Monoclonal anti-erythrocyte autoantibodies derived from NZB mice cause autoimmune hemolytic anemia by two distinct pathogenic mechanisms

Shibata, Takanori; Berney, Thierry; Reininger, Luc; Chicheportiche, Yves; Ozaki, Shoichi; Shirai, Toshikazu; Izui, Shozo

doi:10.1093/intimm/2.12.1133

Cited by 90 publications

(139 citation statements)

References 13 publications

(14 reference statements)

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“…WT, Ga i2 KO, or Ga i3 KO mice were injected with 150 mg anti-erythrocyte band 3 (34-3C) self-reactive Abs, and ingestion of IgG-bound RBC by liver macrophages was monitored as described previously (29,37,38). In this type of autoimmune disease model, cellular RBC destruction is induced by simultaneous activation of IgG FcRs and the Ga i -coupled C5aR on Kupffer cells (26,28).…”

Section: Resultsmentioning

confidence: 99%

Defective Macrophage Migration in Gαi2- but Not Gαi3-Deficient Mice

Wiege

Syed

et al. 2012

The Journal of Immunology

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Various heterotrimeric Gi proteins are considered to be involved in cell migration and effector function of immune cells. The underlying mechanisms, how they control the activation of myeloid effector cells, are not well understood. To elucidate isoform-redundant and -specific roles for Gαi proteins in these processes, we analyzed mice genetically deficient in Gαi2 or Gαi3. First, we show an altered distribution of tissue macrophages and blood monocytes in the absence of Gαi2 but not Gαi3. Gαi2-deficient but not wild-type or Gαi3-deficient mice exhibited reduced recruitment of macrophages in experimental models of thioglycollate-induced peritonitis and LPS-triggered lung injury. In contrast, genetic ablation of Gαi2 had no effect on Gαi-dependent peritoneal cytokine production in vitro and the phagocytosis-promoting function of the Gαi-coupled C5a anaphylatoxin receptor by liver macrophages in vivo. Interestingly, actin rearrangement and CCL2- and C5a anaphylatoxin receptor-induced chemotaxis but not macrophage CCR2 and C5a anaphylatoxin receptor expression were reduced in the specific absence of Gαi2. Furthermore, knockdown of Gαi2 caused decreased cell migration and motility of RAW 264.7 cells, which was rescued by transfection of Gαi2 but not Gαi3. These results indicate that Gαi2, albeit redundant to Gαi3 in some macrophage activation processes, clearly exhibits a Gαi isoform-specific role in the regulation of macrophage migration.

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Section: Resultsmentioning

confidence: 99%

Defective Macrophage Migration in Gαi2- but Not Gαi3-Deficient Mice

Wiege

Syed

et al. 2012

The Journal of Immunology

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“…38 Thus, we used the antimouse Band 3 mAb 34-3C for opsonization, a mAb that induces RBC phagocytosis both in vivo and in vitro and shows enhanced binding to aged murine RBCs in vivo. 23,28,31 In the presence of serum, phagocytosis of IgG-opsonized WT Ox-RBCs was increased, compared with equally opsonized untreated WT RBCs (84.3 Ϯ 8.0 vs 52.3 Ϯ 0.5 RBCs/100 macrophages, respectively; P Ͻ .05) ( Figure 4A). Phagocytosis of IgG-opsonized CD47 Ϫ/Ϫ RBCs was strongly increased for both untreated RBCs and Ox-RBCs, compared with equally opsonized corresponding WT RBCs (P Ͻ .001 and P Ͻ .01, respectively; Figure 4A).…”

Section: Cd47 On Ox-rbcs Can Still Inhibit Fc␥r-mediated Phagocytosismentioning

confidence: 99%

“…Dr Shozo Izui, University of Geneva, Geneva, Switzerland) established from autoimmune-prone NZB mice 31 were purified from hybridoma supernatants by ammonium sulfate precipitation and protein A/G chromatography (Amersham Pharmacia, Piscataway, NJ). Functional blocking CD36 mAb 63 (mouse IgA) and SR-A mAb 2F8 (mouse IgG2a) were from Chemicon-Millipore (Molsheim, France) and Hycult Biotechnology (Uden, The Netherlands), respectively.…”

Section: Introductionmentioning

confidence: 99%

CD47 on experimentally senescent murine RBCs inhibits phagocytosis following Fcγ receptor–mediated but not scavenger receptor–mediated recognition by macrophages

Olsson

Oldenborg

2008

Blood

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IntroductionRemoval of senescent red blood cells (RBCs) from the circulation is a selective process mediated mainly by macrophages in the liver and spleen. 1 Several molecular patterns, which may be involved as ligands in recognition by macrophages, appear on the surface of senescent RBCs. Macrophages can either directly recognize these ligands, or recognition can be dependent on binding of bridging plasma proteins that may interact with the RBC ligands. [2][3][4][5][6][7] As such, these RBC ligands may include alterations in protein carbohydrate moieties, 8 loss of plasma membrane phospholipid asymmetry, [9][10][11] and/or clustering of Band 3 with subsequent binding of complement or antibodies. 12-14 Phagocytosis by macrophages can for instance be induced following ligation of receptors such as Fc␥ receptors (Fc␥R), complement receptors, or scavenger receptors (SRs). [15][16][17] Fc␥R recognizes the Fc portion of immunoglobulin G (IgG) bound to a target cell, resulting in rapid phagocytosis of the IgG-opsonized target. SRs make up a large family of receptors with a broad ligand-binding ability, where most known ligands are polyanionic molecules such as proteins, polyribonucleotides, polysaccharides, and lipids. 16 "Altered" host molecules (eg, oxidized low-density lipoprotein [oxLDL]) can be recognized by most SRs, whereas other ligands interact more specifically with SRs. 16 Oxidative damage is likely to be one important cause of RBC senescence and exposure of senescence-associated ligands. 13,18 RBCs oxidized in vitro (Ox-RBCs) are efficiently phagocytosed by macrophages in the absence of further opsonization, a process shown to be inhibited by oxLDL or other SR ligands, such as fucoidan, dextran sulfate, or poly-I, both in vivo and in vitro. 4,7,19 Phagocytosis of Ox-RBCs has also been suggested to be serum dependent, 6 and involve recognition of phosphatidylserine (PS) on the RBC surface. 9,10 Macrophage phagocytosis of target host cells is regulated by the balance between signaling through prophagocytic receptors (eg, Fc␥R or complement receptors) and inhibitory receptors. Recognition of the cell surface glycoprotein CD47 by the inhibitory receptor signal regulatory protein alpha (SIRP␣) inhibits phagocytosis of unopsonized RBCs, as well as IgG or complementopsonized RBCs, both in vivo and in vitro. 20-23 CD47 is highly expressed on RBCs, but ubiquitously expressed by most cells in the body, and can also negatively regulate phagocytosis of platelets and leukocytes. [24][25][26] The amount of CD47 on the cell surface regulates macrophage phagocytosis, since IgG-opsonized RBCs from CD47 ϩ/Ϫ mice (expressing about 50% of normal levels of CD47) are taken up faster than wild-type (WT) RBCs, but slower than CD47 Ϫ/Ϫ RBCs. 27 We have shown that the phagocytosis-inhibitory effect of CD47 does not come into play on apoptotic nucleated cells, where CD47 is clustered into patches on the apoptotic cell surface and segregated away from prophagocytic ligands such as PS or calreticulin. 25 Although older circulating RBC...

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“…The purity of the resulting Fc fragments was analysed by acrylamide gel electrophoresis. Antibody 31-9D and 34-3C anti-mouse erythrocyte MoAbs, derived from NZB mice, were a kind gift of S. Izui [32,33].…”

Section: Iggmentioning

confidence: 99%

“…The two anti-erythrocyte MoAbs 31-9D and 34-3C derived from NZB mice have been shown by Shibata and colleagues to induce autoimmune anaemia by separate and distinct mechanisms [33]. Whereas 31-9D of isotype IgG1 causes erythrocyte sequestration in the liver and spleen, 34-3C of isotype IgG2a induces erythrophagocytosis.…”

Section: Igg Treatment Of Passively Induced Autoimmune Haemolytic Anamentioning

confidence: 99%

The mode of action of treatment by IgG of haemolytic anaemia induced by an anti-erythrocyte monoclonal antibody

Pottier

Pierard

Barclay

et al. 1996

Clinical and Experimental Immunology

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SUMMARYIn order to gain insight into the mechanisms by which the infusion of IgG can improve some autoimmune diseases, we induced haemolytic anaemia in mice by the injection of anti-erythrocyte MoAbs derived from NZB mice by S. Izui (Geneva). The IgG1 antibody 31-9D induces anaemia by erythrocyte sequestration in the spleen and liver, whereas the IgG2a antibody 34-3C triggers erythrophagocytosis (Shibata et al., Int Immunol 1990; 2:1133). Treatment of mice with pools of either human or mouse IgG clearly attenuated the anaemia induced by 34-3C, but not by 31-9D. Similar protection was obtained with human monoclonal IgGs from myeloma patients. Prior absorption by mouse erythrocytes did not affect the efficacy of the injected IgG. Treatment with Fc fragments also reduced the anaemia. In vitro experiments confirmed that 34-3C, but not 31-9D, triggered erythrocyte phagocytosis by murine macrophages. This process was completely inhibited by addition of polyclonal or myeloma IgG or of human Fc fragments. These results indicate that, in this model of autoimmune pathology, the protective effect of IgG is mediated by its interaction with the macrophage Fc receptors.

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Monoclonal anti-erythrocyte autoantibodies derived from NZB mice cause autoimmune hemolytic anemia by two distinct pathogenic mechanisms

Abstract: In vivo pathological manifestations of eight monoclonal anti-mouse red blood cell (MRBC) autoantibodies obtained from unmanipulated NZB mice were determined in BALB/c mice. Three

Cited by 90 publications

References 13 publications

Defective Macrophage Migration in Gαi2- but Not Gαi3-Deficient Mice

Defective Macrophage Migration in Gαi2- but Not Gαi3-Deficient Mice

CD47 on experimentally senescent murine RBCs inhibits phagocytosis following Fcγ receptor–mediated but not scavenger receptor–mediated recognition by macrophages

The mode of action of treatment by IgG of haemolytic anaemia induced by an anti-erythrocyte monoclonal antibody

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