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

Abstract

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.

Autoimmune Hemolytic Anemia Triggered by Infection with Human Parvovirus B19 after Total Abdominal Colectomy for Ulcerative Colitis

“…Musaji et al hypothesized that hemolysis in AIHA requires two consecutive steps according to the results in a murine AIHA model (17). In the first step, autoantibody production in the blood cells is mediated.…”

A murine model of severe immune thrombocytopenia is induced by antibody- and CD8+ T cell–mediated responses that are differentially sensitive to therapy

“…There have been several animal models of ITP, including the secondary autoimmune model, in which ITP is secondary to either other diseases (eg, lupus nephritis [17][18][19][20] or infections, [21][22][23] and the passive transfer model, in which continuous injection of plateletspecific antibodies are required to maintain a steady state of thrombocytopenia. [9][10][11][12] Although these models have been instrumental in understanding the pathophysiology of secondary ITP and the mechanisms of action of treatments such as IVIg, they are not ideal for chronic ITP pathophysiology where both T-cell and B-cell autoimmune attacks are focused on platelet-specific antigens.…”

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

“…Depletion of macrophages with phagocytic activity inhibited platelet destruction, including in animals infected with LDV, a virus that we had previously shown to enhance IgG-opsonized erythrocyte and platelet ingestion, resulting in anemia and thrombocytopenia (18)(19)(20).…”

“…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).…”