inhibitory fc gamma receptors: from gene to disease

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pp1212-joci-487184 JOCI.cls May 18, 2004 22:59

Journal of Clinical Immunology, Vol. 24, No. 4, July 2004 (C© 2004)

Inhibitory Fc Gamma Receptors: From Gene to Disease

RADU N. STEFANESCU,1 MIKHAIL OLFERIEV, 1 YI LIU, 1 and LUMINITA PRICOP1,2

Multiple lines of evidence have revealed a key role for inhibitoryFc gamma receptors class IIb (FcγRIIb) as negative modulatorsof innate and adaptive immune responses. Acquired and geneticfactors regulate the expression of FcγRIIb receptors and mod-ify their inhibitory potential. Recent advances have highlightedthe importance of FcγRIIb receptors in influencing the develop-ment of cancer and autoimmunity. The association of increasedFcγRIIb expression with tumor development is believed to op-erate at effector cell level resulting in inhibition of antitumorcytotoxicity. In autoimmune diseases, FcγRIIb receptors play amajor role in controlling the amplitude of antibody- and immunecomplex-mediated reactions. Generally, FcγRIIb deficiency isassociated with increased susceptibility and severity to organ-specific and systemic autoimmunity. This article discusses theproposed mechanisms for FcγRIIb deregulation associated withmalignant and autoimmune pathology in animal models and hu-man diseases.

KEY WORDS: Inhibitory Fc receptors; FcγRIIB gene; lymphoma;autoimmunity; gene regulation; polymorphisms.

INTRODUCTION

Functional redundancy of Fc gamma receptors (FcγR) ascellular mediators of antibody reactions has been entailed,over the past decades, upon their structural homology andtheir common ability to interact with immunoglobulin G.The cloning of eight human FcγR genes has revealed un-expected variety and distinct biological functions amongmembers of this gene family. Extensive structural diver-sity has been identified between the signaling domainsof FcγRIIb receptors and other members of the classi-cal FcγR family. A specific amino acid sequence in theintracytoplasmic domain of FcγRIIb receptors mediates

1Research Division, Hospital for Special Surgery, Graduate Program inImmunology and Department of Medicine, Weill Medical College ofCornell University, New York.

2To whom correspondence should be addressed at Hospital for SpecialSurgery, 535 East 70th Street, New York, New York 10021; e-mail:[email protected].

inhibition of cell activation and is a common operat-ing mechanism for a large number of receptors involvedin negative signaling. In contrast with other innate in-hibitory receptors, signaling through FcγRIIb receptorsrequires antibodies as ligands, revealing the main func-tion of these receptors as suppressors of adaptive immuneresponses. This article will highlight the literature onthe biology of inhibitory FcγR and will review the cur-rent knowledge on the role of these receptors in immunesurveillance and autoimmunity.

GENOMIC ORGANIZATION AND STRUCTURE

Within the human genome, the classical low affinityFcγR genes are located on the long arm of chromosome1 (1q21-23). The nucleotide sequence of several FcγRgenes exhibits extensive similarity, resulting from dupli-cation and recombination events that occurred during theevolution of this cluster (1, 2). The 1q21-23 region is alsoa hotspot for translocation events that have been definedin a number of human malignancies, discussed in moredetail below.

In humans, the FcγRII group spans over 15 kb of DNAand comprises three genes: FcγRIIA, FcγRIIB, andFcγRIIC (3). A map of the region constructed with a BACclone library, located FcγRIIA centromeric and FcγRIIBat the telomeric end of 1q23 (4). FcγRIIA and FcγRIIBgenes are derived by gene duplication from a commonancestral gene. The FcγRIIC gene is highly homologousin the 5′ end with the FcγRIIB gene, whereas its 3′ regionis highly homologous with the FcγRIIA gene, suggestingthat the FcγRIIC gene resulted from a crossover betweenFcγRIIA and FcγRIIB (2, 5). The Fc receptor cluster issplit in the mouse between chromosomes 1 and 3. Thelocation of the FcγRIIB gene is synthenic with that inhumans on mouse chromosome 1. The murine orthologof the human FcγRIIB gene encodes receptors bearinginhibitory motives. No murine orthologs of the humanFcγRIIA and FcγRIIC genes have been identified.

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316 STEFANESCU, OLFERIEV, LIU, AND PRICOP

FcγRIIb receptors are single-chain molecules bear-ing IgG-binding sites in their extracellular domains sim-ilar to their activating counterparts, and cytoplasmicdomains containing an immunoreceptor tyrosine-basedinhibitory motif (ITIM). The crystallographic structureof human FcγRIIb revealed folding into two Ig-likedomains arranged near perpendicular to each other, form-ing a heart-shaped overall structure with extensive con-tact between the domains (6). A 13-amino acid sequencepresent in the intracytoplasmic domain of FcγRIIb isrequired for inhibitory function (7). The comparison ofsequences of several inhibitory receptors revealed the con-servation of a valine or an isoleucine residue at posi-tion Y-2, resulting in the characteristic ITIM sequenceV/IxYxxL (8, 9).

FcγRIIb receptors suppress cellular activation by pro-moting dephosphorylation reactions, resulting from the re-cruitment of the src homology 2 (SH2) domain-containinginositol 5-phosphatase 1 (SHIP-1) to the ITIM (7). SHIP-1 decreases the cellular levels of phosphatidylinositol-3,4,5-triphosphate (PtdIns-3,4,5-P3), ultimately prevent-ing the influx of extracellular Ca2+ (10, 11). A distinctinhibitory mechanism of FcγRIIb has been describedmore recently. The inhibition of cell activation was pro-posed to be mediated by the adaptor protein p62dok throughsuppression of activation of extracellular signal-relatedkinases (12).

Alternative splicing of FcγRIIB generates two tran-scripts, FcγRIIB1 and FcγRIIB2, which differ only intheir intracytoplasmic exons (13). As a result of an ad-ditional exon, the human and mouse FcγRIIb1 proteinscontain insertions in their cytoplasmic tails of 19 and 47amino acids, respectively, which alter the ability of thesereceptors to mediate endocytosis and cell cycle entry (14,15). Recombinant FcγRIIb1 and FcγRIIb2 have equalcapacity to downregulate Ca2+ fluxes and cell activation(16).

In mast cells and basophils, coclustering of FcγRIIb1and FcγRIIb2 isoforms with activating FcγR caused in-hibition of degranulation (17). FcγRIIb2 isoforms arecoexpressed with activating FcγR in primary monocytes,neutrophils and monocyte-derived dendritic cells (18–21). Follicular dendritic cells (FDC) also express highlevels of FcγRIIb. FcγRIIb receptors expressed on FDCin germinal centers are involved in the retention of im-mune complexes and in the generation of recall responses(22). A defect in the maturation of FDC in the germinalcenters was noticed in FcγRIIb-deficient animals (23).Because of their ability to inhibit cell activation, FcγRIIbreceptors are believed to promote noninflammatory clear-ance of immune complexes (24). The inhibitory capacityof FcγRIIb2 in cells of the mononuclear phagocyte sys-

tem is exerted upon coaggregation with ITAM-bearingFcγRs, leading to inhibition of effector functions (18).In monocytes and macrophages, FcγRIIb2 receptors reg-ulate the production of cytokines and the amplitude ofinflammation in response to immune complexes (25).

FcγRIIb1 receptor isoforms are preferentially ex-pressed in B lymphocytes, and are involved in the negativeregulation of antibody production and B cell prolifera-tion (16, 26). FcγRIIb1 receptors are important factorsin controlling the amplitude of B cell activation in re-sponse to antigen. Specific IgG antibodies that bind to theB cell receptor (BCR) through their Fab region can inter-act through their Fc portion with inhibitory FcγRIIb1 onB cells and deliver an inhibitory signal. Coaggregation ofFcγRIIb1 with the BCR inhibited independently ligatedreceptors whose signalling required PtdIns-3,4,5-P3 (27).Negative signaling by FcγRIIb1 represents a feedbacksuppression system that functions to inhibit B cell acti-vation, proliferation and antibody production. A role forFcγRIIb receptors in antigen independent B-lymphocytedevelopment has also been suggested. A number of stud-ies show that signaling through these receptors stimulatesthe growth and development of lymphocyte progenitorcells in vitro, and that mice deficient in FcγRIIb showsignificantly reduced B cell compartments (28).

ROLE OF FcγRIIb IN TUMOR IMMUNE SURVEILLANCE

Rearrangements of chromosomal bands 1q21-23 arefrequent aberrations in hematological malignancies. Cy-togenetic analysis in several forms of B cell non-Hodgkinlymphomas and acute lymphoblastic leukemia revealedthis region as a hotspot for translocation events, witht(1;22) accompanying other specific rearrangements, suchas t(14;18) (BCL2) and t(8;14) (MYC) (29–31). Increasedexpression of the FcγRIIB2 splicing variant in malignantlymphocytes was the principal consequence of the translo-cation t(1;22). Overexpression of FcγRIIB2 transcriptsand accumulation of multiple additional FcγRII splicingintermediates was the result of abnormally high levels oftranscription from the FcγRIIB promoter, a possible con-sequence of its proximity to the immunoglobulin lambdatranscriptional enhancer (32). Expression of FcγRIIb inB cell lymphomas was linked to transformation and isthought to have prognostic value (33).

Frequent implication of the 1q21-23 region in pri-mary chromosomal translocations was also describedin hematological malignancies of myeloid origin (34).Overexpression of FcγRIIb enhanced the tumorigenicphenotype of nonlymphoid tumors as well, suggest-ing its role in facilitating the escape from antitumor

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INHIBITORY FC GAMMA RECEPTORS 317

Table I. Deregulated Expression and Function of FcγRIIb Receptors Associated with Disease

Disease/animal model Species Association/mechanism Reference

B cell lymphoma and lymphoblastic leukemia Human FcγRIIB hyperexpression (29–33)Melanoma Mouse FcγRIIB expression inhibits ADCC (49)

Human FcγRIIB1 expression in malignant cells (50)Graves disease Human FcγRIIB2 expression in thyrocytes (97)Autoimmune hemolytic anemia Mouse FcγRIIB deficiency (25, 57, 58)Idiopathic thrombocytic purpura Mouse FcγRIIB deficiency (59, 60)Autoimmune glomerulonephritis Mouse FcγRIIB deficiency (61–64)Autoimmune lung disease Mouse FcγRIIB deficiency (25, 65)Autoimmune arthritis Mouse FcγRIIB deficiency (66–71)SLE Mouse FcγRIIB deficiency (57, 73, 74, 120)

Human FcγRIIB polymorphisms (87–91)Autoimmune-prone mice Mouse FcγRIIB polymorphisms (57, 80, 81)

antibody-mediated immunity (35). The proposed mech-anistic basis for the malignant proliferation in these caseswas that the constitutive overexpression of FcγRIIbmight allow tumor cells to inhibit binding of antitumorantibodies and thereby evade antitumor attack. These re-ports pointed to the potential pathological connection ofderegulated FcγRIIb expression in tumor progression.Table I presents a list of diseases having a malfunction ofinhibitory FcγRIIb as a proposed mechanism.

Recognition of tumor antigens by specific antibodies isa described phenomenon in cancer patients. Recent re-ports attest that presentation of tumor antigens can befacilitated by phagocytosis in the form of IgG immunecomplexes (36, 37). Uptake of antibody-coated myelomacells by FcγR-mediated phagocytosis promoted cross-presentation of the cancer antigens, and stimulation ofcytotoxic T lymphocytes. Enhanced cross-presentation ofantibody-coated tumor cells was dependent on FcγR-mediated phagocytosis of opsonized tumor cells, as itwas inhibited by a cocktail of Fc receptors blocking an-tibodies. This pathway of antigen processing is reminis-cent of the selective antigen transport mediated via ac-tivating FcγR (38–40). Using panels of FcγR-deficientmice, antigen targeting to both activating and inhibitoryFcγR on bone marrow-derived DC and primary epidermalLangerhans’ cells was shown to augment T cell prolifera-tion. Surprisingly, DC fromγ -chain-deficient mice whichonly expressed FcγRIIb receptors, showed significant im-mune complex-uptake and T cell proliferation, suggest-ing efficient antigen presentation of IgG-complexed anti-gens mediated by FcγRIIb receptors (41). At the presenttime, there is no consensus between groups supportingthe concept that FcγRIIb-mediated immune complex up-take can upregulate the priming of T lymphocytes, andother reports suggesting that the binding of immune com-plexes to FcγRIIb on DC is inhibitory (42–45). Struc-tural differences between the human and mouse FcγRIIBgenes could account for distinct functional properties of

FcγRIIb receptors in the two species. Importantly, whilemouse FcγRIIb2 is phagocytosis competent, the humanFcγRIIb2 isoform does not internalize opsonized parti-cles, although it is to some extent able to mediate uptakeof small soluble immune complexes (16, 46). Further re-search will be required to elucidate the complex nature ofthese processes in mice and humans.

In animal models of melanoma, antibody-dependentcellular cytotoxicity (ADCC) induced tumor rejection andabrogated pulmonary metastasis (47). In these models,activating FcγR were involved in the eradication of es-tablished tumors and metastases by antitumor antibodies(48). Interestingly, enhanced tumor immunogenicity ledto autoimmunity in some cases. Inhibitory Fc receptorshave been proposed to modulate the cytotoxic responseagainst tumor targets, based on the observation that anti-tumor antibodies were more effective at preventing lungmetastases in mice deficient in inhibitory FcγRIIb recep-tors. Mechanistically, engagement of inhibitory FcγRIIbon myeloid cells was shown to enhance tumor growthby virtue of their ability to downregulate the ADCC trig-gered through activating FcγR (49). Tumor cells in metas-tases of melanoma patients were found to express FcγRIIb(50). As in the case of hematological malignancies, poten-tial overexpression of FcγRIIb in certain cancer patientsmight allow tumor cells to inhibit binding of antitumor an-tibodies and thereby evade antitumor attack. In support ofthis speculation, the described property of certain virusesto bind Fc receptors is believed to constitute a strategy thathas evolved to allow viral escape from antibody-mediatedimmunity. Measles virus nucleocapsid protein specificallytargets the FcγRIIb receptor and inhibits human B cell an-tibody production, a mechanism that may play a role inthe virus-induced immunosuppression (51).

Increasing interest in exploring means to stimulate thenatural immune response to tumor-specific antigens isconstantly fueled by both advances and challenges inthe development of cancer vaccines. Antibodies against


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CD20 and the HER2/neu growth factor receptor preventthe growth of B cell non-Hodgkin’s lymphoma and breastcarcinoma, respectively (52, 53). In addition to a directproapoptotic activity, the cytotoxic potential of human-ized antitumor antibodies against CD20 (Rituxan) andHER2/neu (Herceptin) is believed to depend on the abilityof these antibodies to mediate ADCC by engaging activat-ing FcγR on monocytes and macrophages. Mice deficientin FcγRIIb showed more ADCC and were effective at ar-resting tumor growth at subtherapeutic doses of antitumorantibodies, indicating a contribution of inhibitory FcγRIIbreceptors to the action of these cytotoxic antibodies (49).The requirement to generate antitumor antibodies with di-minished binding affinities for FcγRIIb, as suggested bythese studies, is a challenging task, due to the high degreeof homology in the extracellular domains of activating andinhibitory FcγR. Strategies to change the balance of ac-tivating versus inhibitory FcγR, described below, couldtherefore constitute more feasible approaches to increaseefficacy of antibody action. Exploiting these propertiesmay offer new opportunities for the therapeutic manage-ment of malignant tumors.

FcγRIIb RECEPTORS AND AUTOIMMUNITY

The significance of the inhibitory pathways mediatedby FcγRIIb receptors for the immune homeostasis hasbeen first verifiedin vivo a decade ago. Targeted deletionof the FcγRIIB gene greatly enhanced the pathologicalsigns of antibody- and immune complex-mediated inflam-matory reactions (54). Augmented humoral and anaphy-lactic responses correlated with decreased expression ofFcγRIIb receptors on B cells, macrophages and mast cells.Elevated levels of immunoglobulins in FcγRIIB-deficientmice suggested a role for inhibitory FcγRIIb in controllinghumoral autoimmunity. Diminished FcγRIIb1 expressionon B cells resulted in reduced negative feedback, allowingfor continued production of autoantibodies. In addition tothe humoral immunity aspects of downregulation, engage-ment of FcγRIIb receptors has been proven to reduce in-flammatory reactions at the effector cell level. Coligationof FcγRIIb with activating Fc receptors on mononuclearphagocytes inhibited phagocytosis and production of in-flammatory mediators (25). The concept that inhibitoryFcγRIIb could influence the clinical outcome of immunecomplex-mediated diseases has since then prompted nu-merous studies on the role of these receptors in experi-mental models of autoimmune diseases.

Pathophysiology of autoimmune diseases resultslargely from hyperactivation of lymphocytes, productionof autoantibodies, and persistent inflammation at sites of

immune complex deposition. Given that autoimmunityhas been associated with decreased negative feedback inhumoral and effector immune responses, the fundamentalquestion arose whether FcγRIIb might be conferring pro-tection for autoimmune diseases. Indeed, multiple lines ofevidence now support the concept that structural defectsin inhibitory FcγRIIb or functional alterations in FcγRIIbsignaling can trigger, sustain or accelerate diseases suchas autoimmune cytopenias, glomerulonephritis, alveolitis,arthritis, and lupus (Table I).

Autoimmune hemolytic anemia (AIHA) and idiopathicthrombocytic purpura (ITP) are autoimmune cytopeniasin which mononuclear phagocytes ingest the antibody-coated erythrocytes and platelets, via an FcγR-mediatedmechanism (55). A contribution for FcγRIIb recep-tors in the regulation of erythrophagocytosis has beensuggested. AIHA manifestations resembling the hu-man disease are common pathologic findings in strainsof autoimmune mice displaying reduced expression ofFcγRIIb on macrophages and increased ability to phago-cytose erythrocytes (56, 57). FcγRIIb was not foundto be an important regulator of autoantibody inducedhemolysis by another group, suggesting different effectsdependent on the experimental system (58). In murineautoimmune thrombocytopenia (ITP), genetic ablationof inhibitory FcγRIIB resulted in uncontrolled systemicreaction and severe hemorrhage leading to enhanced mor-tality in response to antiplatelet antibodies (59). Inductionof FcγRIIb on macrophages prevented the clearance ofplatelets opsonized with autoantibodies in ITP (60).

The pathogenic involvement of inhibitory FcγRIIbreceptors has also been validated in animal models of au-toimmune nephritis. Accelerated disease manifestations inantiglomerular basement membrane glomerulonephritiswere described in FcγRIIB knock-out mice (61). Down-regulated expression of FcγRIIb on glomerular mesangialcells contributed to the renal inflammation in an animalmodel of Goodpasture’s syndrome (62). Immunizationwith bovine collagen IV induced crescentic glomeru-lonephritis in FcγRIIB-deficient but not in wild type mice(63). Similarly, in cryoglobulin-associated membranopro-liferative glomerulonephritis induced by overexpressionof thymic stromal lymphopoietin, deletion of FcγRIIBcaused massive influx of macrophages and increased cel-lular proliferation, aggravating the disease progression(64). These results suggested that modulation of FcγRIIBexpression may be a useful therapeutic approach fortreating glomerular diseases of different etiologies.

Mice deficient in inhibitory FcγRIIb receptors werereported to develop robust alveolar inflammation tosubthreshold concentrations of immune complexes(25). FcγRIIb knock-out mice had a massive influx of


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neutrophils in the lungs and their macrophages hadgreater phagocytic responses and secreted higher levelsof tumor necrosis factor-alpha (TNF-α). Interestingly,soluble immune complexes were reported to suppressinhibitory FcγRIIb expression in autoimmune lung dis-ease, a mechanism that required the interaction of thecomplement component C5a with the receptor C5aR oninflammatory cells (65).

Deletion of the FcγRIIB gene in a nonpermissive HLAhaplotype rendered DBA/1 mice susceptible to collageninduced arthritis (CIA), in association with marked cel-lular infiltration in the joints and enhanced productionof interleukin-1 (IL-1) (66). Signaling through FcγRIIbinhibited the degradation of aggrecan and collagen bymatrix metalloproteinases (MMP), causing inhibition ofsevere cartilage destruction in CIA (67). Enhancement ofarthritis in DBA/1 mice lacking inhibitory FcγRIIB bysingle anticollagen type II mAb was also reported (68).An augmented susceptibility and severity of arthritis wasdescribed in aged FcγRIIB deficient BALB/c mice, af-ter the injection of anticollagen antibodies and cytokines(69). Genetic ablation of FcγRIIB in the K/BxN serumtransfer arthritis model had no functional consequences,suggesting that differences in the inhibitory activity viaFcγRIIb could be strain-dependent (70). Although acontribution by the FcγRIIB gene was excluded in theK/BxN serum transfer model, decreased expression ofFcγRIIB due to an autoimmune promoter haplotypepresent in both NOD and 129Sv backgrounds could haveinfluenced the development of arthritis in this model (57,70). Analysis of the acute phase of arthritis transferred byK/BxN sera into FcγRIIB-deficient mice was reportedto accelerate the onset and severity of disease by anothergroup (71). Although alterations in expression of FcγRon synovial macrophages of rheumatoid arthritis (RA)patients have been documented and are believed to resultin higher production of TNF-α and MMP, a direct rolefor inhibitory FcγRIIb receptors in the pathogenesis ofhuman RA has not been yet demonstrated (72).

FcγRIIB has been identified as a modulator of periph-eral tolerance with the observation that FcγRIIB-deficientmice develop systemic autoimmunity. The deficiencyof FcγRIIB led to lupus-like manifestations in specificgenetic backgrounds, thus identifying this gene as a sus-ceptibility factor for murine lupus (73, 74). Genetic studiesprovided evidence for susceptibility alleles mapped in thevicinity of the FcγRIIB gene in the telomeric region onchromosome 1 in murine models of systemic lupus ery-thematosus (SLE) (75–78). In NZB mice, mutations inthe second extracellular domain of both FcγRIIb1 andFcγRIIb2 have been reported (79). Polymorphisms havebeen detected in transcription regulatory regions of the

FcγRIIB gene in several autoimmune mouse strains, butnot in nonautoimmune disease prone strains (57, 80, 81).Allelic polymorphisms in the FcγRIIB promoter region,consisted of several nucleotide deletion sites (81). Thesepolymorphisms correlated with extents of downregulationof FcγRIIb expression on macrophages and B cells, andwith increased phagocytosis by macrophages and upreg-ulation of IgG antibody responses. Given the importanceof FcγRIIb-initiated inhibitory signals for controllingcellular activation, these genetic alterations in FcγRIIBare believed to contribute to the lupus phenotype. Theseconverging studies suggested a role for FcγRIIB inmodulating tolerance in animal models of autoimmunity.

The hypothesis that FcγRIIB is functioning to suppressthe development of autoimmunity in susceptible animalsraised the possibility that alterations in FcγRIIB coulddetermine susceptibility to and severity of autoimmunedisorders in humans. To date, a small number of studieshave investigated polymorphisms in the FcγRIIB geneand their association with autoimmune diseases. A singlenucleotide polymorphism (SNP) at nucleotide 208 C> Twas recently identified and predicted an amino acid changein the signal peptide (82). A SNP at nucleotide 846 C>T which predicted a change within the first cytoplasmicdomain of FcγRIIB was reported by the same group. Ina study of Japanese patients with RA association of the695 T> C SNP coding for a nonsynonymous substitu-tion, Ile232Thr (I232T), representing two alleles withinthe transmembrane domain of the human FcγRIIB genedid not detect significant difference in genotype frequen-cies or phenotype between patients and healthy individuals(83).

Genome-wide scans and linkage studies suggested thechromosomal region containing the FcγR cluster includ-ing the FcγRIIB gene to be one of the strongest candidateregions for human SLE (84–86). Support for this view-point was recently published. The association of the 695T> C SNP coding for the I232T substitution in the trans-membrane domain of FcγRIIb with SLE has been firstreported in the Japanese population (87). The frequencyof the 232T/T genotype was increased in Japanese, Chi-nese and Thai patients with SLE compared with healthyindividuals, pointing toward FcγRIIB as a common sus-ceptibility gene in the Asian populations (87–89). Thepresence of this threonine in the transmembrane domainof FcγRIIb was found to mediate a higher level of CD19dephosphorylation and a greater degree of inhibition ofthe calcium response when coengaged with BCR (82).In spite of these functional changes, there were no sig-nificant differences in African American and Caucasianpatients with SLE and matched controls bearing the twotransmembrane alleles (82). A novel polymorphism was


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Fig. 1. Schematic representation of genetic and acquired factors involved in the regulation of theFcγRIIB expression and function. Downregulation of FcγRIIB gene expression is indicated bydownward arrows. Induction of FcγRIIB gene expression is indicated by upward arrows. Abbrevi-ations: B lymphocytes (B); monocytes (Mo); dendritic cells (DC); polymorphonuclear neutrophils(PMN); complement component 5a (C5a); C5a receptor (C5aR); intravenous immunoglobulin(IVIG); phorbol ester (PMA); dibutyryl cyclic AMP (dbcAMP).

recently identified in the human FcγRIIB promoter. In ho-mozygosity, this FcγRIIB promoter SNP was associatedwith SLE in Caucasians and correlated with deregulatedFcγRIIb expression in activated B cells from SLE patients(90). A rare haplotype present in the FcγRIIB promoterwas described in African Americans (91). These alle-les were differentially distributed between SLE patientsand non-SLE controls in African Americans but not inCaucasians. Corroborated with the genome-wide linkagestudies, these studies raise the possibility for FcγRIIB tobe one of the susceptibility factors for the developmentof SLE in humans. Alterations in FcγRIIb1-mediatedsignaling in SLE in the absence of major differences inFcγRIIb1 expression on peripheral B cells from SLEpatients were also detected (92). The complexity of theFcγRIIb-mediated signaling pathways calls for furtherinsight into the relationship between these inhibitory Fcreceptors and autoimmune pathology in humans.

REGULATION OF THE FcγRIIB GENE EXPRESSION

The importance of understanding the mechanisms in-volved in the FcγRIIB gene regulation is underscored byobservations that relatively small reductions in expressionof FcγRIIb receptors can contribute to the breakdown of

self-tolerance (57, 93). Mice heterozygous for deletionsin FcγRIIB exhibit only modest reductions in protein ex-pression, but have a predisposition to autoimmunity (74).Given the robust experimental evidence indicating thatinhibitory FcγRIIb receptors are crucial modulators ofimmune reactions, how is the expression of these sur-face molecules to be regulated to respond to activationand environmental triggers? The current knowledge ofgenetic and acquired factors involved in the regulationof the FcγRIIB gene is summarized below and presentedschematically in Fig. 1.

The factors that directly regulate the FcγRIIB gene ex-pression are largely unknown. The first observations thatthe status of cell activation could influence the expres-sion of various FcγR subtypes were made more than adecade ago. Early reports documented that increased cellactivation induced by phorbol ester (PMA) and dibutyrylcAMP increased FcγRII expression and phagocytosis inthe human monoblastic cell line, U937 (94). PMA causeda fivefold increase in all three FcγRII RNA transcriptsin Northern analysis. The effect of dibutyryl cAMP onFcγRII expression and function was mainly due to theupregulation of the inhibitory FcγRIIB1 isoform (95).

Several lines of evidence suggested that hormonesare important elements in the regulation of FcγRIIbexpression and function in nonhematopoietic tissues.


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Heterogeneous expression of FcγRIIb in the human pla-centa was observed (96). The transcripts of the FcγRIIBgene dramatically increased in placenta at the second andthird trimesters. Interestingly, while FcγRIIB mRNAcould be induced in uterine endometrium by pseudopreg-nancy therapy using estrogen and progesterone, therewere no detectable FcγRIIB mRNA transcripts in hor-mone unprimed normal endometrium. These findingssuggested that FcγRIIB is expressed at the feto-maternalinterface, and can be transcriptionally regulated by sexsteroid hormones.

A role for hormones in the transcriptional regulationof FcγRIIB gene is further supported by data showingthat thyrocytes from patients with autoimmune Graves’disease express FcγRIIb2 isoforms in contrast with thy-rocytes from healthy controls (97). Although an effectof thyroid hormones on the expression of FcγRIIB2 onthyrocytes has not been documented, dihydrotestosteronewas found to repress FcγRIIB2 expression, suggesting arole for sex hormones in the onset and/or progression ofautoimmune thyroid disease. The androgen-mediated de-crease of FcγRIIB2 expression in Graves’ disease alsoprovides a rationale for the predominant susceptibility ofwomen to develop autoimmune thyroid disease. Thesefindings revealed new potential mechanisms involved inautoimmune thyroiditis, linking the role of this target or-gan to the sex dependence in autoimmune disease (97).

Surface expression of FcγRIIb receptors in macro-phages was upregulated following treatment with intra-venous immunoglobulin (IVIG), a mechanism thoughtto contribute to the antiinflammatory activity of IVIG inautoimmune diseases. In ITP, the macrophage-mediatedclearance of platelets opsonized with pathogenic an-tibodies could be prevented by IVIG (60). Similarly,IVIG conferred protection against arthritis induced byautoantibodies in the K/BxN arthritis model (98, 99).In both cases, the IVIG-mediated protection was associ-ated with increased expression of inhibitory FcγRIIb onmacrophages. Dissection of the mechanisms responsiblefor the upregulation of FcγRIIb on effector macrophagesfollowing IVIG treatment indicated the requirement for asubset of colony-stimulating factor-1-dependent “sensor”macrophages (98). The IVIG-mediated inhibitory path-ways operating via FcγRIIB were shown to be indepen-dent of SHIP1 in monocytes and may involve signalingpathways different from those operating in B cells (100).

The cytokine milieu constitutes a key component inthe regulation of FcγR mediated effector functions. Dis-tinct subsets of T lymphocytes producing T helper 1(Th1) and Th2 cytokines were found to alter FcγRIIb ex-pression (18, 93, 101). An important consequence of theTh1/Th2 polarization was the differential modulation of

activating and inhibitory FcγR (18, 101, 102). IFN-γ , aprototypic Th1 cytokine, induced the expression of acti-vating FcγR, while downregulating inhibitory FcγRIIbisoforms, changing the balance of FcγR to an activatingphenotype. In contrast, Th2 cytokines such as IL-4 in-creased the expression of inhibitory FcγRIIb, while down-regulating all classes of activating FcγR in primary mono-cytes and THP-1 cells (18, 19, 103).

Other reports demonstrated the ability of IL-4 to down-regulate FcγRIIb expression and inhibitory function on Bcells (93, 101). In splenic B cells, IL-4 decreased the cellsurface expression of FcγRIIb and other ITIM receptors,and determined losses in inhibitory function (93). Theopposite regulation of FcγRIIB expression in monocytesand B cells could be related to the fact that IL-4 pro-motes B cell activation and proliferation, while it acts as amonocyte deactivator. The disparity between the IL-4 me-diated downregulation of FcγRIIb1 levels on B cells andits effect of increasing FcγRIIb2 expression on mono-cytes could be due to differences in transactivation of theFcγRIIB gene in monocytes versus B lymphocytes, me-diated by lineage-specific transcriptional regulators (104).The inhibitory effect of IL-4 was not seen in the absenceof B cell activation via the BCR or by lipopolysaccharide.In combination with IL-4, these stimuli likely inducedthe expression of secondary transcription factors (105).

The concept of cross-regulation between the comple-ment system and inhibitory FcγRIIb receptors has beenput forward, recently. Complement components werefound to regulate the balance of activating and inhibitoryFcγR in a mouse model of autoimmune lung disease(65). As a result of C5a-C5aR interactions, inflamma-tory cells were attracted at sites of immune-complex de-position and released inflammatory mediators, event thatwas associated with a downregulation in FcγRIIb ex-pression. This study indicated a regulatory link betweencomplement components, inflammatory mediators and in-hibitory FcγRIIb receptors during the initiation of im-mune complex-mediated reactions. Thesein vivofindingsfurther support the concept that inflammation could in-duce major alterations in the relative expression of FcγRwith opposing function and, thus may regulate the am-plitude of cellular responses to IgG immune complexes(Fig. 1).

The differential regulation of activating FcγRIIA andinhibitory FcγRIIB gene transcription seems to be op-erative at promoter level. Although the FcγRIIA andFcγRIIB genes share a high degree of homology in theirfirst six exons and introns, the 5′ flanking sequence of thehuman FcγRIIB gene showed no apparent homology tothat of the human FcγRIIA gene (106–109). These find-ings suggested that the expression profiles of the FcγRIIA


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and FcγRIIB genes could be differentially regulated attranscriptional level. Lack of similarity in potential bind-ing sites for essential transcription factors could explainthe disparity in cytokine responsiveness of the two genes.

The functional characterization of the human FcγRIIBpromoter and the molecular mechanisms underlying theregulation of the human FcγRIIB gene expression are stillobscure. Described regulatory elements of the FcγRIIBpromoter are located within the first 500 bp upstream of thetranscription initiation site (106, 108). Consensus motivespresent in the human FcγRIIB promoter include GATAand activating protein-4 (AP-4) binding sites. Cytokine-dependent regulation of gene transcription could be me-diated via signal transducer and activator of transcription(STAT) binding sites, present in the promoter of humanFcγRIIB. Two nuclear proteins that bind to the humanFcγRIIB promoter and function as transcriptional repres-sors were characterized (108). They were identified ashuman zinc-finger protein 140 (ZNF140) and zinc-fingerprotein 91 (ZNF91) containing a Kruppel-associated box(110–112). Interestingly, in electromobility shift assay(EMSA), nuclear lysates extracted from monocytic THP-1cells and Raji B cells gave different band patterns, indi-cating that various types of cells might contain differentnuclear factors for the FcγRIIB promoter region (108).

Sequence analysis of the 5′ UTR of the mouse FcγRIIBreceptor gene indicated the presence of regulatory ele-ments, including three binding sites for the transcriptionfactor Sp1, an AP-4 binding site, and a tandem gluco-corticoid response element upstream of the transcriptioninitiation site (113). In addition, sites of methylation thatregulate gene expression were also located at the 5′ end ofthe mouse FcγRIIB gene (114). Sequence analysis of the5′ UTR of the FcγRIIB genes in mice and humans showedlittle homology, suggesting potential differences in theregulation of the promoter activities in the two organisms.

Major autoimmune-prone mouse strains (NZB, BXSB,SB/Le, 129, MRL and NOD) share a common FcγRIIBpromoter haplotype, characterized by several sequence al-terations confined to the proximal 300-bp upstream pro-moter sequence (57, 80, 115). A 13 nucleotide deletionsite in the autoimmune FcγRIIB promoter region wasshown to alter transcription of the gene by interferingwith normal interactions between cis-acting element(s)and trans-acting factor(s). In luciferase reporter assay itwas shown that the 13-nucleotide deletion site downreg-ulated the transcription activity and EMSA analysis re-vealed that the defect in transcription activity was likelydue to absence of transactivation by AP-4 (115).

In addition to deletion polymorphisms in the promoterregion, sequence analysis of the mouse FcγRIIB geneidentified an insertion polymorphism of 16 nucleotides in

the first intron. This insertion site did not have consensussequences for known transcription factors. Spontaneousautoimmune-prone mouse strains, i.e. MRL and NOD,shared deletion sites in the promoter region and in thethird intron of the FcγRIIB gene (81, 116). Interestingly,mouse strains thatper seare not autoimmune-prone, butdo have the potential to accelerate or modify autoimmunediseases in the F1 hybrid, i.e. NZB/NZW, NZB/SWR andSWR/SJL shared deletion sites in the third intron (117–119).

Taken together, these lines of evidence indicate thatpolymorphisms in the regulatory regions of FcγRIIBcan alter transcriptional regulation and gene expressionand may associate with autoimmunity. In addition, hor-mones and cytokines induce pronounced alterations inthe expression and function of FcγRIIb, and could al-ter inhibitory FcγRIIb function. The identification andutilization of agents that modulate the expression of in-hibitory FcγR expression and/or pharmocological target-ing of FcγRIIb signaling pathways may yield effectivetreatments in the future. The implementation of strate-gies to upregulate the FcγRIIb inhibitory pathway mayreduce IgG-triggered inflammatory responses. However,an imbalanced suppression of immune reactions follow-ing induction of FcγRIIb might decrease host defense dueto inefficient phagocytosis, ADCC and cytokine release.Moreover, the potential pathological relationship betweenupregulated FcγRIIb expression and tumor progressionhas to be addressed. Therefore, to be considered as atherapeutic target and for a comprehensive understand-ing of the clinical consequences of FcγRIIb modulation,further insight into the mechanisms involved in the regu-lation of inhibitory FcγRIIb receptors in human cells isimperative.

ACKNOWLEDGMENTS

This work was supported by grants from the Arthri-tis Foundation and the National Institutes of Health, R21AR050643, and RO1 AR 38889 (to L. Pricop).

REFERENCES

1. Qiu WQ, de Bruin D, Brownstein BH, Pearse R, Ravetch JV: Orga-nization of the human and mouse low-affinity Fc gamma R genes:Duplication and recombination. Science 248:732–735, 1990

2. Warmerdam PA, Nabben NM, van de Graaf SA, van de WinkelJG, Capel PJ: The human low affinity immunoglobulin G Fc re-ceptor IIC gene is a result of an unequal crossover event. J BiolChem 268:7346–7349, 1993

3. Hulett MD, Hogarth PM: Molecular basis of Fc receptor function.Adv Immunol 57:1–127, 1994


P1: JQX



4. Su K, Wu J, Edberg JC, McKenzie SE, Kimberly RP: Genomicorganization of classical human low-affinity Fcgamma receptorgenes. Genes Immun 3:S51–S56, 2002

5. Metes D, Ernst LK, Chambers WH, Sulica A, Herberman RB,Morel PA: Expression of functional CD32 molecules on hu-man NK cells is determined by an allelic polymorphism of theFcgammaRIIC gene. Blood 91:2369–2380, 1998

6. Sondermann P, Huber R, Jacob U: Crystal structure of the sol-uble form of the human fcgamma-receptor IIb: A new memberof the immunoglobulin superfamily at 1.7 A resolution. EMBO J18:1095–1103, 1999

7. Muta T, Kurosaki T, Misulovin Z, Sanchez M, Nussenzweig MC,Ravetch JV: A 13-amino-acid motif in the cytoplasmic domainof Fc gamma RIIB modulates B-cell receptor signalling. Nature369:340, 1994

8. Reth M: Antigen receptor tail clue [letter]. Nature 338:383–384,1989

9. Bruhns P, Vely F, Malbec O, Fridman WH, Vivier E, Daeron M:Molecular basis of the recruitment of the SH2 domain-containinginositol 5-phosphatases SHIP1 and SHIP2 by fcgamma RIIB. JBiol Chem 275:37357–37364, 2000

10. Bolland S, Pearse RN, Kurosaki T, Ravetch JV: SHIP modulatesimmune receptor responses by regulating membrane associationof Btk. Immunity 8:509–516, 1998

11. Scharenberg AM, El-Hillal O, Fruman DA, Beitz LO, Li Z, Lin S,Gout I, Cantley LC, Rawlings DJ, Kinet JP: Phosphatidylinositol-3, 4, 5-trisphosphate (PtdIns-3, 4, 5-P3)/Tec kinase-dependentcalcium signaling pathway: A target for SHIP-mediated inhibitorysignals. EMBO J 17:1961–1972, 1998

12. Tamir I, Stolpa JC, Helgason CD, Nakamura K, Bruhns P, DaeronM, Cambier JC: The RasGAP-binding protein p62dok is a me-diator of inhibitory FcgammaRIIB signals in B cells. Immunity12:347–358, 2000

13. Brooks DG, Qiu WQ, Luster AD, Ravetch JV: Structure and ex-pression of human IgG FcRII(CD32). Functional heterogeneity isencoded by the alternatively spliced products of multiple genes. JExp Med 170:1369–1385, 1989

14. Amigorena S, Bonnerot C, Drake JR, Choquet D, Hunziker W,Guillet JG, Webster P, Sautes C, Mellman I, Fridman WH: Cyto-plasmic domain heterogeneity and functions of IgG Fc receptorsin B lymphocytes. Science 256:1808–1812, 1992

15. Sarmay G, Rozsnyay Z, Koncz G, Gergely J: Interaction of sig-naling molecules with human Fc gamma RIIb1 and the role ofvarious Fc gamma RIIb isoforms in B-cell regulation. ImmunolLett 44:125–131, 1995

16. Van Den Herik-Oudijk IE, Westerdaal NA, Henriquez NV, CapelPJ, Van De Winkel JG: Functional analysis of human Fc gammaRII (CD32) isoforms expressed in B lymphocytes. J Immunol152:574–585, 1994

17. Daeron M: Negative regulation of mast cell activation by receptorsfor IgG. Int Arch Allergy Immunol 113:138–141, 1997

18. Pricop L, Redecha P, Teillaud JL, Frey J, Fridman WH, Sautes-Fridman C, Salmon JE: Differential modulation of stimulatoryand inhibitory Fc gamma receptors on human monocytes by Th1and Th2 cytokines. J Immunol 166:531–537, 2001

19. Tridandapani S, Siefker K, Teillaud JL, Carter JE, WewersMD, Anderson CL: Regulated expression and inhibitory func-tion of Fcgamma RIIb in human monocytic cells. J Biol Chem277:5082–5089, 2002

20. Amigorena S, Lankar D, Briken V, Gapin L, Viguier M,Bonnerot C: Type II and III receptors for immunoglobulinG (IgG) control the presentation of different T cell epitopes

from single IgG-complexed antigens. J Exp Med 187:505–515,1998

21. Liu Y, Masuda E, Blank MC, Pricop L: Fc receptors on dendriticcells enhance cross-presentation of antigenic peptides to CD8+ Tlymphocytes. Arthritis Rheum 48:S268, 2003

22. Qin D, Wu J, Vora KA, Ravetch JV, Szakal AK, Manser T, TewJG: Fc gamma receptor IIB on follicular dendritic cells reg-ulates the B cell recall response. J Immunol 164:6268–6275,2000

23. Rao SP, Vora KA, Manser T: Differential expression of the in-hibitory IgG Fc receptor FcgammaRIIB on germinal center cells:Implications for selection of high-affinity B cells. J Immunol169:1859–1868, 2002

24. Dijstelbloem HM, van de Winkel JG, Kallenberg CG: Inflam-mation in autoimmunity: Receptors for IgG revisited. TrendsImmunol 22:510–516, 2001

25. Clynes R, Maizes JS, Guinamard R, Ono M, Takai T, RavetchJV: Modulation of immune complex-induced inflammationinvivo by the coordinate expression of activation and inhibitory Fcreceptors. J Exp Med 189:179–186, 1999

26. Phillips NE, Parker DC: Cross-linking of B lymphocyte Fcgamma receptors and membrane immunoglobulin inhibits anti-immunoglobulin-induced blastogenesis. J Immunol 132:627–632,1984

27. Brauweiler AM, Cambier JC: Fc gamma RIIB activation leadsto inhibition of signalling by independently ligated receptors.Biochem Soc Trans 31:281–285, 2003

28. de Andres B, Mueller AL, Verbeek S, Sandor M, Lynch RG: Aregulatory role for Fcgamma receptors CD16 and CD32 in thedevelopment of murine B cells. Blood 92:2823–2829, 1998

29. Callanan MB, Le Baccon P, Mossuz P, Duley S, Bastard C,Hamoudi R, Dyer MJ, Klobeck G, Rimokh R, Sotto JJ, Leroux D:The IgG Fc receptor, FcgammaRIIB, is a target for deregulationby chromosomal translocation in malignant lymphoma. Proc NatlAcad Sci USA 97:309–314, 2000

30. Itoyama T, Nanjungud G, Chen W, Dyomin VG, Teruya-FeldsteinJ, Jhanwar SC, Zelenetz AD, Chaganti RS: Molecular cytogeneticanalysis of genomic instability at the 1q12–22 chromosomal sitein B-cell non-Hodgkin lymphoma. Genes Chromosomes Cancer35:318–328, 2002

31. Greer WL, Lee CL, Callanan MB, Zayed E, Sadek I: Case of acutelymphoblastic leukemia presenting with t(14;18)/BCL2, t(8;14)/cMYC, and t(1;2)/FCGR2B. Am J Hematol 74:112–118, 2003

32. Chen W, Palanisamy N, Schmidt H, Teruya-Feldstein J,Jhanwar SC, Zelenetz AD, Houldsworth J, Chaganti RS: Deregu-lation of FCGR2B expression by 1q21 rearrangements in follicularlymphomas. Oncogene 20:7686–7693, 2001

33. Camilleri-Broet S, Cassard L, Broet P, Delmer A, Le Touneau A,Diebold J, Fridman WH, Molina TJ, Sautes-Fridman C: Fcgam-maRIIB is differentially expressed during B cell maturation andin B-cell lymphomas. Br J Haematol 124:55–62, 2004

34. Johansson B, Brondum-Nielsen K, Billstrom R, Schiodt I,Mitelman F: Translocations between the long arms of chromo-somes 1 and 5 in hematologic malignancies are strongly associatedwith neoplasms of the myeloid lineages. Cancer Genet Cytogenet99:97–101, 1997

35. Zusman T, Lisansky E, Arons E, Anavi R, Bonnerot C, SautesC, Fridman WH, Witz IP, Ran M: Contribution of the intra-cellular domain of murine Fcgamma receptor type IIB1 to itstumor-enhancing potential. Int J Cancer 68:219–227, 1996

36. Dhodapkar KM, Krasovsky J, Williamson B, Dhodapkar MV:Antitumor monoclonal antibodies enhance cross-presentation


P1: JQX



ofcCellular antigens and the generation of myeloma-specific killerT cells by dendritic cells. J Exp Med 195:125–133, 2002

37. Nagata Y, Ono S, Matsuo M, Gnjatic S, Valmori D, Ritter G,Garrett W, Old LJ, Mellman I: Differential presentation of a solubleexogenous tumor antigen, NY-ESO-1, by distinct human den-dritic cell populations. Proc Natl Acad Sci USA 99:10629–10634,2002

38. Rodriguez A, Regnault A, Kleijmeer M, Ricciardi-Castagnoli P,Amigorena S: Selective transport of internalized antigens to thecytosol for MHC class I presentation in dendritic cells. Nat CellBiol 1:362–368, 1999

39. Hamano Y, Arase H, Saisho H, Saito T: Immune complex andFc receptor-mediated augmentation of antigen presentation forinvivoTh cell responses. J Immunol 164:6113–6119, 2000

40. Wallace PK, Tsang KY, Goldstein J, Correale P, Jarry TM, SchlomJ, Guyre PM, Ernstoff MS, Fanger MW: Exogenous antigen tar-geted to FcgammaRI on myeloid cells is presented in associationwith MHC class I. J Immunol Methods 248:183–194, 2001

41. Yada A, Ebihara S, Matsumura K, Endo S, Maeda T, NakamuraA, Akiyama K, Aiba S, Takai T: Accelerated antigen presentationand elicitation of humoral responsein vivoby FcgammaRIIB- andFcgammaRI/III-mediated immune complex uptake. Cell Immunol225:21–32, 2003

42. Antoniou AN, Watts C: Antibody modulation of antigen presen-tation: Positive and negative effects on presentation of the tetanustoxin antigen via the murine B cell isoform of FcgammaRII. EurJ Immunol 32:530–540, 2002

43. Akiyama K, Ebihara S, Yada A, Matsumura K, Aiba S, Nukiwa T,Takai T: Targeting apoptotic tumor cells to Fc gamma R providesefficient and versatile vaccination against tumors by dendriticcells. J Immunol 170:1641–1648, 2003

44. Regnault A, Lankar D, Lacabanne V, Rodriguez A, Thery C,Rescigno M, Saito T, Verbeek S, Bonnerot C, Ricciardi-CastagnoliP, Amigorena S: Fcgamma receptor-mediated induction of den-dritic cell maturation and major histocompatibility complexclass I-restricted antigen presentation after immune complexinternalization. J Exp Med 189:371–380, 1999

45. Kalergis AM, Ravetch JV: Inducing tumor immunity throughthe selective engagement of activating Fcgamma receptors ondendritic cells. J Exp Med 195:1653–1659, 2002

46. Van den Herik-Oudijk IE, Capel PJ, van der Bruggen T, Van deWinkel JG: Identification of signaling motifs within human Fcgamma RIIa and Fc gamma RIIb isoforms. Blood 85:2202–2211,1995

47. Hara I, Takechi Y, Houghton AN: Implicating a role for im-mune recognition of self in tumor rejection: Passive immunizationagainst the brown locus protein. J Exp Med 182:1609–1614, 1995

48. Clynes R, Takechi Y, Moroi Y, Houghton A, Ravetch JV: Fc re-ceptors are required in passive and active immunity to melanoma.Proc Natl Acad Sci USA 95:652–656, 1998

49. Clynes RA, Towers TL, Presta LG, Ravetch JV: Inhibitory Fc re-ceptors modulatein vivocytoxicity against tumor targets. Nat Med6:443–446, 2000

50. Cassard L, Cohen-Solal JF, Galinha A, Sastre-Garau X, Mathiot C,Galon J, Dorval T, Bernheim A, Fridman WH, Sautes-Fridman C:Modulation of tumor growth by inhibitory Fc(gamma) receptor ex-pressed by human melanoma cells. J Clin Invest 110:1549–1557,2002

51. Ravanel K, Castelle C, Defrance T, Wild TF, Charron D, LotteauV, Rabourdin-Combe C: Measles virus nucleocapsid protein bindsto FcgammaRII and inhibits human B cell antibody production. JExp Med 186:269–278, 1997

52. Taji H, Kagami Y, Okada Y, Andou M, Nishi Y, Saito H, Seto M,Morishima Y: Growth inhibition of CD20-positive B lymphomacell lines by IDEC-C2B8 anti-CD20 monoclonal antibody. Jpn JCancer Res 89:748–756, 1998

53. Hudziak RM, Lewis GD, Winget M, Fendly BM, Shepard HM,Ullrich A: p185HER2 monoclonal antibody has antiproliferativeeffectsin vitro and sensitizes human breast tumor cells to tumornecrosis factor. Mol Cell Biol 9:1165–1172, 1989

54. Takai T, Ono M, Hikida M, Ohmori H, Ravetch JV: Augmentedhumoral and anaphylactic responses in Fc gamma RII-deficientmice. Nature 379:346–349, 1996

55. Clynes R, Ravetch JV: Cytotoxic antibodies trigger inflammationthrough Fc receptors. Immunity 3:21–26, 1995

56. Shibata T, Berney T, Reininger L, Chicheportiche Y, Ozaki S,Shirai T, Izui S: Monoclonal anti-erythrocyte autoantibodies de-rived from NZB mice cause autoimmune hemolytic anemia by twodistinct pathogenic mechanisms. Int Immunol 2:1133–1141, 1990

57. Pritchard NR, Cutler AJ, Uribe S, Chadban SJ, Morley BJ, SmithKG: Autoimmune-prone mice share a promoter haplotype asso-ciated with reduced expression and function of the Fc receptorFcgammaRII. Curr Biol 10:227–230, 2000

58. Schiller C, Janssen-Graalfs I, Baumann U, Schwerter-StrumpfK, Izui S, Takai T, Schmidt RE, Gessner JE: Mouse Fcgam-maRII is a negative regulator of FcgammaRIII in IgG immunecomplex-triggered inflammation but not in autoantibody-inducedhemolysis. Eur J Immunol 30:481–490, 2000

59. Nieswandt B, Bergmeier W, Schulte V, Takai T, Baumann U,Schmidt RE, Zirngibl H, Bloch W, Gessner JE: Targeting ofplatelet integrin alphaIIbbeta3 determines systemic reaction andbleeding in murine thrombocytopenia regulated by activating andinhibitory FcgammaR. Int Immunol 15:341–349, 2003

60. Samuelsson A, Towers TL, Ravetch JV: Anti-inflammatory activ-ity of IVIG mediated through the inhibitory Fc receptor. Science291:484–486, 2001

61. Suzuki Y, Shirato I, Okumura K, Ravetch JV, Takai T, TominoY, Ra C: Distinct contribution of Fc receptors and angiotensinII-dependent pathways in anti-GBM glomerulonephritis. KidneyInt 54:1166–1174, 1998

62. Radeke HH, Janssen-Graalfs I, Sowa EN, Chouchakova N,Skokowa J, Loscher F, Schmidt RE, Heeringa P, Gessner JE:Opposite regulation of type II and III receptors for immunoglob-ulin G in mouse glomerular mesangial cells and in the inductionof anti-glomerular basement membrane (GBM) nephritis. J BiolChem 277:27535–27544, 2002

63. Nakamura A, Yuasa T, Ujike A, Ono M, Nukiwa T, Ravetch JV,Takai T: Fcgamma receptor IIB-deficient mice develop Good-pasture’s syndrome upon immunization with type IV collagen:A novel murine model for autoimmune glomerular basementmembrane disease. J Exp Med 191:899–906, 2000

64. Muhlfeld AS, Segerer S, Hudkins K, Carling MD, Wen M, FarrAG, Ravetch JV, Alpers CE: Deletion of the fcgamma receptorIIb in thymic stromal lymphopoietin transgenic mice aggra-vates membranoproliferative glomerulonephritis. Am J Pathol163:1127–1136, 2003

65. Shushakova N, Skokowa J, Schulman J, Baumann U, ZwirnerJ, Schmidt RE, Gessner JE: C5a anaphylatoxin is a major reg-ulator of activating versus inhibitory FcgammaRs in immunecomplex-induced lung disease. J Clin Invest 110:1823–1830, 2002

66. Yuasa T, Kubo S, Yoshino T, Ujike A, Matsumura K, Ono M,Ravetch JV, Takai T: Deletion of Fcgamma receptor IIB rendersH-2(b) mice susceptible to collagen-induced arthritis. J Exp Med189:187–194, 1999


P1: JQX



67. Blom AB, van Lent PL, Holthuysen AE, Jacobs C, van den BergWB: Skewed balance in basal expression and regulation of activat-ing v inhibitory Fcgamma receptors in macrophages of collageninduced arthritis sensitive mice. Ann Rheum Dis 62:465–471, 2003

68. Nandakumar KS, Andren M, Martinsson P, Bajtner E, HellstromS, Holmdahl R, Kleinau S: Induction of arthritis by single mon-oclonal IgG anti-collagen type II antibodies and enhancement ofarthritis in mice lacking inhibitory FcgammaRIIB. Eur J Immunol33:2269–2277, 2003

69. Kagari T, Tanaka D, Doi H, Shimozato T: Essential role ofFc gamma receptors in anti-type II collagen antibody-inducedarthritis. J Immunol 170:4318–4324, 2003

70. Ji H, Ohmura K, Mahmood U, Lee DM, Hofhuis FM, BoackleSA, Takahashi K, Holers VM, Walport M, Gerard C, EzekowitzA, Carroll MC, Brenner M, Weissleder R, Verbeek JS, DuchatelleV, Degott C, Benoist C, Mathis D: Arthritis critically dependenton innate immune system players. Immunity 16:157–168, 2002

71. Corr M, Crain B: The role of FcgammaR signaling in the K/B x Nserum transfer model of arthritis. J Immunol 169:6604–6609, 2002

72. Blom AB, Radstake TR, Holthuysen AE, Sloetjes AW, PesmanGJ, Sweep FG, van de Loo FA, Joosten LA, Barrera P, van LentPL, van den Berg WB: Increased expression of Fcgamma recep-tors II and III on macrophages of rheumatoid arthritis patientsresults in higher production of tumor necrosis factor alpha andmatrix metalloproteinase. Arthritis Rheum 48:1002–1014, 2003

73. Yajima K, Nakamura A, Sugahara A, Takai T: FcgammaRIIB de-ficiency with Fas mutation is sufficient for the development ofsystemic autoimmune disease. Eur J Immunol 33:1020–1029, 2003

74. Bolland S, Yim YS, Tus K, Wakeland EK, Ravetch JV: Geneticmodifiers of systemic lupus erythematosus in FcgammaRIIB(-/-)mice. J Exp Med 195:1167–1174, 2002

75. Kono DH, Burlingame RW, Owens DG, Kuramochi A, BalderasRS, Balomenos D, Theofilopoulos AN: Lupus susceptibility lociin New Zealand mice. Proc Natl Acad Sci USA 91:10168–10172,1994

76. Vyse TJ, Kotzin BL: Genetic susceptibility to systemic lupuserythematosus. Annu Rev Immunol 16:261–292, 1998

77. Haywood ME, Hogarth MB, Slingsby JH, Rose SJ, Allen PJ,Thompson EM, Maibaum MA, Chandler P, Davies KA, SimpsonE, Walport MJ, Morley BJ: Identification of intervals on chromo-somes 1, 3, and 13 linked to the development of lupus in BXSBmice. Arthritis Rheum 43:349–355, 2000

78. Xie S, Chang S, Yang P, Jacob C, Kaliyaperumal A, DattaSK, Mohan C: Genetic contributions of nonautoimmuneSWR mice toward lupus nephritis. J Immunol 167:7141–7149,2001

79. Sawchuk DJ, Mahmoudi M, Cairns E, Sinclair NR: Nonsynony-mous mutations in an Fc-receptor structural gene in NZB mice.Immunogenetics 43:112–113, 1996

80. Luan JJ, Monteiro RC, Sautes C, Fluteau G, Eloy L, Fridman WH,Bach JF, Garchon HJ: Defective Fc gamma RII gene expressionin macrophages of NOD mice: Genetic linkage with up-regulationof IgG1 and IgG2b in serum. J Immunol 157:4707–4716, 1996

81. Jiang Y, Hirose S, Abe M, Sanokawa-Akakura R, Ohtsuji M, Mi X,Li N, Xiu Y, Zhang D, Shirai J, Hamano Y, Fujii H, Shirai T: Poly-morphisms in IgG Fc receptor IIB regulatory regions associatedwith autoimmune susceptibility. Immunogenetics 51:429–435,2000

82. Li X, Wu J, Carter RH, Edberg JC, Su K, Cooper GS, KimberlyRP: A novel polymorphism in the Fcgamma receptor IIB (CD32B)transmembrane region alters receptor signaling. Arthritis Rheum48:3242–3252, 2003

83. Kyogoku C, Tsuchiya N, Matsuta K, Tokunaga K: Studies on theassociation of Fc gamma receptor IIA, IIB, IIIA and IIIB poly-morphisms with rheumatoid arthritis in the Japanese: Evidence fora genetic interaction between HLA-DRB1 and FCGR3A. GenesImmun 3:488–493, 2002

84. Moser KL, Neas BR, Salmon JE, Yu H, Gray-McGuire C, AsundiN, Bruner GR, Fox J, Kelly J, Henshall S, Bacino D, DietzM, Hogue R, Koelsch G, Nightingale L, Shaver T, Abdou NI,Albert DA, Carson C, Petri M, Treadwell EL, James JA, Harley JB:Genome scan of human systemic lupus erythematosus: Evidencefor linkage on chromosome 1q in African-American pedigrees.Proc Natl Acad Sci USA 95:14869–14874, 1998

85. Tsao BP: Lupus susceptibility genes on human chromosome 1. IntRev Immunol 19:319–334, 2000

86. Wakeland EK, Liu K, Graham RR, Behrens TW: Delineatingthe genetic basis of systemic lupus erythematosus. Immunity15:397–408, 2001

87. Kyogoku C, Dijstelbloem HM, Tsuchiya N, Hatta Y, Kato H,Yamaguchi A, Fukazawa T, Jansen MD, Hashimoto H, van deWinkel JG, Kallenberg CG, Tokunaga K: Fcgamma receptor genepolymorphisms in Japanese patients with systemic lupus ery-thematosus: Contribution of FCGR2B to genetic susceptibility.Arthritis Rheum 46:1242–1254, 2002

88. Chu ZT, Tsuchiya N, Kyogoku C, Ohashi J, Qian YP, Xu SB,Mao CZ, Chu JY, Tokunaga K: Association of Fcgamma receptorIIb polymorphism with susceptibility to systemic lupus erythe-matosus in Chinese: A common susceptibility gene in the Asianpopulations. Tissue Antigens 63:21–27, 2004

89. Siriboonrit U, Tsuchiya N, Sirikong M, Kyogoku C,Bejrachandra S, Suthipinittharm P, Luangtrakool K, SrinakD, Thongpradit R, Fujiwara K, Chandanayingyong D, TokunagaK: Association of Fcgamma receptor IIb and IIIb polymorphismswith susceptibility to systemic lupus erythematosus in Thais.Tissue Antigens 61:374–383, 2003

90. Blank MC, Masuda E, Marti F, King PD, Redecha PB, WurzburgerRJ, Peterson MGE, Tanaka S, Pricop L: A novel polymorphism inthe human FcgRIIB gene promoter alters transcriptional activityand associates with systemic lupus erythematosus in Caucasians.Arthritis and Rheum 46:S287, 2002

91. Su K, Edberg JC, Wu J, McKenzie SE, Kimberly RP: Singlenucleotide polymorphism in the FcgRIIB gene promoter whichalter receptor expression and associate with systemic lupus ery-thematosus in African Americans. Arthritis Rheum 44:S248,2001

92. Enyedy EJ, Mitchell JP, Nambiar MP, Tsokos GC: DefectiveFcgammaRIIb1 signaling contributes to enhanced calcium re-sponse in B cells from patients with systemic lupus erythematosus.Clin Immunol 101:130–135, 2001

93. Rudge EU, Cutler AJ, Pritchard NR, Smith KG: Interleukin 4 re-duces expression of inhibitory receptors on B cells and abolishesCD22 and Fc gamma RII-mediated B cell suppression. J Exp Med195:1079–1085, 2002

94. Nambu M, Morita M, Watanabe H, Uenoyama Y, Kim KM,Tanaka M, Iwai Y, Kimata H, Mayumi M, Mikawa H: Regulationof Fc gamma receptor expression and phagocytosis of a humanmonoblast cell line U937. Participation of cAMP and proteinkinase C in the effects of IFN-gamma and phorbol ester. J Immunol143:4158–4165, 1989

95. Cameron AJ, McDonald KJ, Harnett MM, Allen JM: Differen-tiation of the human monocyte cell line, U937, with dibutyrylcyclicAMP induces the expression of the inhibitory Fc receptor,FcgammaRIIb. Immunol Lett 83:171–179, 2002


P1: JQX



96. Koyama M, Saji F, Kameda T, Kimura T, Nishikiori N, KikuchiT, Tanizawa O: Differential mRNA expression of three distinctclasses of Fc gamma receptor at the feto-maternal interface. JReprod Immunol 20:103–113, 1991

97. Estienne V, Duthoit C, Reichert M, Praetor A, Carayon P, HunzikerW, Ruf J: Androgen-dependent expression of FcgammaRIIB2 bythyrocytes from patients with autoimmune Graves’ disease: A pos-sible molecular clue for sex dependence of autoimmune disease.Faseb J 16:1087–1092, 2002

98. Bruhns P, Samuelsson A, Pollard JW, Ravetch JV: Colony-stimulating factor-1-dependent macrophages are responsiblefor IVIG protection in antibodyinduced autoimmune disease.Immunity 18:573–581, 2003

99. Matsumoto I, Maccioni M, Lee DM, Maurice M, Simmons B,Brenner M, Mathis D, Benoist C: How antibodies to a ubiqui-tous cytoplasmic enzyme may provoke joint-specific autoimmunedisease. Nat Immunol 3:360–365, 2002

100. Crow AR, Song S, Freedman J, Helgason CD, Humphries RK,Siminovitch KA, Lazarus AH: IVIg-mediated amelioration ofmurine ITP via FcgammaRIIB is independent of SHIP1, SHP-1,and Btk activity. Blood 102:558–560, 2003

101. Snapper CM, Hooley JJ, Atasoy U, Finkelman FD, Paul WE: Dif-ferential regulation of murine B cell Fc gamma RII expression byCD4+ T helper subsets. J Immunol 143:2133–2141, 1989

102. Grattage LP, McKenzie IF, Hogarth PM: Effects of PMA, cy-tokines and dexamethasone on the expression of cell surfaceFc receptors and mRNA in U937 cells. Immunol Cell Biol70(Pt 2):97–105, 1992

103. te Velde AA, Huijbens RJ, de Vries JE, Figdor CG: IL-4 decreasesFc gamma R membrane expression and Fc gamma R-mediated cy-totoxic activity of human monocytes. J Immunol 144:3046–3051,1990

104. Ulgiati D, Holers VM: CR2/CD21 proximal promoter activity iscritically dependent on a cell type-specific repressor. J Immunol167:6912–6919, 2001

105. Schroder AJ, Pavlidis P, Arimura A, Capece D, Rothman PB: Cut-ting edge: STAT6 serves as a positive and negative regulator ofgene expression in IL-4-stimulated B lymphocytes. J Immunol168:996–1000, 2002

106. Engelhardt W, Geerds C, Frey J: Organization of human FcRIIand FcRIIlike (beta FcRII) genes: Structural homology to HLAclass I and class II genes. Mol Immunol 27:379–382, 1990.

107. McKenzie SE, Keller MA, Cassel DL, Schreiber AD, SchwartzE, Surrey S, Rappaport EF: Characterization of the 5′-flankingtranscriptional regulatory region of the human Fc gamma receptorgene, Fc gamma RIIA. Mol Immunol 29:1165–1174, 1992

108. Nishimura T, Narita T, Miyazaki E, Ito T, Nishimoto N, YoshizakiK, Martial JA, Bellfroid EJ, Vissing H, Taniyama T: Character-ization of the human Fc gamma RIIB gene promoter: Human

zinc-finger proteins (ZNF140 and ZNF91) that bind to differ-ent regions function as transcription repressors. Int Immunol13:1075–1084, 2001

109. Pricop L, Li L, Salmon JE, Jacob CO: Characterization of theFcgammaRIIA promoter and 5’UTR sequences in patients withsystemic lupus erythematosus. Genes Immun 3(Suppl 1):S47–S50,2002

110. Tommerup N, Vissing H: Isolation and fine mapping of 16 novelhuman zinc finger-encoding cDNAs identify putative candidategenes for developmental and malignant disorders. Genomics27:259–264, 1995

111. Bellefroid EJ, Marine JC, Ried T, Lecocq PJ, Riviere M, AmemiyaC, Poncelet DA, Coulie PG, de Jong P, Szpirer C,et al.: Clus-tered organization of homologous KRAB zinc-finger geneswith enhanced expression in human T lymphoid cells. EMBO J12:1363–1374, 1993

112. Bellefroid EJ, Lecocq PJ, Benhida A, Poncelet DA, Belayew A,Martial JA: The human genome contains hundreds of genes codingfor finger proteins of the Kruppel type. DNA 8:377–387, 1989

113. Hogarth PM, Witort E, Hulett MD, Bonnerot C, Even J,Fridman WH, McKenzie IF: Structure of the mouse beta Fcgamma receptor II gene. J Immunol 146:369–376, 1991

114. Bonnerot C, Daeron M, Varin N, Amigorena S, Hogarth PM, EvenJ, Fridman WH: Methylation in the 5’ region of the murine betaFc gamma R gene regulates the expression of Fc gamma receptorII. J Immunol 141:1026–1033, 1988

115. Xiu Y, Nakamura K, Abe M, Li N, Wen XS, Jiang Y, ZhangD, Tsurui H, Matsuoka S, Hamano Y, Fujii H, Ono M, Takai T,Shimokawa T, Ra C, Shirai T, Hirose S: Transcriptional regulationof Fcgr2b gene by polymorphic promoter region and its contribu-tion to humoral immune responses. J Immunol 169:4340–4346,2002

116. Andrews BS, Eisenberg RA, Theofilopoulos AN, Izui S, WilsonCB, McConahey PJ, Murphy ED, Roths JB, Dixon FJ: Spontaneousmurine lupus-like syndromes. Clinical and immunopathologi-cal manifestations in several strains. J Exp Med 148:1198–1215,1978

117. Helyer BJ, Howie JB: Renal disease associated with positive lu-pus erythematosus tests in a cross-bred strain of mice. Nature197:197, 1963

118. Gavalchin J, Datta SK: The NZB X SWR model of lupus nephritis.II. Autoantibodies deposited in renal lesions show a distinc-tive and restricted idiotypic diversity. J Immunol 138:138–148,1987

119. Vidal S, Gelpi C, Rodriguez-Sanchez JL: (SWR x SJL)F1 mice: Anew model of lupus-like disease. J Exp Med 179:1429–1435, 1994

120. Bolland S, Ravetch JV: Spontaneous autoimmune disease inFc(gamma)RIIB-deficient mice results from strain-specificepistasis. Immunity 13:277–285, 2000


inhibitory fc gamma receptors: from gene to disease

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