Monomeric IgG2 enhances Ig production and proliferation in human B cells

The effect of purified polyclonal human IgG subclasses on B-cell responses was studied using the human IgA-producing B-cell line GM-1056. IgG2 at concentrations of 0.01-1 microgram/mL enhanced both IgA production and proliferation, while IgG1, IgG3, and IgG4 each failed to do so at tested concentrations between 0.001 and 10 micrograms/mL. This enhancement was Fc gamma R mediated, since IgG2 Fc fragments enhanced IgA production and proliferation to the same extent as did the whole IgG2 molecule, whereas F(ab')2 fragments did not. However, in contrast to monomeric IgG2, aggregated IgG2, which was expected to bind Fc gamma RII on B cells, affected neither IgA production nor proliferation. Similarly, anti-CDw32 mAb (2E1, anti-Fc gamma RII), anti-CD 64 mAb (32.2 anti-Fc gamma RI), and anti-CD16 mAb (Leu 11a, anti-Fc gamma RIII) mAb each failed to stimulate GM-1056 cells, and more importantly did not block IgG2-induced stimulation. Of various cytokines tested, including IFN-alpha, IFN-gamma, IL-1 beta, IL-2, IL-3, IL-4, IL-5, and IL-6, IL-6 alone augmented IgG2-induced enhancement of IgA production and proliferation. Moreover, the IL-6 effect was lost following preabsorption with anti-IL-6 antibody but not following preabsorption with control antibody. IgG2 also enhanced Ig production and proliferation in tonsillar large activated B cells, while IgG1, IgG3 and IgG4 each failed to do so. In contrast, IgG2 had no effect on Ig production and proliferation in tonsillar small resting B cells or SAC-stimulated small B cells. IgG2-induced enhancement of Ig production and proliferation in large B cells was not blocked by 2E1, 32.2, or Leu 11a, while enhancement was augmented in a specific fashion by IL-6. These results indicate that monomeric IgG2 specifically enhances B cell responses via an Fc gamma R receptor distinct from Fc gamma RI, Fc gamma RII, and Fc gamma RIII, and that IL-6 may play a role in augmenting this response.     

Murine IgG1 complexes trigger immune effector functions predominantly via Fc gamma RIII (CD16)

Previously, we have demonstrated that phagocytosis of IgG1-coated particles by macrophages in vitro is impaired by deletion of Fc gamma RIII in mice, suggesting that IgG1 may interact preferentially with Fc gamma RIII. In the present study, the biologic relevance of this observation was addressed by triggering various effector functions of the immune system in Fc gamma RIII(-/-) mice, using panels of mAbs of different IgG subclasses. Both binding and phagocytosis of IgG1-coated sheep or human erythrocytes by Fc gamma RIII(-/-) macrophages in vitro were strongly impaired, indicating that the impaired ingestion of complexed IgG1 by Fc gamma RIII(-/-) macrophages is due to a defect in binding. An in vivo consequence of the defective phagocytosis was observed by resistance of Fc gamma RIII-deficient mice to experimental autoimmune hemolytic anemia, as shown by a lack of IgG1-mediated erythrophagocytosis in vivo by liver macrophages. Furthermore, trapping of soluble IgG1-containing immune complexes by follicular dendritic cells in mesenteric lymph nodes from Fc gamma RIII(-/-) mice was abolished. Whole blood from Fc gamma RIII(-/-) mice was unable to induce lysis of tumor cells in the presence of IgG1 antitumor Abs. Finally, IgG1 mAbs proved unable to mount a passive cutaneous anaphylaxis in Fc gamma RIII(-/-) mice. Together, these results demonstrate that IgG1 complexes, either in particulate or in soluble form, trigger in vitro and in vivo immune effector functions in mice predominantly via Fc gamma RIII.     

Human placental Fc receptors and the trapping of immune complexes

Monomeric maternal antibodies are transmitted to the fetus, but most immune complexes are trapped in the placental stroma. The receptors responsible for trapping immune complexes appear to be Fc gamma RIa, Fc gamma RIIa, and Fc gamma RIIIa on stromal macrophages, and Fc gamma RII on fetal capillary endothelial cells.     

Effects of antibody isotype and host cell type on in vitro neutralization of Chlamydia trachomatis

Monoclonal antibodies (MAbs) E-4, E-21, and DIII A3, which recognize the same or similar overlapping peptides in the variable domain IV of the major outer membrane protein of Chlamydia trachomatis but differ in isotype, were used in a complement-independent (CI) in vitro neutralization assay. These MAbs had previously been shown to neutralize chlamydial infectivity in HeLa 229 cells in a complement-dependent assay. In this report, all three MAbs neutralized chlamydial infectivity in HaK cells in a CI assay. However, when HeLa cells were used as the host cell, MAb E-4 (immunoglobulin G2b [IgG2b]) and MAb DIII A3 (IgG2b) failed to neutralize infectivity, while MAb E-21 (IgG1) neutralized chlamydial infectivity. These findings are consistent with the proposal that because of the presence of Fc gamma RIII receptors, HeLa cells facilitate infectivity and thus block neutralization through the uptake of an IgG2b-chlamydia complex. Since Fc gamma RIII receptors do not bind or bind poorly to IgG1, neutralization of C. trachomatis by MAb E-21 in HeLa cells is also corroborative evidence for the role of Fc gamma RIII receptors in this interaction. A fivefold enhancement of infectivity was seen when 10 and 1 micrograms of MAb E-4 per ml were tested in a CI assay with HeLa cells. In performing CI neutralization synergy studies in HeLa cells with MAbs E-4 and E-21, antagonism between MAbs E-4 and E-21 was observed at MAb E-4 concentrations of 10 and 1 micrograms/ml for all concentrations of MAb E-21 tested (10 to 0.1 micrograms/ml). When HaK cells were used in the same studies, no antagonism between the MAbs was found. In addition, when HeLa cells were used in a CI assay, polyclonal serum raised to a peptide representing variable domain IV of the major outer membrane protein inhibited the neutralizing ability of MAb E-21. The blocking of neutralization and the enhancement of infectivity by chlamydia-specific antibodies seen in this investigation with HeLa cells may have important clinical implications for developing preventive strategies for chlamydial infections.     

Monoclonal antibody to the type II Fc receptor for human IgG blocks potentiation of monocyte and neutrophil IgG-induced respiratory burst activation by aggregated C-reactive protein

The acute phase protein, CRP, when heat-aggregated (Agg-CRP), binds to human monocytes and neutrophils and potentiates the respiratory burst stimulated by heat-aggregated IgG (Agg-IgG). Earlier data from our laboratory and others have indicated that CRP binds to phagocytic cells at membrane sites associated with IgG Fc receptors. The present study utilized monoclonal antibodies (MAb) to determine whether the Agg-CRP potentiation of oxidative metabolism could be linked to activation through Fc gamma RI, Fc gamma RII, or Fc gamma RIII. Preincubation of monocytes with MAb 32.2, which recognizes an Fc gamma RI epitope distinct from its IgG binding site, had only a minimal (20%) inhibitory effect on Agg-IgG-induced luminol chemiluminescence (CL) and exerted no significant effect on its enhancement by Agg-CRP. MAb 10.1, which blocks IgG binding to Fc gamma RI, reduced Agg-IgG-induced monocyte CL by 40%, but did not alter the Agg-CRP-mediated enhancement. In contrast, exposure to MAb IV.3, which binds to Fc gamma RII on monocytes and neutrophils and blocks IgG binding to this receptor, resulted in a greater than 70%, inhibition of Agg-IgG-induced CL and also significantly suppressed the enhancement by Agg-CRP. MAb Leu-11b, which reacts with Fc gamma RIII on neutrophils, reduced Agg-IgG-induced CL by 70% but did not suppress the Agg-CRP potentiation. Preincubation of monocytes and neutrophils with anti-Leu-M1, anti-CR1, or anti-CR3 failed to block Agg-IgG-induced CL or its enhancement by Agg-CRP. Although the potentiating effect of Agg-CRP on Agg-IgG-elicited CL was blocked by MAb IV.3, this antibody failed to reduce binding of Agg-CRP to either monocytes or neutrophils. These results indicate that, although Agg-CRP does not bind to phagocytic cells at the IgG-binding determinant of Fc gamma RII, it alters Agg-IgG-induced cell activation through this receptor.     

Differential expression of CR3, Fc epsilon RII and Fc gamma RIII on polymorphonuclear leukocytes in gingival crevicular fluid

Polymorphonuclear leukocytes (PMNLs) are the most numerous cell population among the cellular infiltrates in gingival crevicular fluid (GCF) and play important roles in the host-defensive system in the gingival crevices. We determined the percentage of neutrophils, eosinophils and basophils in total PMNLs by light microscopic observation using Randolph-methylene blue staining, then assessed flow cytometric differences in the expression of CR3, Fc gamma RIII, Fc epsilon RII, LFA-1 alpha, and LFA-1 beta on PMNL in GCF and peripheral blood (PB) from 21 patients with adult periodontitis (AP) and 13 healthy donors. Percentages of basophils and eosinophils were higher in GCF than in PB. In both AP patients and healthy subjects, expression of CR3 and Fc epsilon RII was higher while Fc gamma RIII was lower in GCF than in PB. The statistical analysis showed that the expressions of Fc gamma RIII and Fc epsilon RII on GCF PMNLs were lower in AP patients than in healthy subjects. Expressions of LFA-1 alpha and beta on GCF were similar to those on PB PMNLs. PB PMNLs stimulated in vitro with Porphyromonas gingivalis culture supernatant and fMLP displayed an expression pattern of CR3, Fc gamma RIII and Fc epsilon RII on GCF PMNLs. However, C5a and IL-1 failed to induce changes in Fc gamma RIII and Fc epsilon RII. The results indicate that GCF neutrophils are activated, present enhanced adhesion and a decreased IgG-binding ability which would reflect that they are at the terminal stage of activation, and that GCF contains a larger eosinophil fraction than in PB. Moreover, these GCF eosinophils appear to be activated.     

Distinct intracytoplasmic sequences are required for endocytosis and phagocytosis via murine Fc gamma RII in mast cells

In the present work, we studied the phagocytic and endocytic properties of murine Fc gamma RII in mast cells. Mouse mast cells express high-affinity receptors for monomeric IgE and three low-affinity receptors for complexed IgG: Fc gamma RIIb1, Fc gamma RIIb2, and Fc gamma RIII. In previous studies we showed that, when aggregated by multivalent ligands, murine Fc gamma RIII, but not Fc gamma RII, triggers the release of inflammatory mediators and cytokines by mast cells. Upon Fc gamma R aggregation, mast cells not only release intracellular materials, they also internalize particulate and soluble immune complexes. We compared the ability of the two Fc gamma RII isoforms to trigger phagocytosis and endocytosis in RBL-2H3 cells stably transfected with cDNAs encoding wild-type, deleted, and tyrosine mutant Fc gamma RIIb1 or Fc gamma RIIb2. We found that Fc gamma RIIb2, but not Fc gamma RIIb1, triggered both phagocytosis and endocytosis. We identified distinct intracytoplasmic sequences necessary for Fc gamma RIIb2-mediated endocytosis and phagocytosis respectively, and we observed that two tyrosine residues, located in each of these sequences, are critical for endocytosis and/or phagocytosis. Our data indicate that the two internalization pathways diverge as early as signal transduction.     

Expression of the Fc receptor for IgG (Fc gamma RII/CDw32) by human circulating T and B lymphocytes

Tissue-specific isoforms of the human FcR for IgG Fc gamma RII (CDw32) have previously been described by using mAb. These mAb were shown to exhibit different patterns of reactivity with lymphocytes. Among human PBL, Fc gamma RII has been detected on B cells but not T cells when assessed by flow cytometry and microscopy with the use of mAb KB61 and 41H16. Although KB61 and 41H16 were found to react with B cells, the mAb IV.3, CIKM5, and 2E1 did not react with any PBL subset. In this study, we show that KB61 and 41H16 react strongly with the majority (93-96%) of B cells (CD20+), and weakly with a proportion (18-42%) of T cells (CD3+), including 10 to 14% of CD4+ and 27 to 69% of CD8+ cells. In addition, mRNA for Fc gamma RII was detected in purified CD3+CD8high+ lymphocytes by polymerase chain reaction. KB61 and 41H16 also reacted with a majority of CD3-CD16/CD56+ cells, and CD3-CD20- cells. These findings indicate that a subset of T cells and non-T/non-B cells express Fc gamma RII, and are of interest in the light of previous studies which postulate that human Fc gamma R+ cells and Fc gamma RII+ murine T cells suppress the B cell immune response.     

Multiple regions of human Fc gamma RII (CD32) contribute to the binding of IgG

The low affinity receptor for IgG, Fc gamma RII (CD32), has a wide distribution on hematopoietic cells where it is responsible for a diverse range of cellular responses crucial for immune regulation and resistance to infection. Fc gamma RII is a member of the immunoglobulin superfamily, containing an extracellular region of two Ig-like domains. The IgG binding site of human Fc gamma RII has been localized to an 8-amino acid segment of the second extracellular domain, Asn154-Ser161. In this study, evidence is presented to suggest that domain 1 and two additional regions of domain 2 also contribute to the binding of IgG by Fc gamma RII. Chimeric receptors generated by exchanging the extracellular domains and segments of domain 2 between Fc gamma RII and the structurally related Fc epsilon RI alpha chain were used to demonstrate that substitution of domain 1 in its entirety or the domain 2 regions encompassing residues Ser109-Val116 and Ser130-Thr135 resulted in a loss of the ability of these receptors to bind hIgG1 in dimeric form. Site-directed mutagenesis performed on individual residues within and flanking the Ser109-Val116 and Ser130-Thr135 domain 2 segments indicated that substitution of Lys113, Pro114, Leu115, Val116, Phe129, and His131 profoundly decreased the binding of hIgG1, whereas substitution of Asp133 and Pro134 increased binding. These findings suggest that not only is domain 1 contributing to the affinity of IgG binding by Fc gamma RII but, importantly, that the domain 2 regions Ser109-Val116 and Phe129-Thr135 also play key roles in the binding of hIgG1. The location of these binding regions on a molecular model of the entire extracellular region of Fc gamma RII indicates that they comprise loops that are juxtaposed in domain 2 at the interface with domain 1, with the putative crucial binding residues forming a hydrophobic pocket surrounded by a wall of predominantly aromatic and basic residues.     

Anti-Fc gamma receptor III autoantibody is associated with soluble receptor in rheumatoid arthritis serum and synovial fluid

We sought to detect anti-Fc gamma receptor (Fc gamma R) autoantibodies and soluble Fc gamma R in the serum and synovial fluid (SF) from patients with rheumatoid arthritis (RA) and to correlate these serological abnormalities to the polymorphonuclear cell (PMN) activation state. Paired samples of blood and SF were obtained from 33 RA patients as well as blood from 25 normal adults from SF from 20 non-RA patients. Anti-Fc gamma R autoantibodies were assessed by an enzyme-linked immunosorbent assay (ELISA) using recombinant human Fc gamma R as the substrate. Soluble Fc gamma RIII was determined by an ELISA based on the combination of two monoclonal antibodies (MAb). The mean fluorescence intensity (MFI) of complement receptor 1 (CD35) and 3 (CD11b) and Fc gamma RIII (CD16) was evaluated by flow cytometry on the membrane of PMN. IgM anti-Fc gamma RIII activity was present in seven RA sera and five SF, and IgG in eight RA sera and six SF. The average concentration of soluble Fc gamma RIII was 1.80 +/- 3.50 micrograms/ml in RA patients and 0.33 +/- 0.06 micrograms/ml in normal adults (P < 0.05). This was elevated in the SF of 15 RA, while normal in that of all the non-RA patients. There was an inverse correlation between the CD16 MFI on the PMN and the serum/SF soluble Fc gamma RIII level, whereas the density of CD35 and CD11b was markedly augmented. Anti-Fc gamma RIII activity exists in RA patients, associated with soluble Fc gamma RIII. PMN activation could be due to these autoantibodies and thereby obviate the clearance of immune complexes.     

Fc gamma receptor II dependency of enhanced presentation of major histocompatibility complex class II peptides by a B cell lymphoma

Here we show that the B cell lymphoma A20.292 is capable of enhanced antigen presentation to CD4+ T cells in the presence of specific antibodies. This enhancement was inhibited by anti-Fc gamma receptor (R) antibodies, suggesting that it might be due to preferential uptake of the antigen/antibody complex through the Fc gamma RII receptor. However, immunoprecipitation studies revealed that the FcR of A20.292 cells was of the B cell type, Fc gamma RIIb1, which is not thought to be able to internalize antigen/antibody complexes via clathrin-coated pits. It was considered unlikely that A20.292 had an altered form of the B cell Fc gamma R (RIIb1) receptor that enabled internalization, since similar enhancing effects were also observed using an Fc gamma RII cell line that had been transfected with Fc gamma RIIb1. To reconcile these findings with the expression of Fc gamma RIIb1, it is postulated that immune complexes are concentrated on the cell surface by the Fc gamma RIIb1 and are thus available for preferential uptake by random fluid-phase endocytosis. This results in more efficient generation of the epitopes recognized by these T cell hybridomas.     

Neutropenia due to antibodies against Type III Fc receptors on neutrophil granulocytes: 3 children with different clinical courses

Three children (girls) suffered from neutropenia mediated by anti-neutrophil IgG-Fc receptor type III (Fc gamma RIII) antibodies. The first patient (newborn) had asymptomatic and transient neutropenia caused by maternal Fc gamma RIII iso-antibodies. The second patient (6 months), whose neutropenia was diagnosed as a 'benign neutropenia of childhood' caused by transient anti-NAI autoantibodies, suffered from mild bacterial infections. The third patient (12 years) suffered from serious infections. The anti-Fc gamma RIII autoantibodies showed neither anti-NA1 nor anti-NA2 specificity. She also developed autoimmune thyroiditis (Graves' disease). Both the duration of the neutropenia and the seriousness of the bacterial infection were variable in our patient group. The first two patients both made spontaneous recoveries, while the third patient depended ultimately on granulocyte-colony stimulating factor (G-CSF).     

Surface makers for mast cell subtypes: low affinity IgG receptors and gp49 family

Members of the Immunoglobulin Superfamily (Ig) present in the surface of rodent mast cells include the high affinity IgE receptor (Fc epsilon RI), the low affinity receptors for the Fc portion of IgG, the Fc gamma RII family and Fc gamma RIII as well as the recently cloned gp49 family that includes three members gp49A, gp49B1 and gp49B2. Fc epsilon RI and Fc gamma RIII are members of the multi-chain immune recognition receptor (MIRR) family since they possess a multimeric structure in which the signal transducing chains (gamma chains) contain six acids that conform the Antigen Homology Receptor 1 Motif (ARH1M), also present in the T cell receptor (TCR) transducing chains. gp49B1, gp49B2 and the FC gamma R family are monomeric chains that also contain the partial of full AHR1M motif in their cytoplasmic domain indicating the capability for signal transduction through tyrosine phosphorylation and the possibility of cell activation with mediator (s) or cytokine (s) release. Distribution of the Fc gamma R receptors and gp49 family members varies in the different stages of mast cell differentiation and maturation.     

Structure-activity relationships of glucagon-like peptide-1(7-36)amide: insulinotropic activities in perfused rat pancreases, and receptor binding and cyclic AMP production in RINm5F cells

There are three classes of Fc gamma receptor proteins, Fc gamma RI (CD64), Fc gamma RII (CDw32), and Fc gamma RIII (CD16), which are encoded by at least eight genes. In this review we summarize some of the biological advances in the Fc gamma receptors during the past year, specifically: 1) identification of genes and their products; 2) regulation of gene expression and modulation of receptor number; 3) cellular functions and mechanisms of signal transduction; 4) ligand binding and the role of polymorphisms; and 5) soluble Fc gamma receptors. We also highlight the direct clinical applications of this Fc gamma receptor research.     

Bispecific-armed, interferon gamma-primed macrophage-mediated phagocytosis of malignant non-Hodgkin's lymphoma

To show that macrophages can be effectively targeted against malignant B cells, bispecific antibodies (BsAb) were constructed from two antibodies having specificity for the high-affinity Fc receptor for IgG (Fc gamma RI/CD64) and the B-cell differentiation antigens CD19 and CD37. Using a flow cytometry-based assay and confocal imaging, we show that these constructs mediated significant phagocytosis of B lymphocytes by macrophages that could be enhanced with interferon gamma (IFN gamma) and IFN gamma in combination with macrophage colony-stimulating factor. BsAb-dependent phagocytosis was triggered through Fc gamma RI and could be blocked only by using F(ab')2 fragments from the parent molecule or by cross-linking Fc gamma RI. BsAb-dependent phagocytosis was not blocked by antibodies to the other Fc receptors, Fc gamma RII and Fc gamma RIII. Because these antibody constructs bind to an epitope outside the Fc gamma RI ligand binding site, we show that autologous serum, polyclonal IgG, and monomeric IgG1 did not block BsAb-dependent phagocytosis, whereas autologous serum and the IgG fractions blocked parent molecule monoclonal antibody-dependent phagocytosis due to the avid binding of monomeric IgG to Fc gamma RI. Finally, BsAb-mediated phagocytosis was effective against the malignant B cells of patients with mantle cell lymphoma, prolymphocytic leukemia, and chronic lymphocytic leukemia. Based on these studies, we propose that BsAbs may provide an effective means of immunomodulation for patients with B-cell malignancies.     

Fc gamma RI blockade and modulation for immunotherapy

Splenectomy and corticosteroids are the treatment of choice for patients with immune thrombocytopenic purpura (ITP). However, for the 10%-15% of patients who do not respond to conventional therapy, high-dose i.v. IgG can induce life-saving transient responses. The benefits of i.v. IgG have been attributed to Fc receptor blockade; however, the involvement of the individual Fc receptors for IgG (Fc gamma R) in ITP remain to be more completely defined. Recently a mAb, designated mAb H22, which recognizes an epitope on Fc gamma RI (CD64) outside the ligand-binding domain, was humanized. Because mAb H22 is a human IgG1 and Fc gamma RI has a high affinity for human IgG1 antibodies, we predicted that mAb H22 would bind to the Fc gamma RI ligand-binding site through its Fc domain and to its external Fc gamma RI epitope through both Fab domains. These studies demonstrate that mAb H22 blocked Fc gamma RI-mediated phagocytosis of opsonized red blood cells more effectively than an irrelevant IgG. Moreover, cross-linking Fc gamma RI with mAb H22 down-modulated Fc gamma RI expression on monocytes, an effect seen within 2 h.     

Neisserial porins inhibit human neutrophil actin polymerization, degranulation, opsonin receptor expression, and phagocytosis but prime the neutrophils to increase their oxidative burst

Porins are trimeric proteins that constitute water-filled pores that allow transmembrane diffusion of small solutes through the outer membrane layer of gram-negative bacteria. The porins are capable of inserting into the membranes of eucaryotic cells, and in the present study we have examined the in vitro effects on neutrophil functions of the following purified porins: meningococcal outer membrane protein classes 1 and 3 and gonococcal outer membrane protein 1B (P1B). The neisserial porins inhibited human neutrophil chemoattractant-induced actin polymerization and degranulation of both primary and secondary granules. The neutrophil expression of immunoglobulin G (IgG) Fc receptors II (Fc gamma RII; CDw32) and III (Fc gamma RIII; CD16), as well as the activation-dependent downregulation of Fc gamma RIII, were reduced by the meningococcal and gonococcal porins. The neisserial porins impaired the upregulation of complement receptors 1 (CD35) and 3 (CD11b) and inhibited the phagocytic capacity of neutrophils, as evaluated by the uptake of meningococci (strain 44/76) in the presence of patient serum containing known amounts of IgG against meningococcal porins. The porins also primed neutrophils to increase their intracellular hydrogen peroxide production in response to FMLP, whereas no such priming was observed if the neutrophil protein kinase C was stimulated directly with phorbol myristate acetate. The neisserial porins influenced neutrophil functions in a time- and concentration-dependent manner. The meningococcal class 1 outer membrane protein and the gonococcal P1B tended to alter neutrophil functions more than the meningococcal class 3 protein. Thus, the neisserial porins inhibited human neutrophil actin polymerization, degranulation, opsonin receptor expression, and phagocytosis but primed the neutrophils to increase their oxidative burst. It remains to be determined whether these in vitro observations reflect mechanisms that may be of importance for the interaction between neutrophils and Neisseria species in vivo.     

Trypanosoma cruzi infection in mice enhances the membrane expression of low-affinity Fc receptors for IgG and the release of their soluble forms

The membrane expression of low-affinity Fc receptors for IgG (Fc gamma RII/III) on cells and the number of Fc gamma RII/III(+) cells were studied by flow cytometry, using the 2.4G2 MoAb, in mice infected by Trypanosoma cruzi. Cells from spleen, mesenteric lymph nodes and peritoneum were collected on days 10, 20, 30 and 40 post infection (p.i.). The in vivo serum level of soluble Fc gamma RII/III, as well as its in vitro release by cells from infected mice were studied. Parasitaemia and IgG1, IgG2a and IgG2b T. cruzi-specific antibody titres were also recorded. Both the expression of Fc gamma R on cell membrane and the absolute number of Fc gamma R(+) cells increased in spleen and in mesenteric lymph nodes, but not in peritoneum. The modifications in spleen occurred in the early and late parasitaemic phase of infection, i.e., before and after detection of T. cruzi-specific antibodies (from day 10 to 40 p.i.). In mesenteric lymph nodes, the variations were observed only in the early acute infection, when antibodies were not yet detectable at significant levels (on days 10 and 20 p.i.). Higher levels of soluble Fc gamma R were detected in sera and in culture supernatants of spleen and lymph node cells from day 20 to 40 p.i. These results show that T. cruzi infection in mice upregulates the expression and the release of Fc gamma RII/III, in the acute phase of infection, before as well as after the rise of antibody response.