IgG-opsonized particles (49). The SH allotype has been associated with higher FcγRIIIB expression levels (51).

Gene copy number variation (CNV)

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 FCGR2C, FCGR3A, and FCGR3B (Table 1) have been shown to correlate with protein expression levels. Duplications of the gene encoding FCGR3B can lead to the expression of the three different FcγRIIIB variants (NA1, NA2, and SH) in a single individual (51). CNV in FCGR3A (deletion of one allele) correlated with a reduced expression of FcγRIIIA on NK cells and impaired cytotoxic function (47). Deletion of a large portion of the FCGR locus, including FCGR2C and FCGR3B, also resulted in abnormal expression of FcγRIIB on NK cells, presumably due to deletion of upstream regulatory elements. Expression of this inhibitory receptor enabled negative regulation of IgG-induced NK cell activation (17). To the extent of our knowledge, CNV of the FCGR2A and FCGR2B genes have not been reported (47).

Association with disease susceptibility and/or success of antibody-based therapies

Several FCGR polymorphisms modify the affinity between FcγRs and human IgG, and therefore the efficacy of immune complex clearance can be affected. Reduced immune complex clearance is indeed a risk factor for diseases like Systemic Lupus Erythematosus and Wegener’s granulomatosis (60, 61). Other polymorphisms may favor detrimental inflammatory responses and thus predispose to autoimmunity. Diseases that have been associated with FcγR polymorphisms are presented in Table 1.

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 (8, 62). The first report to assess the predictive value of FcγR polymorphisms in responses to antibody therapies associated homozygous FCGR3A-V/V₁₅₈ individuals with better clinical responses to anti-CD20 therapy (Rituximab) in the treatment of non-Hodgkin lymphomas (63). Homozygous FCGR3A-V/V₁₅₈ individuals have since been found to have improved biological responses to anti-CD20 therapy in immune thrombocytopenia (64) and rheumatoid arthritis (RA) (65); and anti-TNF-α therapy (Infliximab) to treat Crohn’s disease (66, 67); compared to carriers of one or two FCGR3A-F₁₅₈ alleles. In arthritis patients, however, findings are controversial regarding the association of FCGR3A polymorphisms with clinical response to TNF-α inhibitors (infliximab, adalimumab, etanercept): although one study describes a better clinical response in FCGR3A-F/F₁₅₈ patients (68); another, larger study with a more homogenous patient cohort found no association (69). Homozygous FCGR3A-V/V₁₅₈ individuals were more likely to experience complete remission from immune thrombocytopenia following medication, but conversely remission rates after splenectomy were higher in homozygous FCGR3A-F/F₁₅₈ or heterozygous individuals (70). The FCGR2A-H131 variant associates with susceptibility to Kawasaki Disease (Table 1), whereas responsiveness to IVIG therapy in Kawasaki Disease patients is strongly associated with the FCGR3B genotype: the NA1 variant significantly decreases the odds of an appropriate clinical outcome (71). Similarly, CNV of both FCGR3B and FCGR2C were associated with Kawasaki Disease susceptibility and influenced IVIG treatment response (72). Furthermore, the FCGR2B minor alleles (IIB-386c and IIB-120a) conferring increased promoter activity were positively correlated to IVIG therapeutic response, although with limited statistical power over a small sample size (73). Each of these genetic associations is also constrained by unequal polymorphic variation between the different ethnic groups studied.

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 (FCGR2A, FCGR3A, FCGR2B, FCGR2C, FCGR3B) and may display a high degree of linkage disequilibrium, as reported for FCGR2A and FCGR3A (74) and for FCGR2C and FCGR3B (44). Association studies of FcγR-encoding genes should therefore include analyses of all FcγR-encoding genes from the 1q23 locus, and not focus on one particular gene.

In vivo Roles of Human FcγRs: Lessons from Mouse Models¹

Transgenic mouse models expressing hFcγR(s)

Transgenic mouse studies have greatly enhanced our understanding of the in vivo function of hFcγRs. In particular, these studies have highlighted the respective contributions of hFcγRs to antibody-mediated inflammatory and allergic diseases (refer to Section “Understanding the Role of hFcγRs In vivo Using Transgenic Mouse Models: Illustrated in Autoimmune, Inflammatory, and Allergic Diseases”). Over the last two decades, various transgenic mouse strains have been generated that carry single or multiple hFcγR-encoding genes (Table 2). Transgenic strains were initially generated on a wild-type mouse background; however, later studies have examined transgene expression in mice deficient for multiple endogenous mFcγRs, to specifically study the function of the transgenic human receptor.

The common approach to reproduce hFcγR expression patterns in mice is to use the genuine human promoter to drive transgene expression (Table 2). Whereas this strategy was successful for hFcγRIIA^tg and hFcγRIIIB^tg mice, both hFcγRI^tg mice and hFcγRIIB^tg mice exhibit somewhat abnormal expression [discussed in Ref. (62)]. hFcγRI^tg mice, for example, constitutively express substantial amounts of this receptor on neutrophils (37), while in humans hFcγRI is only inducibly expressed on neutrophils in contexts of inflammation, infection and during particular therapies [reviewed in Ref. (62)]. An alternative strategy consists of using a cell-specific promoter to drive hFcγR expression. hFcγRIIA^tg, hFcγRIIIB^tg, or double-transgenic mice were generated using the human MRP8 promoter to express these receptors on neutrophils and, abnormally for hFcγRIIIB, on a proportion of monocytes (34). Finally, efforts made to cross the five single hFcγR-transgenic mouse strains with mFcγR^null mice – lacking mFcγRI, IIB, III, and IV – yielded a mouse model expressing most human IgG receptors – hFcγRI, IIA, IIB, IIIA, and IIIB – that preserves most human expression patterns (119) (Table 2).

Understanding the role of hFcγRs in vivo using transgenic mouse models: Illustrated in autoimmune, inflammatory, and allergic diseases

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 hFcγRI^tg mice induced a strong antibody response, suggesting that hFcγRI on myeloid cells is capable of mediating antigen uptake and presentation in vivo (37, 120, 121). Various studies have demonstrated the capacity for hFcγRI and hFcγRIIIA to mediate cytotoxicity in the form of anti-tumor activity when engaged by bi-specific antibodies or antibodies with enhanced FcR binding, highlighting the effectiveness of such engineered antibody therapeutics in vivo (122–125). The role of FcγR in mediating anti-tumor therapies has recently been well-reviewed elsewhere (126, 127) and will not be discussed further in this review. hFcγR-transgenic mice have been useful both in understanding the in vivo function of these receptors and dissecting pathological mechanisms of disease; for illustration this section will describe results obtained in models of autoimmune thrombocytopenia, anaphylaxis, inflammation, and RA. Clearly, the biological responses to immobilized IgG are a function of their location, structure, and deposition, determining the subsequent recruitment and FcγR-mediated activation of immune cells: hFcγR-transgenic mice can assist us also in understanding the cell-specific role of FcγR in recruitment and immune complex clearance.

Autoimmune thrombocytopenia

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 (128). Using transgenic mice, both hFcγRI and hFcγRIIA were found to be independently sufficient for platelet clearance (9, 129). In hFcγRI^tg mice, thrombocytopenia was mediated by monocyte/macrophages outside of the spleen (9), whereas in hFcγRIIA^tg mice, splenectomy was found to provoke a more severe phenotype of thrombosis and systemic shock when thrombocytopenia was induced by activating anti-platelet antibodies (130). Importantly, hFcγRIIA is the only FcγR expressed on platelets, in humans and hFcγRIIA^tg mice. It is likely, therefore, that the presence of this FcγR on the platelets themselves contributes to antibody-induced intravascular platelet activation that is most efficiently resolved by phagocytes in the spleen. These findings have implications for understanding human immune-mediated thrombocytopenic disorders, such as heparin-induced thrombocytopenia/thrombosis (HIT/T), a serious complication arising from the clinical use of heparin. Using hFcγRIIA^tg mice it was identified that antibodies against heparin–platelet factor 4 complexes are responsible for hFcγRIIA-mediated platelet activation, thrombocytopenia, and thrombi formation in the lung vasculature (131, 132). Similarly, thromboembolic complications from the use of monoclonal antibody therapies may be a result of hFcγRIIA-dependent platelet activation due to circulating immune complexes (133, 134). Another important outcome of these mouse studies is that the density of hFcγRIIA expression in the transgenic animal affects the severity of antibody-induced disease (130), which has critical ramifications for understanding differences in immune reactions between individuals. Finally, a therapeutic intervention targeting the hFcγRIIA-signaling pathway proved successful for the prevention of thrombocytopenia in hFcγRIIA^tg mice (135).

Anaphylactic reactions

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 (9, 136). PSA mediated by hFcγRIIA was found to be independent of mast cells and basophils, but rather dependent on neutrophils and monocytes/macrophages (136). Furthermore, hFcγRI and hFcγRIIA were identified as each individually sufficient to mediate ASA in transgenic mice, resulting in both hypothermia and death (9, 136). hFcγRI-dependent ASA required neutrophils and the release of platelet activating factor (9). These data demonstrate that hFcγR expressed on neutrophils and monocytes can mediate fatal anaphylactic reactions in vivo. Furthermore, in hFcγRI^tgIIA^tgIIB^tgIIIA^tgIIIB^tg mice (on the mFcγR^null background), administration of aggregated IgG was sufficient to trigger anaphylaxis (119). In addition, directly targeting either hFcγRI or hFcγRIIA by injection of agonistic mAb could induce anaphylaxis in transgenic mice (9, 136). Altogether, these data support the notion that anaphylaxis may also occur in humans in an hFcγR-dependent manner when allergen-specific IgGs are produced by an individual.

Immune complex induced inflammation

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 hFcγRIIA^tg 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 (136). Inflammation of the airways due to local formation of immune complexes is characterized by granulocyte infiltration, elevated levels of myeloperoxidase, and subsequent damage to the lung epithelium, mimicking symptoms of asthmatic disease in humans. Whereas FcRγ-subunit^−/− mice are resistant to IC-induced airway inflammation, transgenic expression of either hFcγRI or hFcγRIIA was sufficient to restore this antibody-mediated pathology (9, 136).

Rheumatoid arthritis

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. hFcRn^tg mice provided direct evidence for the role of this receptor in serum persistence and transport of antibodies into tissues (23). Indeed, mFcRn^−/− mice are resistant to passive arthritis induction, and transgenic expression of hFcRn could restore arthritis susceptibility (137, 138); suggesting that greater IgG serum persistence may have implications for many autoimmune and inflammatory conditions (139). Surprisingly, transgenic expression of hFcγRIIA-R₁₃₁ on a wild-type mouse background was associated with the spontaneous development of an RA-like joint pathology (140). Expression of hFcγRIIA indeed renders mice highly susceptible to various models of arthritis (140, 141), even if its expression is purposely restricted to neutrophils (142). Small inhibitors designed to bind antagonistically to hFcγRIIA were found to be protective (143), proposing a hFcγR-targeted therapy for RA. Besides hFcγRIIA^tg mice, other hFcγR-transgenic mice do not exhibit spontaneous joint inflammation. Nevertheless, hFcγRI^tg mice demonstrated that this receptor is sufficient to mediate arthritis induction in transgenic mice, dependent on the presence of both neutrophils and monocytes/macrophages (9). Therapeutic elimination of inflammatory macrophages by an hFcγRI-targeting immunotoxin inhibited the progression of experimental arthritis in hFcγRI^tg rats (144), and resolved cutaneous inflammation (145).

Cell-specific function of FcγR

Studies using hFcγR^tg mice have enabled the description of specific in vivo functions not only for these IgG receptors, but also the cells that express them. Neutrophils are a particularly relevant example: the two main human neutrophil IgG receptors, hFcγRIIA and hFcγRIIIB, were found to individually and cooperatively promote IC-induced neutrophil recruitment and accumulation in the tissues. hFcγRIIA alone, however, promoted associated injury and inflammation in multiple models of antibody-dependent autoimmunity. Importantly, neutrophil recruitment occurred despite the absence of FcγR expression on other cell types such as mast cells and macrophages, indicating a prominent role for hFcγRs on neutrophils in IC-induced recruitment (34). Furthermore, specialized functions may be attributed to these two neutrophil FcγR: hFcγRIIIB seems to play an important role in homeostatic clearance of immune complexes deposited within the vasculature, whereas in a complex environment of immune complex deposition within the tissue and the vasculature, hFcγRIIA was required for the formation of neutrophil extracellular traps (NETs) (146). Collectively, these data in hFcγR^tg mice demonstrate the value of a transgenic approach to appreciate the role of human FcγR and the cells expressing them.

Final Considerations

While genetic association studies identify important risk factors and inform on the involvement of FcγR in human disease; hFcγR^tg 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.

References

• 1

  WilsonTJFuchsAColonnaM. Cutting edge: human FcRL4 and FcRL5 are receptors for IgA and IgG. J Immunol (2012) 188:4741–5.10.4049/jimmunol.1102651

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 2

  FrancoADamdinsurenBIseTDement-BrownJLiHNagataSet alHuman Fc receptor-like 5 binds intact IgG via mechanisms distinct from those of Fc receptors. J Immunol (2013) 190:5739–46.10.4049/jimmunol.1202860

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 3

  YangYEversoleTLeeDJSontheimerRDCapraJD. Protein-protein interactions between native Ro52 and immunoglobulin G heavy chain. Scand J Immunol (1999) 49:620–8.10.1046/j.1365-3083.1999.00547.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 4

  SimisterNEMostovKE. An Fc receptor structurally related to MHC class I antigens. Nature (1989) 337:184–7.10.1038/337184a0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 5

  OberRJMartinezCVaccaroCZhouJWardES. Visualizing the site and dynamics of IgG salvage by the MHC class I-related receptor, FcRn. J Immunol (2004) 172:2021–9.10.4049/jimmunol.172.4.2021

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 6

  JamesLCKeebleAHKhanZRhodesDATrowsdaleJ. Structural basis for PRYSPRY-mediated tripartite motif (TRIM) protein function. Proc Natl Acad Sci U S A (2007) 104:6200–5.10.1073/pnas.0609174104

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 7

  MalleryDLMcEwanWABidgoodSRTowersGJJohnsonCMJamesLC. Antibodies mediate intracellular immunity through tripartite motif-containing 21 (TRIM21). Proc Natl Acad Sci U S A (2010) 107:19985–90.10.1073/pnas.1014074107

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 8

  BruhnsPIannascoliBEnglandPMancardiDAFernandezNJorieuxSet alSpecificity and affinity of human Fc{gamma} receptors and their polymorphic variants for human IgG subclasses. Blood (2009) 113:3716–25.10.1182/blood-2008-09-179754

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 9

  MancardiDAAlbanesiMJonssonFIannascoliBvan RooijenNKangXet alThe high-affinity human IgG receptor FcgammaRI (CD64) promotes IgG-mediated inflammation, anaphylaxis, and antitumor immunotherapy. Blood (2013) 121:1563–73.10.1182/blood-2012-07-442541

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 10

  RavetchJVKinetJP. Fc receptors. Annu Rev Immunol (1991) 9:457–92.10.1146/annurev.iy.09.040191.002325

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 11

  OkayamaYKirshenbaumASMetcalfeDD. Expression of a functional high-affinity IgG receptor, Fc gamma RI, on human mast cells: up-regulation by IFN-gamma. J Immunol (2000) 164:4332–9.10.4049/jimmunol.164.8.4332

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 12

  VeriMCGorlatovSLiHBurkeSJohnsonSStavenhagenJet alMonoclonal antibodies capable of discriminating the human inhibitory Fcgamma-receptor IIB (CD32B) from the activating Fcgamma-receptor IIA (CD32A): biochemical, biological and functional characterization. Immunology (2007) 121:392–404.10.1111/j.1365-2567.2007.02588.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 13

  CassardLJonssonFArnaudSDaeronM. Fcgamma receptors inhibit mouse and human basophil activation. J Immunol (2012) 189:2995–3006.10.4049/jimmunol.1200968

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 14

  MagnussonSEEngstromMJacobUUlfgrenAKKleinauS. High synovial expression of the inhibitory FcgammaRIIb in rheumatoid arthritis. Arthritis Res Ther (2007) 9:R51.10.1186/ar2206

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 15

  ZhaoWKepleyCLMorelPAOkumotoLMFukuokaYSchwartzLB. Fc gamma RIIa, not Fc gamma RIIb, is constitutively and functionally expressed on skin-derived human mast cells. J Immunol (2006) 177:694–701.10.4049/jimmunol.177.1.694

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 16

  MetesDErnstLKChambersWHSulicaAHerbermanRBMorelPA. Expression of functional CD32 molecules on human NK cells is determined by an allelic polymorphism of the FcgammaRIIC gene. Blood (1998) 91:2369–80.

  • Pubmed Abstract
  • Google Scholar
  • View reference in article

• 17

  van der HeijdenJBreunisWBGeisslerJDe BoerMvan den BergTKKuijpersTW. Phenotypic variation in IgG receptors by nonclassical FCGR2C alleles. J Immunol (2012) 188:1318–24.10.4049/jimmunol.1003945

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 18

  MeknacheNJönssonFLaurentJGuinnepainMTDaëronM. Human basophils express the glycosylphosphatidylinositol-anchored low-affinity IgG receptor Fc{gamma}RIIIB (CD16B). J Immunol (2009) 182:2542–50.10.4049/jimmunol.0801665

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 19

  EspinosaADardalhonVBraunerSAmbrosiAHiggsRQuintanaFJet alLoss of the lupus autoantigen Ro52/Trim21 induces tissue inflammation and systemic autoimmunity by disregulating the IL-23-Th17 pathway. J Exp Med (2009) 206:1661–71.10.1084/jem.20090585

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 20

  GuilliamsMBruhnsPSaeysYHammadHLambrechtBN. The function of Fcgamma receptors in dendritic cells and macrophages. Nat Rev Immunol (2014) 14:94–108.10.1038/nri3582

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 21

  ZhuXMengGDickinsonBLLiXMizoguchiEMiaoLet alMHC class I-related neonatal Fc receptor for IgG is functionally expressed in monocytes, intestinal macrophages, and dendritic cells. J Immunol (2001) 166:3266–76.10.4049/jimmunol.166.5.3266

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 22

  VidarssonGStemerdingAMStapletonNMSpliethoffSEJanssenHRebersFEet alFcRn: an IgG receptor on phagocytes with a novel role in phagocytosis. Blood (2006) 108:3573–9.10.1182/blood-2006-05-024539

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 23

  RoopenianDCAkileshS. FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol (2007) 7:715–25.10.1038/nri2155

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 24

  SmithKGClatworthyMR. FcgammaRIIB in autoimmunity and infection: evolutionary and therapeutic implications. Nat Rev Immunol (2010) 10:328–43.10.1038/nri2762

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 25

  PricopLRedechaPTeillaudJLFreyJFridmanWHSautes-FridmanCet alDifferential modulation of stimulatory and inhibitory Fc gamma receptors on human monocytes by Th1 and Th2 cytokines. J Immunol (2001) 166:531–7.10.4049/jimmunol.166.1.531

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 26

  van der PoelCEKarssemeijerRABorossPvan der LindenJABloklandMvan de WinkelJGet alCytokine-induced immune complex binding to the high-affinity IgG receptor, FcgammaRI, in the presence of monomeric IgG. Blood (2010) 116:5327–33.10.1182/blood-2010-04-280214

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 27

  DaëronM. Fc receptor biology. Annu Rev Immunol (1997) 15:203–34.10.1146/annurev.immunol.15.1.203

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 28

  NimmerjahnFRavetchJV. Fcgamma receptors as regulators of immune responses. Nat Rev Immunol (2008) 8:34–47.10.1038/nri2206

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 29

  BlankULaunayPBenhamouMMonteiroRC. Inhibitory ITAMs as novel regulators of immunity. Immunol Rev (2009) 232:59–71.10.1111/j.1600-065X.2009.00832.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 30

  AmigorenaSBonnerotCDrakeJRChoquetDHunzikerWGuilletJGet alCytoplasmic domain heterogeneity and functions of IgG Fc receptors in B lymphocytes. Science (1992) 256:1808–12.10.1126/science.1535455

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 31

  OnoMBollandSTempstPRavetchJV. Role of the inositol phosphatase SHIP in negative regulation of the immune system by the receptor Fc(gamma)RIIB. Nature (1996) 383:263–6.10.1038/383263a0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 32

  ZhuZLiRLiHZhouTDavisRS. FCRL5 exerts binary and compartment-specific influence on innate-like B-cell receptor signaling. Proc Natl Acad Sci U S A (2013) 110:E1282–90.10.1073/pnas.1215156110

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 33

  KimberlyRPAhlstromJWClickMEEdbergJC. The glycosyl phosphatidylinositol-linked Fc gamma RIIIPMN mediates transmembrane signaling events distinct from Fc gamma RII. J Exp Med (1990) 171:1239–55.10.1084/jem.171.4.1239

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 34

  TsuboiNAsanoKLauterbachMMayadasTN. Human neutrophil Fcgamma receptors initiate and play specialized nonredundant roles in antibody-mediated inflammatory diseases. Immunity (2008) 28:833–46.10.1016/j.immuni.2008.04.013

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 35

  ToddRFIIIPettyHR. Beta 2 (CD11/CD18) integrins can serve as signaling partners for other leukocyte receptors. J Lab Clin Med (1997) 129:492–8.10.1016/S0022-2143(97)90003-2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 36

  McEwanWATamJCWatkinsonREBidgoodSRMalleryDLJamesLC. Intracellular antibody-bound pathogens stimulate immune signaling via the Fc receptor TRIM21. Nat Immunol (2013) 14:327–36.10.1038/ni.2548

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 37

  HeijnenIAvan VugtMJFangerNAGrazianoRFDe WitTPHofhuisFMet alAntigen targeting to myeloid-specific human Fc gamma RI/CD64 triggers enhanced antibody responses in transgenic mice. J Clin Invest (1996) 97:331–8.10.1172/JCI118420

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 38

  WarmerdamPAvan de WinkelJGGosselinEJCapelPJ. Molecular basis for a polymorphism of human Fc gamma receptor II (CD32). J Exp Med (1990) 172:19–25.10.1084/jem.172.1.19

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 39

  ParrenPWWarmerdamPABoeijeLCArtsJWesterdaalNAVlugAet alOn the interaction of IgG subclasses with the low affinity Fc gamma RIIa (CD32) on human monocytes, neutrophils, and platelets. Analysis of a functional polymorphism to human IgG2. J Clin Invest (1992) 90:1537–46.10.1172/JCI116022

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 40

  SalmonJEEdbergJCBrogleNLKimberlyRP. Allelic polymorphisms of human Fc gamma receptor IIA and Fc gamma receptor IIIB. Independent mechanisms for differences in human phagocyte function. J Clin Invest (1992) 89:1274–81.10.1172/JCI115712

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 41

  van der HeijdenJGeisslerJvan MirreEvan DeurenMvan der MeerJWSalamaAet alA novel splice variant of FcgammaRIIa: a risk factor for anaphylaxis in patients with hypogammaglobulinemia. J Allergy Clin Immunol (2013) 131(1408–1416):e1405.10.1016/j.jaci.2013.02.009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 42

  SuKWuJEdbergJCLiXFergusonPCooperGSet alA promoter haplotype of the immunoreceptor tyrosine-based inhibitory motif-bearing FcγRIIb alters receptor expression and associates with autoimmunity. I. Regulatory FCGR2B polymorphisms and their association with systemic lupus erythematosus. J Immunol (2004) 172:7186–91.10.4049/jimmunol.172.11.7186

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 43

  LiXWuJCarterRHEdbergJCSuKCooperGSet alA novel polymorphism in the Fcγ receptor IIB (CD32B) transmembrane region alters receptor signaling. Arthritis Rheum (2003) 48:3242–52.10.1002/art.11313

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 44

  BreunisWBvan MirreEBruinMGeisslerJDe BoerMPetersMet alCopy number variation of the activating FCGR2C gene predisposes to idiopathic thrombocytopenic purpura. Blood (2008) 111:1029–38.10.1182/blood-2007-03-079913

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 45

  WuJEdbergJCRedechaPBBansalVGuyrePMColemanKet alA novel polymorphism of FcgammaRIIIa (CD16) alters receptor function and predisposes to autoimmune disease. J Clin Invest (1997) 100:1059–70.10.1172/JCI119616

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 46

  FerraraCStuartFSondermannPBrunkerPUmanaP. The carbohydrate at FcgammaRIIIa Asn-162. An element required for high affinity binding to non-fucosylated IgG glycoforms. J Biol Chem (2006) 281:5032–6.10.1074/jbc.M510171200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 47

  BreunisWBvan MirreEGeisslerJLaddachNWolbinkGvan der SchootEet alCopy number variation at the FCGR locus includes FCGR3A, FCGR2C and FCGR3B but not FCGR2A and FCGR2B. Hum Mutat (2009) 30:E640–50.10.1002/humu.20997

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 48

  OryPAClarkMRKwohEEClarksonSBGoldsteinIM. Sequences of complementary DNAs that encode the NA1 and NA2 forms of Fc receptor III on human neutrophils. J Clin Invest (1989) 84:1688–91.10.1172/JCI114350

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 49

  SalmonJEEdbergJCKimberlyRP. Fc gamma receptor III on human neutrophils. Allelic variants have functionally distinct capacities. J Clin Invest (1990) 85:1287–95.10.1172/JCI114566

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 50

  BuxJSteinELBierlingPFromontPClayMStroncekDet alCharacterization of a new alloantigen (SH) on the human neutrophil Fc gamma receptor IIIb. Blood (1997) 89:1027–34.

  • Pubmed Abstract
  • Google Scholar

• 51

  KoeneHRKleijerMRoosDDe HaasMVon Dem BorneAEGK. FcγRIIIB gene duplication: evidence for presence and expression of three distinct FcγRIIIB genes in NA(1+,2+)SH(+) individuals. Blood (1998) 91:673–9.

  • Pubmed Abstract
  • Google Scholar

• 52

  WillcocksLCLyonsPAClatworthyMRRobinsonJIYangWNewlandSAet alCopy number of FCGR3B, which is associated with systemic lupus erythematosus, correlates with protein expression and immune complex uptake. J Exp Med (2008) 205:1573–82.10.1084/jem.20072413

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 53

  WarmerdamPAvan de WinkelJGVlugAWesterdaalNACapelPJ. A single amino acid in the second Ig-like domain of the human Fc gamma receptor II is critical for human IgG2 binding. J Immunol (1991) 147:1338–43.

  • Pubmed Abstract
  • Google Scholar

• 54

  OsborneJMChackoGWBrandtJTAndersonCL. Ethnic variation in frequency of an allelic polymorphism of human Fc gamma RIIA determined with allele specific oligonucleotide probes. J Immunol Methods (1994) 173:207–17.10.1016/0022-1759(94)90299-2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 55

  LehrnbecherTFosterCBZhuSLeitmanSFGoldinLRHuppiKet alVariant genotypes of the low-affinity Fcγ receptors in two control populations and a review of low-affinity Fcγ receptor polymorphisms in control and disease populations. Blood (1999) 94:4220–32.

  • Pubmed Abstract
  • Google Scholar

• 56

  van der HeijdenJNagelkerkeSZhaoXGeisslerJRispensTvan den BergTKet alHaplotypes of FcgammaRIIa and FcgammaRIIIb polymorphic variants influence IgG-mediated responses in neutrophils. J Immunol (2014) 192(6):2715–21.10.4049/jimmunol.1203570

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 57

  FlotoRAClatworthyMRHeilbronnKRRosnerDRMacaryPARankinAet alLoss of function of a lupus-associated Fc[gamma]RIIb polymorphism through exclusion from lipid rafts. Nat Med (2005) 11:1056–8.10.1038/nm1288

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 58

  TakaiT. Fc receptors and their role in immune regulation and autoimmunity. J Clin Immunol (2005) 25:1–18.10.1007/s10875-005-0353-8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 59

  HuizingaTKleijerMTetterooPRoosDVon Dem BorneA. Biallelic neutrophil Na-antigen system is associated with a polymorphism on the phospho-inositol-linked Fc gamma receptor III (CD16). Blood (1990) 75:213–7.

  • Pubmed Abstract
  • Google Scholar

• 60

  DijstelbloemHMScheepersRHMOostWWStegemanCAvan der PolWLSluiterWJet alFcγ receptor polymorphisms in Wegener’s granulomatosis: risk factors for disease relapse. Arthritis Rheum (1999) 42:1823–7.10.1002/1529-0131(199909)42:9<1823::AID-ANR5>3.0.CO;2-X

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 61

  DijstelbloemHMBijlMFijnheerRScheepersRHMOostWWJansenMDet alFcγ receptor polymorphisms in systemic lupus erythematosus: association with disease and in vivo clearance of immune complexes. Arthritis Rheum (2000) 43:2793–800.10.1002/1529-0131(200012)43:12<2793::AID-ANR20>3.0.CO;2-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 62

  BruhnsP. Properties of mouse and human IgG receptors and their contribution to disease models. Blood (2012) 119:5640–9.10.1182/blood-2012-01-380121

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 63

  CartronGDacheuxLSallesGSolal-CelignyPBardosPColombatPet alTherapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene. Blood (2002) 99:754–8.10.1182/blood.V99.3.754

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 64

  CooperNStasiRCunningham-RundlesSCesarmanEMcFarlandJGBusselJB. Platelet-associated antibodies, cellular immunity and FCGR3a genotype influence the response to rituximab in immune thrombocytopenia. Br J Haematol (2012) 158:539–47.10.1111/j.1365-2141.2012.09184.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 65

  Ruyssen-WitrandARouanetSCombeBDougadosMLe LoëtXSibiliaJet alFcγ receptor type IIIA polymorphism influences treatment outcomes in patients with rheumatoid arthritis treated with rituximab. Ann Rheum Dis (2012) 71:875–7.10.1136/annrheumdis-2011-200337

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 66

  LouisEEl GhoulZVermeireSDall’ozzoSRutgeertsPPaintaudGet alAssociation between polymorphism in IgG Fc receptor IIIa coding gene and biological response to infliximab in Crohn’s disease. Aliment Pharmacol Ther (2004) 19:511–9.10.1111/j.1365-2036.2004.01871.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 67

  MoroiREndoKKinouchiYShigaHKakutaYKurohaMet alFCGR3A-158 polymorphism influences the biological response to infliximab in Crohn’s disease through affecting the ADCC activity. Immunogenetics (2013) 65:265–71.10.1007/s00251-013-0679-8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 68

  TutuncuZKavanaughAZvaiflerNCorrMDeutschRBoyleD. Fcγ receptor type IIIA polymorphisms influence treatment outcomes in patients with inflammatory arthritis treated with tumor necrosis factor α-blocking agents. Arthritis Rheum (2005) 52:2693–6.10.1002/art.21266

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 69

  KastbomABrattJErnestamSLampaJPadyukovLSöderkvistPet alFcγ receptor type IIIA genotype and response to tumor necrosis factor α-blocking agents in patients with rheumatoid arthritis. Arthritis Rheum (2007) 56:448–52.10.1002/art.22390

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 70

  FujimotoT-TInoueMShimomuraTFujimuraK. Involvement of Fcγ receptor polymorphism in the therapeutic response of idiopathic thrombocytopenic purpura. Br J Haematol (2001) 115:125–30.10.1046/j.1365-2141.2001.03109.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 71

  ShresthaSWienerHShendreAKaslowRAWuJOlsonAet alRole of activating FcγR gene polymorphisms in Kawasaki disease susceptibility and intravenous immunoglobulin response. Circ Cardiovasc Genet (2012) 5:309–16.10.1161/CIRCGENETICS.111.962464

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 72

  MakowskyRWienerHWPtacekTSSilvaMShendreAEdbergJCet alFcgammaR gene copy number in Kawasaki disease and intravenous immunoglobulin treatment response. Pharmacogenet Genomics (2013) 23:455–62.10.1097/FPC.0b013e328363686e

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 73

  ShresthaSWienerHWOlsonAKEdbergJCBowlesNEPatelHet alFunctional FCGR2B gene variants influence intravenous immunoglobulin response in patients with Kawasaki disease. J Allergy Clin Immunol (2011) 128:677–80.10.1016/j.jaci.2011.04.027

  • CrossRef
  • Google Scholar

• 74

  LejeuneJThibaultGTernantDCartronGWatierHOhresserM. Evidence for linkage disequilibrium between Fcgamma RIIIa-V158F and Fcgamma RIIa-H131R polymorphisms in white patients, and for an Fcgamma RIIIa-restricted influence on the response to therapeutic antibodies. J Clin Oncol (2008) 26:5489–91.10.1200/JCO.2008.19.4118

  • CrossRef
  • Google Scholar

• 75

  RaknesGSkeieGOGilhusNEAadlandSVedelerC. FcγRIIA and FcγRIIIB polymorphisms in myasthenia gravis. J Neuroimmunol (1998) 81:173–6.10.1016/S0165-5728(97)00174-4

  • CrossRef
  • Google Scholar

• 76

  van der PolW-Lvan den BergLHScheepersRHMvan der BomJGvan DoornPAvan KoningsveldRet alIgG receptor IIa alleles determine susceptibility and severity of Guillain-Barré syndrome. Neurology (2000) 54:1661–5.10.1212/WNL.54.8.1661

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 77

  FosterCBZhuSErichsenHCLehrnbecherTHartESChoiEet alPolymorphisms in inflammatory cytokines and Fcγ receptors in childhood chronic immune thrombocytopenic purpura: a pilot study. Br J Haematol (2001) 113:596–9.10.1046/j.1365-2141.2001.02807.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 78

  BournazosSGrinfeldJAlexanderKMurchisonJWallaceWMcFarlanePet alAssociation of FcgammaRIIa R131H polymorphism with idiopathic pulmonary fibrosis severity and progression. BMC Pulm Med (2010) 10:51.10.1186/1471-2466-10-51

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 79

  KhorCCDavilaSBreunisWBLeeY-CShimizuCWrightVJet alGenome-wide association study identifies FCGR2A as a susceptibility locus for Kawasaki disease. Nat Genet (2011) 43:1241–6.10.1038/ng.981

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 80

  SandersLAMvan de WinkelJGJRijkersGTVoorhorst-OginkMMDe HaasMCapelPJAet alFcã receptor Iia (Cd32) heterogeneity in patients with recurrent bacterial respiratory tract infections. J Infect Dis (1994) 170:854–61.10.1093/infdis/170.4.854

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 81

  DuitsAJBootsmaHDerksenRHSpronkPEKaterLKallenbergCGet alSkewed distribution of IgG Fc receptor IIa (CD32) polymorphism is associated with renal disease in systemic lupus erythematosus patients. Arthritis Rheum (1995) 38:1832–6.10.1002/art.1780381217

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 82

  EdbergJCWainsteinEWuJCsernokESnellerMCHoffmanGSet alAnalysis of FcgammaRII gene polymorphisms in Wegener’s granulomatosis. Exp Clin Immunogenet (1997) 14:183–95.

  • Pubmed Abstract
  • Google Scholar

• 83

  HaseleyLAWisnieskiJJDenburgMRMichael-GrossmanARGinzlerEMGourleyMFet alAntibodies to C1q in systemic lupus erythematosus: characteristics and relation to Fc gamma RIIA alleles. Kidney Int (1997) 52:1375–80.10.1038/ki.1997.464

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 84

  WilliamsYLynchSMcCannSSmithOFeigheryCWhelanA. Correlation of platelet FcγRIIA polymorphism in refractory idiopathic (immune) thrombocytopenic purpura. Br J Haematol (1998) 101:779–82.10.1046/j.1365-2141.1998.00802.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 85

  MyhrK-MRaknesGNylandHVedelerC. Immunoglobulin G Fc-receptor (FcγR) IIA and IIIB polymorphisms related to disability in MS. Neurology (1999) 52:1771.10.1212/WNL.52.9.1771

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 86

  NorsworthyPTheodoridisEBottoMAthanassiouPBeynonHGordonCet alOverrepresentation of the Fcγ receptor type IIA R131/R131 genotype in Caucasoid systemic lupus erythematosus patients with autoantibodies to C1q and glomerulonephritis. Arthritis Rheum (1999) 42:1828–32.10.1002/1529-0131(199909)42:9<1828::AID-ANR6>3.0.CO;2-F

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 87

  YunHRKohHKKimSSChungWTKimDWHongKPet alFcgammaRIIa/IIIa polymorphism and its association with clinical manifestations in Korean lupus patients. Lupus (2001) 10:466–72.10.1191/096120301678416015

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 88

  KarassaFBTrikalinosTAIoannidisJPA. Role of the Fcγ receptor IIa polymorphism in susceptibility to systemic lupus erythematosus and lupus nephritis: a meta-analysis. Arthritis Rheum (2002) 46:1563–71.10.1002/art.10306

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 89

  KarassaFBBijlMDaviesKAKallenbergCGMKhamashtaMAMangerKet alRole of the Fcγ receptor IIA polymorphism in the antiphospholipid syndrome: an international meta-analysis. Arthritis Rheum (2003) 48:1930–8.10.1002/art.11059

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 90

  TanakaYSuzukiYTsugeTKanamaruYHorikoshiSMonteiroRCet alFcgammaRIIa-131R allele and FcgammaRIIIa-176V/V genotype are risk factors for progression of IgA nephropathy. Nephrol Dial Transplant (2005) 20:2439–45.10.1093/ndt/gfi043

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 91

  MorganAWRobinsonJIBarrettJHMartinJWalkerABabbageSJet alAssociation of FCGR2A and FCGR2A-FCGR3A haplotypes with susceptibility to giant cell arteritis. Arthritis Res Ther (2006) 8:R109.10.1186/ar1996

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 92

  GulenFTanacRAltinozSBerdeliAZeyrekDKoksoyHet alThe FcγRIIa polymorphism in Turkish children with asthma bronchial and allergic rhinitis. Clin Biochem (2007) 40:392–6.10.1016/j.clinbiochem.2006.11.014

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 93

  AksuKKitapciogluGKeserGBerdeliAKarabulutGKobakSet alFcgammaRIIa, IIIa and IIIb gene polymorphisms in Behcet’s disease: do they have any clinical implications?Clin Exp Rheumatol (2008) 26:S77–83.

  • Pubmed Abstract
  • Google Scholar

• 94

  WooJ-HSungY-KLeeJ-SChungWTChoeJ-YSongGGet alAssociation of Fcγ receptor polymorphisms with adult onset still’s disease in Korea. J Rheumatol (2009) 36:347–50.10.3899/jrheum.071254

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 95

  KyogokuCDijstelbloemHMTsuchiyaNHattaYKatoHYamaguchiAet alFcγ receptor gene polymorphisms in Japanese patients with systemic lupus erythematosus: contribution of FCGR2B to genetic susceptibility. Arthritis Rheum (2002) 46:1242–54.10.1002/art.10257

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 96

  SiriboonritUTsuchiyaNSirikongMKyogokuCBejrachandraSSuthipinittharmPet alAssociation of Fcγ receptor IIb and IIIb polymorphisms with susceptibility to systemic lupus erythematosus in Thais. Tissue Antigens (2003) 61:374–83.10.1034/j.1399-0039.2003.00047.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 97

  KonoHKyogokuCSuzukiTTsuchiyaNHondaHYamamotoKet alFcγRIIB Ile232Thr transmembrane polymorphism associated with human systemic lupus erythematosus decreases affinity to lipid rafts and attenuates inhibitory effects on B cell receptor signaling. Hum Mol Genet (2005) 14:2881–92.10.1093/hmg/ddi320

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 98

  WillcocksLCCarrEJNiedererHARaynerTFWilliamsTNYangWet alA defunctioning polymorphism in FCGR2B is associated with protection against malaria but susceptibility to systemic lupus erythematosus. Proc Natl Acad Sci U S A (2010) 107:7881–5.10.1073/pnas.0915133107

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 99

  ZhouX-JLvJ-CYuLCuiZZhaoJYangRet alFCGR2B gene polymorphism rather than FCGR2A, FCGR3A and FCGR3B is associated with anti-GBM disease in Chinese. Nephrol Dial Transplant (2010) 25:97–101.10.1093/ndt/gfp374

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 100

  BlankMStefanescuRMasudaEMartiFKingPRedechaPet alDecreased transcription of the human FCGR2B gene mediated by the -343 G/C promoter polymorphism and association with systemic lupus erythematosus. Hum Genet (2005) 117:220–7.10.1007/s00439-005-1302-3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 101

  TackenbergBJelcicIBaerenwaldtAOertelWHSommerNNimmerjahnFet alImpaired inhibitory Fcγ receptor IIB expression on B cells in chronic inflammatory demyelinating polyneuropathy. Proc Natl Acad Sci U S A (2009) 106:4788–92.10.1073/pnas.0807319106

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 102

  KoeneHRKleijerMSwaakAJSullivanKEBijlMPetriMAet alThe Fc gammaRIIIA-158F allele is a risk factor for systemic lupus erythematosus. Arthritis Rheum (1998) 41:1813–8.10.1002/1529-0131(199810)41:10<1813::AID-ART13>3.3.CO;2-Y

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 103

  NietoACálizRPascualMMataránLGarcíaSMartínJ. Involvement of Fcγ receptor IIIA genotypes in susceptibility to rheumatoid arthritis. Arthritis Rheum (2000) 43:735–9.10.1002/1529-0131(200004)43:4<735::AID-ANR3>3.0.CO;2-Q

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 104

  EdbergJCLangefeldCDWuJMoserKLKaufmanKMKellyJet alGenetic linkage and association of Fcγ receptor IIIA (CD16A) on chromosome 1q23 with human systemic lupus erythematosus. Arthritis Rheum (2002) 46:2132–40.10.1002/art.10438

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 105

  van SorgeNMvan der PolWLJansenMDGeleijnsKPWKalmijnSHughesRACet alSeverity of Guillain-Barré syndrome is associated with Fcγ receptor III polymorphisms. J Neuroimmunol (2005) 162:157–64.10.1016/j.jneuroim.2005.01.016

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 106

  MorganAWGriffithsBPonchelFMontagueBMNAliMGardnerPPet alFcγ receptor type IIIA is associated with rheumatoid arthritis in two distinct ethnic groups. Arthritis Rheum (2000) 43:2328–34.10.1002/1529-0131(200010)43:10<2328::AID-ANR21>3.0.CO;2-Z

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 107

  LeeYHJiJDSongGG. Associations between FCGR3A polymorphisms and susceptibility to rheumatoid arthritis: a meta analysis. J Rheumatol (2008) 35:2129–35.10.3899/jrheum.080186

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 108

  BronnerIMHoogendijkJEDe VisserMvan de VlekkertJBadrisingUAWintzenARet alAssociation of the leukocyte immunoglobulin G (Fcγ) receptor IIIa-158V/F polymorphism with inflammatory myopathies in Dutch patients. Tissue Antigens (2009) 73:586–9.10.1111/j.1399-0039.2009.01236.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 109

  ThabetMMHuizingaTWJMarquesRBStoeken-RijsbergenGBakkerAMKurreemanFAet alContribution of Fcγ receptor IIIA gene 158V/F polymorphism and copy number variation to the risk of ACPA-positive rheumatoid arthritis. Ann Rheum Dis (2009) 68:1775–80.10.1136/ard.2008.099309

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 110

  ZhouX-JLvJ-CBuD-FYuLYangY-RZhaoJet alCopy number variation of FCGR3A rather than FCGR3B and FCGR2B is associated with susceptibility to anti-GBM disease. Int Immunol (2010) 22:45–51.10.1093/intimm/dxp113

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 111

  HattaYTsuchiyaNOhashiJMatsushitaMFujiwaraKHagiwaraKet alAssociation of Fc gamma receptor IIIB, but not of Fc gamma receptor IIA and IIIA polymorphisms with systemic lupus erythematosus in Japanese. Genes Immun (1999) 1:53–60.10.1038/sj.gene.6363639

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 112

  TseWYAbadehSJefferisRSavageCOAduD. Neutrophil FcgammaRIIIb allelic polymorphism in anti-neutrophil cytoplasmic antibody (ANCA)-positive systemic vasculitis. Clin Exp Immunol (2000) 119:574–7.10.1046/j.1365-2249.2000.01182.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 113

  XuGHeQShouZWangHZhangXWangYet alNA1/NA2 heterozygote of Fcgr3b is a risk factor for progression of IgA nephropathy in Chinese. J Clin Lab Anal (2007) 21:298–302.10.1002/jcla.20189

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 114

  AitmanTJDongRVyseTJNorsworthyPJJohnsonMDSmithJet alCopy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans. Nature (2006) 439:851–5.10.1038/nature04489

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 115

  FanciulliMNorsworthyPJPetrettoEDongRHarperLKameshLet alFCGR3B copy number variation is associated with susceptibility to systemic, but not organ-specific, autoimmunity. Nat Genet (2007) 39:721–3.10.1038/ng2046

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 116

  BournazosSBournazouIMurchisonJTWallaceWAMcFarlanePHiraniNet alCopy number variation of <i>FCGR3B</i> is associated with susceptibility to idiopathic pulmonary fibrosis. Respiration (2011) 81:142–9.10.1159/000321997

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 117

  GrafSWLesterSNossentJCHillCLProudmanSMLeeAet alLow copy number of the FCGR3B gene and rheumatoid arthritis: a case-control study and meta-analysis. Arthritis Res Ther (2012) 14:R28.10.1186/ar3731

  • CrossRef
  • Google Scholar

• 118

  McKinneyCBroenJCAVonkMCBerettaLHesselstrandRHunzelmannNet alEvidence that deletion at FCGR3B is a risk factor for systemic sclerosis. Genes Immun (2012) 13:458–60.10.1038/gene.2012.15

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 119

  SmithPDililloDJBournazosSLiFRavetchJV. Mouse model recapitulating human Fcgamma receptor structural and functional diversity. Proc Natl Acad Sci U S A (2012) 109(16):6181–6.10.1073/pnas.1203954109

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 120

  GuyrePMGrazianoRFGoldsteinJWallacePKMorganelliPMWardwellKet alIncreased potency of Fc-receptor-targeted antigens. Cancer Immunol Immunother (1997) 45:146–8.10.1007/s002620050418

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 121

  KelerTGuyrePMVitaleLASundarapandiyanKvan de WinkelJGDeoYMet alTargeting weak antigens to CD64 elicits potent humoral responses in human CD64 transgenic mice. J Immunol (2000) 165:6738–42.10.4049/jimmunol.165.12.6738

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 122

  HeijnenIAvan de WinkelJG. A human Fc gamma RI/CD64 transgenic model for in vivo analysis of (bispecific) antibody therapeutics. J Hematother (1995) 4:351–6.10.1089/scd.1.1995.4.351

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 123

  StavenhagenJBGorlatovSTuaillonNRankinCTLiHBurkeSet alFc optimization of therapeutic antibodies enhances their ability to kill tumor cells in vitro and controls tumor expansion in vivo via low-affinity activating Fcgamma receptors. Cancer Res (2007) 67:8882–90.10.1158/0008-5472.CAN-07-0696

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 124

  JunttilaTTParsonsKOlssonCLuYXinYTheriaultJet alSuperior in vivo efficacy of afucosylated trastuzumab in the treatment of HER2-amplified breast cancer. Cancer Res (2010) 70:4481–9.10.1158/0008-5472.CAN-09-3704

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 125

  GerdesCANicoliniVGHerterSvan PuijenbroekELangSRoemmeleMet alGA201 (RG7160): a novel, humanized, glycoengineered anti-EGFR antibody with enhanced ADCC and superior in vivo efficacy compared with cetuximab. Clin Cancer Res (2013) 19:1126–38.10.1158/1078-0432.CCR-12-0989

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 126

  KimJMAshkenaziA. Fcgamma receptors enable anticancer action of proapoptotic and immune-modulatory antibodies. J Exp Med (2013) 210:1647–51.10.1084/jem.20131625

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 127

  MellorJDBrownMPIrvingHRZalcbergJRDobrovicA. A critical review of the role of Fc gamma receptor polymorphisms in the response to monoclonal antibodies in cancer. J Hematol Oncol (2013) 6:1.10.1186/1756-8722-6-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 128

  ClynesRRavetchJV. Cytotoxic antibodies trigger inflammation through Fc receptors. Immunity (1995) 3:21–6.10.1016/1074-7613(95)90155-8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 129

  McKenzieSETaylorSMMalladiPYuhanHCasselDLChienPet alThe role of the human Fc receptor Fc gamma RIIA in the immune clearance of platelets: a transgenic mouse model. J Immunol (1999) 162:4311–8.

  • Pubmed Abstract
  • Google Scholar

• 130

  TaylorSMReillyMPSchreiberADChienPTuckoshJRMcKenzieSE. Thrombosis and shock induced by activating antiplatelet antibodies in human Fc gamma RIIA transgenic mice: the interplay among antibody, spleen, and Fc receptor. Blood (2000) 96:4254–60.

  • Pubmed Abstract
  • Google Scholar

• 131

  ReillyMPTaylorSMHartmanNKArepallyGMSachaisBSCinesDBet alHeparin-induced thrombocytopenia/thrombosis in a transgenic mouse model requires human platelet factor 4 and platelet activation through FcgammaRIIA. Blood (2001) 98:2442–7.10.1182/blood.V98.8.2442

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 132

  RauovaLZhaiLKowalskaMAArepallyGMCinesDBPonczM. Role of platelet surface PF4 antigenic complexes in heparin-induced thrombocytopenia pathogenesis: diagnostic and therapeutic implications. Blood (2006) 107:2346–53.10.1182/blood-2005-08-3122

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 133

  MeyerTRobles-CarrilloLRobsonTLangerFDesaiHDavilaMet alBevacizumab immune complexes activate platelets and induce thrombosis in FCGR2A transgenic mice. J Thromb Haemost (2009) 7:171–81.10.1111/j.1538-7836.2008.03212.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 134

  Robles-CarrilloLMeyerTHatfieldMDesaiHDavilaMLangerFet alAnti-CD40L immune complexes potently activate platelets in vitro and cause thrombosis in FCGR2A transgenic mice. J Immunol (2010) 185:1577–83.10.4049/jimmunol.0903888

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 135

  StollaMStefaniniLAndrePOuelletteTDReillyMPMcKenzieSEet alCalDAG-GEFI deficiency protects mice in a novel model of Fcgamma RIIA-mediated thrombosis and thrombocytopenia. Blood (2011) 118:1113–20.10.1182/blood-2011-03-342352

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 136

  JönssonFMancardiDAZhaoWKitaYIannascoliBKhunHet alHuman FcgammaRIIA induces anaphylactic and allergic reactions. Blood (2012) 119:2533–44.10.1182/blood-2011-07-367334

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 137

  PetkovaSBAkileshSSprouleTJChristiansonGJAl KhabbazHBrownACet alEnhanced half-life of genetically engineered human IgG1 antibodies in a humanized FcRn mouse model: potential application in humorally mediated autoimmune disease. Int Immunol (2006) 18:1759–69.10.1093/intimm/dxl110

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 138

  MancardiDAJonssonFIannascoliBKhunHvan RooijenNHuerreMet alThe murine high-affinity IgG receptor Fc(gamma)RIV is sufficient for autoantibody-induced arthritis. J Immunol (2011) 186:1899–903.10.4049/jimmunol.1003642

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 139

  ChristiansonGJBlankenburgRLDuffyTMPankaDRothsJBMarshak-RothsteinAet albeta2-microglobulin dependence of the lupus-like autoimmune syndrome of MRL-lpr mice. J Immunol (1996) 156:4932–9.

  • Pubmed Abstract
  • Google Scholar

• 140

  Tan SardjonoCMottramPLvan de VeldeNCPowellMSPowerDSlocombeRFet alDevelopment of spontaneous multisystem autoimmune disease and hypersensitivity to antibody-induced inflammation in Fcgamma receptor IIa-transgenic mice. Arthritis Rheum (2005) 52:3220–9.10.1002/art.21344

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 141

  van de VeldeNCMottramPLPowellMSLimBHolmdahlRHogarthPM. Transgenic mice expressing human FcgammaRIIa have enhanced sensitivity to induced autoimmune arthritis as well as elevated Th17 cells. Immunol Lett (2010) 130:82–8.10.1016/j.imlet.2009.12.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 142

  TsuboiNErnandezTLiXNishiHCullereXMekalaDet alRegulation of human neutrophil Fcgamma receptor IIa by C5a receptor promotes inflammatory arthritis in mice. Arthritis Rheum (2011) 63:467–78.10.1002/art.30141

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 143

  PieterszGAMottramPLvan de VeldeNCSardjonoCTEsparonSRamslandPAet alInhibition of destructive autoimmune arthritis in FcgammaRIIa transgenic mice by small chemical entities. Immunol Cell Biol (2009) 87:3–12.10.1038/icb.2008.82

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 144

  van VuurenAJvan RoonJAWalravenVStuijIHarmsenMCMcLaughlinPMet alCD64-directed immunotoxin inhibits arthritis in a novel CD64 transgenic rat model. J Immunol (2006) 176:5833–8.10.4049/jimmunol.176.10.5833

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 145

  ThepenTvan VuurenAJKiekensRCDamenCAVooijsWCvan de WinkelJG. Resolution of cutaneous inflammation after local elimination of macrophages. Nat Biotechnol (2000) 18:48–51.10.1038/71908

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 146

  ChenKNishiHTraversRTsuboiNMartinodKWagnerDDet alEndocytosis of soluble immune complexes leads to their clearance by FcgammaRIIIB but induces neutrophil extracellular traps via FcgammaRIIA in vivo. Blood (2012) 120:4421–31.10.1182/blood-2011-12-401133

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 147

  van VugtMJHeijnenAFCapelPJParkSYRaCSaitoTet alFcR gamma-chain is essential for both surface expression and function of human Fc gamma RI (CD64) in vivo. Blood (1996) 87:3593–9.

  • Pubmed Abstract
  • Google Scholar

• 148

  van Royen-KerkhofASandersEAWalravenVVoorhorst-OginkMSaelandETeelingJLet alA novel human CD32 mAb blocks experimental immune haemolytic anaemia in FcgammaRIIA transgenic mice. Br J Haematol (2005) 130:130–7.10.1111/j.1365-2141.2005.05571.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 149

  ZhiHRauovaLHayesVGaoCBoylanBNewmanDKet alCooperative integrin/ITAM signaling in platelets enhances thrombus formation in vitro and in vivo. Blood (2013) 121:1858–67.10.1182/blood-2012-07-443325

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 150

  HortonHMChuSYOrtizECPongECemerskiSLeungIWet alAntibody-mediated coengagement of FcgammaRIIb and B cell receptor complex suppresses humoral immunity in systemic lupus erythematosus. J Immunol (2011) 186:4223–33.10.4049/jimmunol.1003412

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 151

  LiFRavetchJV. Inhibitory Fcgamma receptor engagement drives adjuvant and anti-tumor activities of agonistic CD40 antibodies. Science (2011) 333:1030–4.10.1126/science.1206954

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 152

  LiFRavetchJV. Antitumor activities of agonistic anti-TNFR antibodies require differential FcgammaRIIB coengagement in vivo. Proc Natl Acad Sci U S A (2013) 110:19501–6.10.1073/pnas.1319502110

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 153

  LiMWirthmuellerURavetchJV. Reconstitution of human Fc gamma RIII cell type specificity in transgenic mice. J Exp Med (1996) 183:1259–63.10.1084/jem.183.3.1259

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 154

  RoopenianDCChristiansonGJSprouleTJBrownACAkileshSJungNet alThe MHC class I-like IgG receptor controls perinatal IgG transport, IgG homeostasis, and fate of IgG-Fc-coupled drugs. J Immunol (2003) 170:3528–33.10.4049/jimmunol.170.7.3528

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 155

  MezoARMcDonnellKAHehirCALowSCPalombellaVJStattelJMet alReduction of IgG in nonhuman primates by a peptide antagonist of the neonatal Fc receptor FcRn. Proc Natl Acad Sci U S A (2008) 105:2337–42.10.1073/pnas.0708960105

  • Pubmed Abstract
  • CrossRef
  • Google Scholar