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

Pottier, Y; Pierard, I.; Barclay, A. Neil; Masson, Pierre; Coutelier, Jean‐Paul

doi:10.1046/j.1365-2249.1996.d01-818.x

Cited by 16 publications

(26 citation statements)

References 43 publications

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“…Injection of both antibodies leads to in vivo anemia in normal uninfected mice, although by distinct pathways. Whereas IgG2a 34-3C triggers erythrophagocytosis (28,29), erythrocyte destruction induced by IgG1 31-9D is mediated by cell sequestration in the spleen and liver (29). As shown in Fig.…”

Section: Resultsmentioning

confidence: 88%

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Exacerbation of Autoantibody-Mediated Hemolytic Anemia by Viral Infection

Meité

Léonard

Idrissi

et al. 2000

J Virol

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Strong enhancement of the pathogenicity of an antierythrocyte monoclonal antibody was observed after infection of mice with lactate dehydrogenase-elevating virus. While injection of the antierythrocyte antibody alone induced only moderate anemia, concomitant infection with this virus, which is harmless in most normal mice, led to a dramatic drop in the hematocrit and to death of infected animals. In vitro and in vivo analyses showed a dramatic increase in the ability of macrophages from infected mice to phagocytose antibody-coated erythrocytes. These results indicate that viruses can trigger the onset of autoimmune disease by enhancing the pathogenicity of autoantibodies. They may explain how unrelated viruses could be implicated in the etiology of autoantibody-mediated autoimmune diseases.A causal connection between viral infection and the development of clinical pathology has long been suspected for a number of autoimmune diseases mediated by autoantibodies (reviewed in reference 36). Interestingly, in most cases, several different viruses have been proposed as etiologic agents of the same disease. Experimental data have suggested that viruses trigger an autoimmune humoral response by distinct mechanisms, including polyclonal B-lymphocyte activation, antigenic mimicry, modification of self-antigen, production of anti-idiotypic antibodies, or enhancement of major histocompatibility complex molecule expression on potential antigen-presenting cells (4,9,11,15,20,25,31,37). However, although it has been conclusively shown in several models that autoantibody secretion was triggered by infection, the actual pathogenicity of these antibodies has not always been demonstrated. Similarly, other stimuli, like immunization of mice with rat red blood cells, may lead to autoantibody production without development of the corresponding disease, in this case, hemolytic anemia (8,24,34). Therefore, it may be that mere autoantibody secretion is not sufficient to trigger an autoimmune disease and that the immune environment of the host plays an important role in the pathogenicity of such autoantibodies.Viruses have also been shown to variably affect macrophage functions, including cytokine production and the ability to present antigens (6, 16). Since it is known that some autoantibody-mediated diseases involve phagocytosis by macrophages, we postulated that modulation of this cellular function may explain the induction of such clinical diseases observed in the course of viral infections. To test this hypothesis, we used an experimental model of anemia induced by administration of antierythrocyte monoclonal antibodies (29). Our results indicate that a viral infection with lactate dehydrogenase-elevating virus (LDV) may trigger a dramatic hemolytic disease by enhancing the pathogenicity of autoantibodies. If confirmed with other models, this observation may indicate how different viruses can trigger similar clinical autoimmune diseases and open the way to novel therapeutic approaches. MATERIALS AND METHODSMice. Female BALB/c mice w...

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Section: Resultsmentioning

confidence: 88%

“…The ability of macrophages to phagocytose sensitized red cells was measured as described previously (28). Briefly, normal mouse red cells were sensitized by incubation of 500 l of packed erythrocytes with 50 g of monoclonal antibody in 10 ml of phosphate-buffered saline with 2% bovine serum albumin for 2 h at room temperature.…”

Section: Methodsmentioning

confidence: 99%

Exacerbation of Autoantibody-Mediated Hemolytic Anemia by Viral Infection

Meité

Léonard

Idrissi

et al. 2000

J Virol

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“…This treatment has previously been shown to inhibit in vivo Fc receptor-mediated phagocytosis of autoantibody-coated red blood cells and to subsequently decrease the resulting hemolytic anemia. 13 Similarly, LDV-enhanced antibody-mediated thrombocytopenia was largely suppressed by administration of total human IgG (significant difference between infected mice that received antiplatelet antibody and treated with total human IgG, or untreated: P ϭ .0286; Figure 5B). However, the major site of this increased phagocytosis of antibody-coated platelets was not the spleen, because administration of antiplatelet antibodies to LDV-infected splenectomized mice and mock-operated animals induced a thrombocytopenia that was not quite significantly different (P ϭ .0571; Figure 6).…”

Section: Mechanisms Involved In Ldv-enhanced Antibodymediated Thrombomentioning

confidence: 86%

Exacerbation of autoantibody-mediated thrombocytopenic purpura by infection with mouse viruses

Musaji

Cormont

Thirion

et al. 2004

Blood

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Antigenic mimicry has been proposed as a major mechanism by which viruses could trigger the development of immune thrombocytopenic purpura (ITP). However, because antigenic mimicry implies epitope similarities between viral and self antigens, it is difficult to understand how widely different viruses can be involved by this sole mechanism in the pathogenesis of ITP. Here, we report that in mice treated with antiplatelet antibodies at a dose insufficient to induce clinical disease by themselves, infection with lactate dehydrogenase-elevating virus (LDV) was followed by severe thrombocytopenia and by the appearance of petechiae similar to those observed in patients with ITP. A similar exacerbation of antiplateletmediated thrombocytopenia was induced by mouse hepatitis virus. This enhancement of antiplatelet antibody pathogenicity by LDV was not observed with F(ab) 2 fragments, suggesting that phagocytosis was involved in platelet destruction. Treatment of mice with clodronate-containing liposomes and with total immunoglobulin G (IgG) indicated that platelets were cleared by macrophages. The increase of thrombocytopenia triggered by LDV after administration of antiplatelet antibodies was largely suppressed in animals deficient for ␥-interferon receptor. Together, these results suggest that viruses may exacerbate autoantibody-mediated ITP by activating macrophages through ␥-interferon production, a mechanism that may account for the pathogenic similarities of multiple infectious agents. (Blood. 2004;

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“…First, the F(abV) 2 fragment of anti-platelet polyclonal antibody does not induce thrombocytopenia, even in infected animals, indicating that the Fc fragment, which is recognized by receptors that may mediate phagocytosis, is required for the antibody pathogenic effect [30]. Second, in vivo treatment with total IgG that block Fc receptors on phagocytic cells (IVIg) [31] or with clodronatecontaining liposomes that suppress macrophages [32] and thus inhibit phagocytosis of autoantibody-coated target cells [15,33,34], prevents the development of antibody-mediated thrombocytopenia in LDV-infected mice [30]. Third, histological analysis shows in vivo phagocytosis of a much larger number of erythrocytes in the liver of LDV-infected mice that had received an anti-RBC monoclonal autoantibody than in control animals [29].…”

Section: Phagocytosis As a Key Factor In Virally Exacerbated Blood Aumentioning

confidence: 99%

Enhancement of autoantibody pathogenicity by viral infections in mouse models of anemia and thrombocytopenia

Musaji

Meité

Detalle

et al. 2005

Autoimmunity Reviews

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Viral infections are involved in the pathogenesis of blood autoimmune diseases such as hemolytic anemia and thrombocytopenia. Although antigenic mimicry has been proposed as a major mechanism by which viruses could trigger the development of such diseases, it is not easy to understand how widely different viruses might induce these blood autoimmune diseases by this sole mechanism. In mice infected with lactate dehydrogenase-elevating virus (LDV), or mouse hepatitis virus, and treated with anti-erythrocyte or anti-platelet monoclonal autoantibodies at a dose insufficient to induce clinical disease by themselves, the infection sharply enhances the pathogenicity of autoantibodies, leading to severe anemia or thrombocytopenia. This effect is observed only with antibodies that induce disease through phagocytosis. Moreover, the phagocytic activity of macrophages from infected mice is increased and the enhancing effect of infection on autoantibody-mediated pathogenicity is strongly suppressed by treatment of mice with clodronate-containing liposomes. Finally, the disease induced by LDV after administration of autoantibodies is largely suppressed in animals deficient for gamma-interferon receptor. Together, these observations suggest that viruses may trigger autoantibody-mediated anemia or thrombocytopenia by activating macrophages through gamma-interferon production, a mechanism that may account for the pathogenic similarities of multiple infectious agents.

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

Cited by 16 publications

References 43 publications

Exacerbation of Autoantibody-Mediated Hemolytic Anemia by Viral Infection

Exacerbation of Autoantibody-Mediated Hemolytic Anemia by Viral Infection

Exacerbation of autoantibody-mediated thrombocytopenic purpura by infection with mouse viruses

Enhancement of autoantibody pathogenicity by viral infections in mouse models of anemia and thrombocytopenia

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