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...
SUMMARYC3HeB/FeJ mice infected with the docile strain of lymphocytic choriomeningitis virus ( LCMV-d) develop a persistent infection with a transient haemolytic anaemia. Immunoglobulin can be eluted from the red blood cells ( RBC ) of these mice but it cannot be detected on the RBC by a conventional antiglobulin test. The present study demonstrates that RBC from such mice bear erythrocyte autoantibodies which are predominantly of the IgG2a subclass, with lower levels of autoantibodies of the IgG1, IgG2b and IgG3 subclasses. To identify the target antigen the autoantibodies were eluted from the RBC of LCMV-infected mice. The eluted autoantibody bound to intact normal RBC and precipitated a 105 000 MW component that corresponds to murine Band 3 protein. A monoclonal antibody derived from mice infected with LCMV-d also precipitated mouse Band 3, and reacted specifically by enzyme-linked immunosorbent assay against a purified preparation of Band 3. This study has shown that in C3H mice infected with LCMV-d which develop autoimmune haemolytic anaemia, the target autoantigen is erythrocyte membrane Band 3.
The effect of LCMV on CD4+ T lymphocytes was analyzed in C3HeB/FeJ mice after infection with the Docile strain of this virus. Our results indicated that LCMV triggers: i) an inhibition of Th2 lymphocyte differentiation induced by concomitant immunization with a nonviral protein antigen; ii) a depression of T helper-dependent antibody responses elicited by such an immunization; and iii) a CD4+ cell-mediated proliferation of spleen cells leading to increased interleukin-4 and interferon-gamma message expression and IgG2a-restricted total immunoglobulin secretion. Taken together, these results indicate that LCMV profoundly affects CD4+ cell-mediated immune responses in infected animals. Such modulations of T-helper functions may explain the preponderance of IgG2a in the antierythrocyte autoimmune response induced by the virus in C3HeB/FeJ mice.
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