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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Meyer, D. Articles by Gessner, J. E. Search for Related Content PubMed PubMed Citation Articles by Meyer, D. Articles by Gessner, J. E. Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, Vol. 92 No. 11 (December 1), 1998: pp. 3997-4002 RAPID COMMUNICATION FcRIII (CD16)-Deficient Mice Show IgG Isotype-Dependent Protection to Experimental Autoimmune Hemolytic Anemia By Dirk Meyer, Carsten Schiller, Jürgen Westermann, Shozo Izui, Wouter L. W. Hazenbos, J. Sjef Verbeek, Reinhold E. Schmidt, and J. Engelbert Gessner From the Departments of Clinical Immunology and Functional Anatomy, Hannover Medical School, Hannover, Germany; the Department of Pathology, CMU, University of Geneva, Geneva, Switzerland; and the Department of Immunology, University Hospital Utrecht, Utrecht, The Netherlands.     ABSTRACT Top Abstract Introduction Materials & Methods Results & Discussion References In autoimmune hemolytic anemia (AIHA), there is accumulating evidence for an involvement of FcR expressed by phagocytic effector cells, but demonstration of a causal relationship between individual FcRs and IgG isotypes for disease development is lacking. Although the relevance of IgG isotypes to human AIHA is limited, we could show a clear IgG isotype dependency in murine AIHA using pathogenic IgG1 (105-2H) and IgG2a (34-3C) autoreactive anti-red blood cell antibodies in mice defective for FcRIII, and comparing the clinical outcome to those in wild-type mice. FcRIII-deficient mice were completely resistent to the pathogenic effects of 105-2H monoclonal antibody, as shown by a lack of IgG1-mediated erythrophagocytosis in vitro and in vivo. In addition, the IgG2a response by 34-3C induced a less severe but persistent AIHA in FcRIII knock-out mice, as documented by a decrease in hematocrit. Blocking studies indicated that the residual anemic phenotype induced by 34-3C in the absence of FcRIII reflects an activation of FcRI that is normally coexpressed with FcRIII on macrophages. Together these results show that the pathogenesis of AIHA through IgG1-dependent erythrophagocytosis is exclusively mediated by FcRIII and further suggest that FcRI, in addition to FcRIII, contributes to this autoimmune disease when other IgG isotypes such as IgG2a are involved. © 1998 by The American Society of Hematology.     INTRODUCTION Top Abstract Introduction Materials & Methods Results & Discussion References AUTOIMMUNE hemolytic anemia (AIHA) is the oldest recognized autoimmune disease in humans. It is characterized by the production of pathogenic self-reactive antibodies causing anemia as a result of immune destruction of red blood cells (RBCs). The antibodies involved are classified as warm autoantibodies, cold agglutinins, and biphasic hemolysins which are cleared by distinct effector mechanisms.1 The predominant forms of AIHA involve warm IgG-autoantibodies accompanied with extravascular hemolysis. It is presumed that hemolysis of IgG opsonized RBCs in warm AIHA is largely mediated through either Fc and/or complement receptors expressed by phagocytic effector cells. Two recent studies in murine models of AIHA have suggested a more prominent role of Fc receptors than of complement activation. First, the treatment with recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF), which normally enhances FcR-dependent phagocytosis, also accelerates the progression of spontaneous AIHA in New Zealand Black (NZB) mice.2 A similar effect of GM-CSF in accelerating the clearance of IgG-coated RBCs has been noted in humans.3 Second, experimentally induced AIHA occurs even in the absence of the complement components C3, C4, and C5, but requires the presence of Fc receptors in association with the common FcR -chain.4 There are three classes of murine receptors for IgG, FcR on leukocytes: the high-affinity receptor FcRI, and the two low-affinity receptors, FcRII and FcRIII.5,6 Although FcRI is capable of binding monomeric IgG2a, both FcRII and FcRIII have been proposed to interact preferentially with murine IgG1 and IgG2b immune complexes.7,8 These receptors are structurally related consisting of similar ligand-binding domains, but differ in their transmembrane and intracellular domains. The FcRII isoforms, termed b1 and b2, are single subunit receptors with inhibitory functions. FcRI and FcRIII are multimeric receptors in association with the common FcR -chain9-11 required for assembly and the triggering of various effector functions, including phagocytosis, antibody-dependent cellular cytotoxicity (ADCC), and the release of inflammatory mediators.6 Knock-out (KO) mice deficient in FcRI, FcRII, FcRIII, and FcR -chain allow dissecting the contribution of FcRs to various normal and pathological immunological events.12-15 For instance, both FcR -chain-deficient mice (which are unable to function through both FcRI and FcRIII) and FcRIII KO mice exhibit an impaired Arthus reaction indicating for FcRIII as the essential Fc receptor in the initiation of IgG immune complex-triggered inflammation and autoimmune disease.14,16,17 FcR -chain-deficient mice also argue for an important role of FcRs expressed on macrophages in the pathogenesis of AIHA.18 But the specific FcR classes involved could not be identified yet. Furthermore, until this study, the relationship between specific FcRs such as FcRIII and IgG isotypes for disease development of AIHA has not been investigated. In the present study, we tested the cytotoxic activities of IgG1 (105-2H) and IgG2a (34-3C)  murine RBC (MRBC) monoclonal antibodies (MoAbs) both reacting with the same autoantigen epitope identified as the erythrocyte anion channel band 3 on MRBCs19,20 in FcRIII KO mice and their wild-type littermates. We show that mice lacking FcRIII are protected to experimental AIHA determined through IgG1-dependent erythrophagocytosis. FcRIII KO mice are not completely resistant to IgG2a-induced anemia indicating, in addition to macrophage FcRIII, the contribution of FcRI. These findings suggest that differences in IgG isotype specificities of individual FcRs are critical in the disease process of AIHA.     MATERIALS AND METHODS Top Abstract Introduction Materials & Methods Results & Discussion References Mice.   FcRIII-deficient and wild-type littermates were developed in collaboration with the group of Dr J.S. Verbeek (Utrecht, The Netherlands), as described previously.14 All mice were bred and maintained under dry barrier conditions in the animal facilities at the Hannover Medical School (Hannover, Germany). Mice were studied at 2 to 4 months of age. All experiments received institutional approval. MRBC and other antibodies.   105-2H (IgG1), and 34-3C (IgG2a) monoclonal MRBC autoantibodies were obtained by fusion of spleen cells from unmanipulated NZB mice as described.19 Hybridoma cells were maintained in RPMI/10% fetal calf serum (FCS). Culture supernatants were concentrated by precipitation in 50% saturated ammonium sulfate followed by purification with protein A affinity chromatography (Pharmacia, Uppsala, Sweden) and dialysis against phosphate-buffered saline (PBS). Purity was confirmed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Concentrations of MRBC MoAb were determined by Ig class-specific enzyme-linked immunosorbent assay (ELISA; DAKO, Hamburg, Germany). Other antibodies in use were: 2.4G2,21 which is directed against FcRII/III (Pharmingen, San Diego, CA), M1/70 against Mac-1 (Pharmingen), the isotype-matched control antibodies 5E5 (murine IgG1), and W6/32 (murine IgG2a). Polyclonal rabbit-anti-rat-IgG (Z0494) and monoclonal APAAP (alkaline phophatase anti-alkaline phosphatase) rat IgG (D0488) were obtained from DAKO. Phagocytosis of IgG-opsonized MRBCs by peritoneal macrophages.   Peritoneal macrophages elicited by intraperitoneal injection with 1 mL 3% thioglycolate (DIFCO Laboratories, Detroit, MI) were flushed out the peritoneal cavity on day 3 postinjection and suspended in PBS. Freshly isolated MRBCs were washed two times with ice-cold PBS by centrifugation at 1,600 rpm and processed for opsonization. Hereby, 10 µL of pelleted MRBCs were incubated at 4°C for 60 minutes with 10 µL of MRBC MoAbs at saturating (determined by fluorescence-activated cell sorting [FACS] analysis) concentrations. Aliquots of 50 µL of 1% opsonized MRBC suspension were added to 50 µL peritoneal macrophages preparation and incubated at 37°C for 60 minutes. For some experiments, peritoneal macrophages were first incubated for 30 minutes at 4°C with the anti-FcRII/III blocking antibody 2.4G2. Noningested extracellular MRBC were lysed by hypotonic shock, immediately followed by two washes with PBS. Peritoneal macrophages were conventionally stained with Giemsa/hematoxylin-eosin, and phagocytosis was determined by light microscopy. Peritoneal macrophages containing more than two MRBCs were considered as phagocytic. Experimental AIHA.   Hemolytic anemia was induced by a single intraperitoneal (IP) injection of the pathogenic MRBC autoantibodies 105-2H (450 µg) or 34-3C (120 µg) or the same amounts of isotype-matched control antibodies 5E5 (mIgG1) or W6/32 (mIgG2a). In some experiments mice received IP 10 µg naja naja cobra venom factor (Calbiochem, La Jolla, CA) 1 day before and 2 days after the injection of 34-3C. This treatment depletes serum levels of complement C3 as determined by CH50-measurements. For FcRII and FcRIII blockade 250 µg 2.4G2 MoAb was injected IP 24 hours before and 24 and 72 hours after administration of MRBC 34-3C.22 Blood samples obtained from the retroorbital plexus were collected into heparinized microhematocrit capillary tubes and centrifuged for 5 minutes at 12,000 rpm in a microfuge. Hematocrits measured by the percentage of packed RBCs were directly determined after centrifugation. Histopathology.   Mice were killed at day 2 after injection of pathogenic MRBC, and major organs including spleens and livers were processed for histological examination. Tissues were fixed in 10% buffered formaline, embedded in paraffin, and stained with hematoxylin and eosin (H + E) according to conventional procedures. In further experiments tissues were prepared for immunocytochemical techniques. Mac-1+ cells were revealed by incubating cryostat sections for 30 minutes with the rat antibody M1/70 and then incubated with the bridging anitbody Z0494 and the rat-APAAP antibody complex (D0488) for 30 minutes. The last two steps were repeated for 15 minutes followed by visualization using naphthyl phosphate and Fast blue.23 Ingested erythrocytes were shown by their endogeneous peroxidase using H2O2 and diaminobenzidine as substrates. Thus, Mac-1+ macrophages phagocytosing erythrocytes were seen as blue cells with brown content. The slides were counterstained with hematoxylin and mounted in glycergel (DAKO).     RESULTS AND DISCUSSION Top Abstract Introduction Materials & Methods Results & Discussion References Phagocytosis of IgG1 versus IgG2a-coated MRBCs in FcRIII-deficient mice.   We first investigated the in vitro-phagocytosis of MRBCs opsonized with 105-2H (IgG1) and 34-3C (IgG2a) using thioglycolate-elicited peritoneal macrophages that normally express FcRI, FcRII, and FcRIII. High levels of phagocytosis were evident with both 105-2H and 34-3C in wild-type mice (Fig 1A). The phagocytosis was either slightly (34-3C) or substantially (105-2H) diminished in the presence of the anti-FcRII/III antibody 2.4G2 (Fig 1B). This is consistent with our observation that FcRIII KO mice lack phagocytosis of 105-2H opsonized MRBCs (Fig 1A), indicating an apparent specificity of IgG1 for FcRIII. In case of the IgG2a MRBC 34-3C the reduced phagocytosis in FcRIII KO mice was not further decreased by 2.4G2 (Fig 1A and C). These data show that the specificity of complexed IgG2a for FcRI15 is not absolute. It appears that FcRIII contributes to some extent to the binding and phagocytosis of IgG2a-coated MRBCs. View larger version (13K): [in this window] [in a new window]   Fig 1. Phagocytosis of IgG-opsonized MRBCs. Thioglycolate-elicited peritoneal macrophages from FcRIII wild-type () and FcRIII KO () mice were incubated with MRBCs opsonized with (A) pathogenic MRBC MoAbs of the IgG1 (105-2H) and IgG2a (34-3C) isotypes or with medium alone. In addition, macrophages from FcRIII wild-type (B) and FcRIII KO (C) mice were first incubated with () or without () the 2.4G2 antibody, which is directed against FcRII and FcRIII, and subsequently opsonized with the MRBC 105-2H and 34-3C. After 1 hour of incubation at 37°C, extracellular erythrocytes were lysed by hypotonic shock and the percentage of positive peritoneal macrophages that had ingested more than two erythrocytes was assessed microscopically. Results are expressed as the mean values ± SEM of five individual experiments. Significances are determined by Student's t-test (*P < .05; **P < .001). FcRIII-deficient mice are resistant to experimental AIHA induced by pathogenic IgG1 but not IgG2a MRBC MoAbs.   We next examined the pathogenicity of MRBC by a single IP injection of purified MoAb in FcRIII KO mice or their wild-type controls. As shown in Fig 2A and B, 450 µg of the IgG1 MoAb 105-2H or 120 µg of the IgG2a MoAb 34-3C was required to develop a strong but transient AIHA with an average hematocrit (Ht) of 23% and 21% at day 4 after injection in wild-type mice, respectively. Under these conditions the decrease in Ht induced by 105-2H and 34-3C recovered to normal levels of about 40% to 50% around day 7. In contrast, FcRIII-deficient mice were completely resistent to the pathogenic effects of 105-2H with mean Ht levels remaining at 40% (Fig 2A). 34-3C induced a less severe but persistent anemia with a decrease in Ht levels to 28% in FcRIII KO mice (Fig 2B), indicating that, in addition to FcRIII, either FcRI and FcRII, or both, may have a contributory role. However, two observations argue against a significant contribution of FcRII but rather indicate that FcRI is responsible for this residual anemic phenotype. First, the prior administration of the FcRII and FcRIII blocking antibody 2.4G2 resulted in partial protection from 34-3C-induced AIHA in wild-type controls at similar levels to those in FcRIII KO mice not receiving 2.4G2 (Fig 3). Second, blocking FcRII in the absence of FcRIII through 2.4G2 did not further improve the protective effect in FcRIII KO mice (Fig 3). These results are consistent with previous evidence obtained with FcR -chain knock-out mice deficient for both FcRI and FcRIII but not FcRII, in which the profound anemia normally induced by 34-3C is completely absent.18 View larger version (18K): [in this window] [in a new window]   Fig 2. Experimental AIHA induced by MRBC antibodies in FcRIII wild-type and FcRIII KO mice. (A and B) Daily hematocrits of FcRIII wild-type () and FcRIII KO () mice injected with the pathogenic MRBC MoAbs 105-2H (A) and 34-3C (B). No decrease of Ht level was observed for mice injected with nonpathogenic isotype control MoAbs (). Ht values lower than 40% were considered as anemic. Shown are the mean values obtained from 5 to 10 mice in each group (SD <3%). View larger version (13K): [in this window] [in a new window]   Fig 3. Experimental AIHA in FcRIII wild-type and FcRIII KO mice treated with CVF and 2.4G2. Mean hematocrits of FcRIII wild-type () and FcRIII KO () mice at day 4 after injection induced by the MRBC antibody 34-3C. Hatched areas indicate the differences in AIHA induction obtained by treatments with cobra venom factor to deplete complement C3 (CVF) or with the anti-FcR MoAb 2.4G2 to block specifically the two low-affinity receptors FcRII and FcRIII (2.4G2). Results are expressed as the percentage of mean hematocrit ± SEM obtained from 5 to 10 mice in each group. Histopathological examination of mice treated with IgG1 MRBC 105-2H showed a marked degree of erythrophagocytosis in the liver accompanied by splenic engorgement in wild-type mice but not in FcRIII-deficient mice, as assessed by conventional eosin/hematoxylin staining (Fig 4). Studies in op/op mice have indicated that in addition to the splenic macrophage, the hepatic Kupffer cell may be an important effector cell to the development of AIHA.18 Thus, we also performed immunohistochemistry with the M1/70 MoAb specific for the Mac-1 antigen on macrophages residing in the spleen and the liver. This allows a more quantitative estimation of FcR-dependent erythrophagocytosis, especially in the liver. From a total number of 196 ± 23 Mac-1+ cells detected per mm2 liver section at day 2 postinjection, 27 ± 5 (n = 6) were Benzidin-positive containing ingested MRBCs (Fig 5). This pathology, equivalent to 13.8% erythrophagocytosis observed for wild-type controls, was completely absent in FcRIII KO mice, supporting the notion that AIHA induced by 105-2H is exclusively mediated through FcRIII. In the case of the IgG2a MRBC 34-3C, a reduced pathology was seen in FcRIII-deficient mice (38 ± 4 Mac-1/Benzidin-positive cells, n = 5) compared with wild-type mice (62 ± 2 Mac-1/Benzidin-positive cells, n = 5). The reduction in erythrophagocytosis by around 40% in FcRIII KO mice is consistent with the idea that FcRIII contributes significantly but not exclusively to the histopathological manifestations typical for AIHA induced by 34-3C. The contribution of both FcRI and FcRIII may also account for the stronger pathogenicity observed in general with 34-3C (IgG2a) compared with 105-2H (IgG1).19 View larger version (120K): [in this window] [in a new window]   Fig 4. Histopathology from anemic FcRIII wild-type and FcRIII KO mice. Representative histological appearance of liver (A) and spleen (B) from FcRIII wild-type and FcRIII KO mice on day 2 after AIHA-induction by the injection of the pathogenic IgG1 105-2H and IgG2a 34-3C MoAbs (hematoxylin and eosin stained; inset: higher magnification). View larger version (15K): [in this window] [in a new window]   Fig 5. Quantitative analysis of in vivo-erythrophagocytosis in the liver from anemic FcRIII wild-type and FcRIII KO mice. Liver sections from FcRIII wild-type () and FcRIII KO () mice on day 2 after injection induced by either 105-2H or 34-3C MRBCs were processed for Mac-1 immunostaining of macrophages counterstained with benzidin for the detection of erythrocytes. The amount of Mac-1+ liver macrophages containing ingested erythrocytes per mm2 was assessed microscopically. Results are expressed as the mean values ± SEM obtained from three to five mice in each group. Significance is determined by Student's t-test (*P < .05; **P < .001). The role of complement in AIHA induced by 105-2H and 34-3C has been analyzed by depleting complement C3 with cobra venom factor (CVF). Similar to several other reports,24 CVF-treated wild-type and FcRIII KO mice were not significantly protected from anemia (Fig 3 and data not shown), indicating only a minor role, if any, of complement receptor-mediated erythrophagocytosis in this model of AIHA. Concluding remarks.   In the present study we identified FcRIII to be involved in the disease process of murine AIHA. Loss of FcRIII in mice resulted in complete protection from disease development induced by the cytotoxic IgG1 autoantibody 105-2H. The lack of IgG1-mediated erythrophagocytosis in vitro and in vivo in FcRIII KO mice coincides with a strong reduction in anemia. This result provides direct in vivo evidence that the interaction between IgG1 and FcRIII contributes significantly to the development of experimental AIHA. In case of 34-3C, partial protection from anemia occurred in FcRIII-deficient mice, indicating that FcRIII is normally involved in experimental AIHA caused by this IgG2a autoantibody. It further suggests that IgG2a may also act via FcR other than FcRIII, the most likely being the high-affinity receptor FcRI. This was supported by functional blocking studies using the anti-FcRII/III 2.4G2 antibody indicating a minor, if any, role of FcRII on macrophages. In accordance, the predominance of FcRI and not FcRII has been recently shown in the phagocytosis of IgG2a-coated MRBCs.25 Because the 105-2H and 34-3C MoAbs reacted with the same autoantigenic epitope on MRBCs their relative affinities for FcRIII (IgG1 = IgG2a) and FcRI (IgG2a > > > IgG1)5,6 are thus of prime importance for the differences in induction of anemia. Previous studies on the pathogenesis of murine idiopathic thrombocytopenic purpura (ITP) suggested a role for FcR,26 supported by findings that disease development induced by the cytotoxic anti-platelet 6A6 MoAb is abolished in FcR -chain-deficient mice.18 Because the 6A6 autoantibody was of the IgG1 subclass, we suggest that the pathology of ITP induced by this antibody may be predominantly mediated by FcRIII. Confirmatory studies in FcRIII-deficient mice would further strengthen this hypothesis. Our observation, at least, that FcRIII-deficient mice have higher platelet counts (1,640 ± 220 × 103/µL, n = 6) than normal mice (1,160 ± 120 × 103/µL, n = 9) suggests a role for FcRIII also in the clearance of IgG-coated platelets. The findings that individual FcR interact differently with IgG isotypes in mediating autoimmune injury might be relevant for the potential use of these receptors as therapeutic targets in the treatment of AIHA in humans. Clinical studies in which AIHA have been treated in similar ways are rather limited. Thus, current approaches on targeting FcR binding sites7 in combination with humanized FcR mouse models27-29 will be useful to establish the significance of either FcRIII or FcRI blockade as therapeutic modalities for human AIHA.     ACKNOWLEDGMENT We thank Margot Zielinska for the isotype-matched control antibodies (5E5, W6/32) and Frank Heusohn for support in histology data processing.     FOOTNOTES    Submitted April 7, 1998; accepted August 24, 1998.    Supported by the Deutsche Forschungsgemeinschaft Grants No. Ge892/2-2 and SFB 265/A09 to J.E.G. and R.E.S., and by a grant from the Swiss National Foundation for Scientific Research to S.I.    The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. section 1734 solely to indicate this fact. Address reprint requests to J. Engelbert Gessner, PhD, Department of Clinical Immunology, Hannover Medical School, Carl-Neuberg Str 1, 30625 Hannover, Germany; e-mail: Gessner.Johannes{at}MH-Hannover.DE.     REFERENCES Top Abstract Introduction Materials & Methods Results & Discussion References 1. Engelfriet CP, Overbeeke MAM, von dem Borne AEGKr: Autoimmune hemolytic anemia. Semin Hematol 29:3, 1992[Medline] [Order article via Infotrieve] 2. Berney T, Shibata T, Merino R, Chicheportiche Y, Kindler V, Vassalli P, Izui S: Murine autoimmune hemolytic anemia resulting from Fc receptor-mediated erythrophagocytosis: Protection by erythropoietin but not by interleukin-3, and aggravation by granulocyte-macrophage colony-stimulating factor. Blood 79:2960, 1992[Abstract/Free Full Text] 3. Rossmann MD, Ruiz P, Comber P, Gomez F, Rottem M, Schreiber AD: Modulation of macrophage Fc receptors by rGM-CSF. Exp Hematol 21:177, 1993[Medline] [Order article via Infotrieve] 4. 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Gessner JE, Grussenmeyer T, Kolanus W, Schmidt RE: The human low affinity immunoglobulin G Fc receptor III-A and III-B genes: Molecular characterization of the promoter regions. J Biol Chem 270:1350, 1995[Abstract/Free Full Text] 28. Gessner JE, Grussenmeyer T, Dumbsky M, Schmidt RE: Separate promoters from proximal and medial control regions contribute to the natural killer cell specific transcription of the human FcRIII-A (CD16-A) receptor gene. J Biol Chem 271:30755, 1996[Abstract/Free Full Text] 29. Li M, Wirthmueller U, Ravetch JV: Reconstitution of human FcRIII cell type specificity in transgenic mice. J Exp Med 183:1259, 1996[Abstract/Free Full Text] © 1998 by The American Society of Hematology.   0006-4971/98/9211-0062$3.00/0 CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. Braun, J. E. Gessner, D. Varga-Szabo, S. N. Syed, S. Konrad, D. Stegner, T. Vogtle, R. E. Schmidt, and B. 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