Exacerbation of Autoantibody-Mediated Hemolytic Anemia by Viral Infection

Abstract

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...

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

“…Therefore, it is not caused by new antibody production in response to infection, because such antibody responses are T-cell dependent and do not start before 4 days after infection, 14 and antigenic mimicry cannot explain this virally induced platelet drop. Because LDV may enhance phagocytosis, 15 it could be postulated that the virus induces thrombocytopenia by this mechanism. Indeed, treatment with clodronate-containing liposomes indicated that the enhancing effect of LDV on autoantibody-dependent thrombocytopenia involves phagocytosis exclusively.…”

Partial tolerance of autoreactive B and T cells to erythrocyte-specific self-antigens in mice

“…[4][5][6] However, in the primary form of AIHA, no inciting cause is identified. 7 The basic pathogenesis of primary AIHA is poorly understood, but clearly results from a failure of tolerance mechanisms.…”

Involvement of Fcα/μ Receptor in IgM Anti-Platelet, but Not Anti–Red Blood Cell Autoantibody Pathogenicity in Mice

“…In vivo, mouse infection with lactate dehydrogenase-elevating virus (LDV) strongly enhances the pathogenicity of both anti-erythrocyte and anti-platelet IgG autoantibodies, leading to severe anemia and thrombocytopenia, respectively (18)(19)(20). This effect of the infection is mediated by an increased phagocytosis activity of macrophages (18,19), resulting from IFN-g secretion by NK cells (21)(22)(23). However, a relationship between inflammatory cytokine secretion and autoantibody-mediated mouse thrombocytopenia has not been observed in all experimental models (24).…”