Hemophagocytosis is a phenomenon in which macrophages phagocytose blood cells. There are reports on up-regulated hemophagocytosis in patients with infectious diseases including typhoid fever, tuberculosis, influenza and visceral leishmaniasis (VL). However, mechanisms of infection-associated hemophagocytosis remained elusive due to a lack of appropriate animal models. Here, we have established a mouse model of VL with hemophagocytosis. At 24 weeks after infection with 1 x 107 Leishmania donovani promastigotes, BALB/cA mice exhibited splenomegaly with an average tissue weight per body weight of 2.96%. In the tissues, 28.6% of macrophages contained phagocytosed erythrocytes. All of the hemophagocytosing macrophages were parasitized by L. donovani, and higher levels of hemophagocytosis was observed in heavily infected cells. Furthermore, more than half of these hemophagocytes had two or more macrophage-derived nuclei, whereas only 15.0% of splenic macrophages were bi- or multi-nuclear. These results suggest that direct infection by L. donovani causes hyper-activation of host macrophages to engulf blood cells. To our knowledge, this is the first report on hemophagocytosis in experimental Leishmania infections and may be useful for further understanding of the pathogenesis.

Anemia is a typical symptom during visceral leishmaniasis (VL). We performed a systematic analysis of the literature on anemia in VL to understand the prevalence, severity, and possible mechanisms. Anemia is very common in VL patients with an overall prevalence higher than 90 %. The degree of anemia in VL is moderate to severe (hemoglobin level ∼7.5 g/dl), and the status can be recovered by treatment with antileishmanial drugs within a certain period of time. Possible pathogeneses of anemia in VL based on clinical observations included anti-RBC antibodies, dysfunction in erythropoiesis, and hemophagocytosis in the bone marrow or spleen, while hemolysis is a more likely cause than dyserythropoiesis. In hamsters with experimental VL, hemophagocytosis induced by immune complex and changes on erythrocyte membrane is speculated as the pathogenesis for anemia. In contrast, our recent study on murine VL indicated that hemophagocytosis contributes to anemia in contrast to lower contribution of anti-RBC antibodies or dysfunction in erythropoiesis. Together, hemophagocytosis is most likely associated with anemia in VL, and elucidation of the immunological mechanisms may lead to development of novel interventions to manage the symptom.

Abstract. Elevation of serum B-cell activating factor (BAFF) is one of the characteristics of immunological disorders, including autoimmunity, but the levels of BAFF in infectious diseases have not been studied well. Here, we showed the elevation of serum BAFF in patients with visceral leishmaniasis (VL). The mean serum BAFF value in VL patients (4.65 ng/mL) was 4.3 times higher than that of healthy controls (1.08 ng/mL), and 90% of VL patients showed serum BAFF above the cutoff that was calculated as the mean + 3 SDs of the controls. This report is the first on elevation of serum BAFF during VL.Leishmaniasis is a spectrum of diseases caused by protozoan parasites of the genus Leishmania. Visceral leishmaniasis (VL) is the most severe form, generally caused by L. donovani and L. infantum. Clinical manifestations of VL include fever, anemia, and splenomegaly, and the disease is fatal if left untreated. Protective immunity against VL is associated with antigen-specific cell-mediated responses represented by lymphoproliferation and delayed-type hypersensitivity 1 and production of type 1 helper T cell (Th1) cytokines, like interferon-γ (IFN-γ) and interleukin-2 (IL-2), on antigen recall.2 In contrast, IL-10, which is associated with T-cell hyporesponsiveness, is the predominant cytokine during active VL.3 Other than the suppressed Th1 responses, immunological characteristics of active VL include strong humoral responses. In fact, high immunoglobulin G (IgG) antibodies and delayed type hypersensitivity to parasite antigens are dichotomic factors in VL, 4 and excess B-cell activation in those patients can also be presumed by the manifestation of hypergammaglobulinemia.

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